Podcasts about erbb2

Featuring perspectives from Dr Priyanka Sharma and Dr Sara M Tolaney, including the following topics: Introduction: Metastatic Triple-Negative Breast Cancer (mTNBC) — The Patient Perspective (0:00) Selection and Sequencing of Antibody-Drug Conjugates (5:09) Dosing and Tolerability of Sacituzumab Govitecan; Use of Anthracyclines (14:39) Case: A woman in her early 60s with relapsed TNBC (HER2 2+) who experiences disease progression on T-DXd (Grade 2 interstitial lung disease) and receives sacituzumab govitecan — Shaachi Gupta, MD, MPH (22:04) Discussing Palliative and End-of-Life Care (32:40) PARP Inhibitors for TNBC with Somatic versus Germline Mutations; Cytopenias with PARP Inhibitors (37:53) The “Art of Oncology” — Building Trust with Patients and Family Members (45:05) Case: A woman in her mid 60s with recurrent TNBC with extensive chest wall involvement — Dr Gupta (48:44) Case: A man in his mid 40s with multiregimen-refractory AR-positive TNBC with an ERBB2 exon 20 insertion mutation — Dr Gupta (52:53) CME information and select publications

CME credits: 0.50 Valid until: 13-08-2025 Claim your CME credit at https://reachmd.com/programs/cme/her2-targeted-adcs-in-advanced-nsclc-a-case-based-approach-to-targeted-treatment-for-metastatic-disease/26285/ The treatment landscape of non-small cell lung cancer (NSCLC) has dramatically changed over the past 20 years. In recent years, the discovery of targetable molecular alterations and the development of targeted therapies have dramatically changed the treatment outlook for NSCLC. Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a receptor tyrosine kinase encoded by the ERBB2 proto-oncogene. Its activation affects downstream signaling pathways implicated in cell proliferation, survival, differentiation, and migration. The inclusion of HER2-directed antibody-drug conjugate (ADC) therapy in lung cancer is relatively new; these agents have been shown to greatly improve outcomes in patients with HER2-expressing NSCLC. In this case-based activity, expert faculty illustrate best practices for the use of HER2-directed ADCs in NSCLC.=

CME credits: 0.50 Valid until: 19-07-2025 Claim your CME credit at https://reachmd.com/programs/cme/chairperson-perspective-precision-payloads-exploring-adc-directed-therapies-in-her2-mutant-and-overexpressing-lung-cancer/16609/ Alterations in ERBB2, the gene encoding HER2, have been recognized as drivers in the development of NSCLC. Therefore, HER2 is an actionable biomarker that has emerged in NSCLC diagnosis and treatment. HER2 mutations activate the HER2 signaling pathway, which facilitates oncogenic transformation and increases tumor proliferation. Although practice guidelines recommend molecular testing to identify alterations, the interpretation of tests and application of testing results to treatment decisions remain areas of educational need. Despite HER2 testing and targeted therapies changing the treatment practices for other solid tumors, the previous standard of care for NSCLC has resulted in persistently low 5-year survival rates in contrast to the high rates of survival for breast cancer. However, successful targeting of HER2-activating mutations in advanced NSCLC has now been achieved through the use of antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd). By effectively targeting HER2-activating mutations, ADCs have emerged as a promising treatment approach for advanced NSCLC. In this educational activity, the expert faculty Chairperson will summarize relevant and timely information on NSCLC with HER2-mutant or overexpressing alterations and highlight the use of HER2-directed ADCs in NSCLC. The Chairperson will also provide their perspectives on the top key takeaways and why they are …=

Drs. Vamsi Velcheti and Nathan Pennell discuss key lung cancer abstracts from the 2024 ASCO Annual Meeting, including data from LUMINOSITY and ADAURA, novel therapies in KRASG12C-mutant advanced NSCLC, and the need for effective adjuvant therapies for patients with rare mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at Perlmutter Cancer Center at NYU Langone Health. Today, I'm delighted to welcome Dr. Nathan Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Dr. Pennell is sharing his valuable insights today on key abstracts in lung cancer that will be presented at the 2024 ASCO Annual Meeting. You'll find our full disclosures in the transcript of the episode.  Nate, it's great to have you here on the podcast. Thank you for being here. Dr. Nathan Pennell: Thanks, Vamsi, for inviting me. I'm always excited for the ASCO Annual Meeting, and we have a tremendous amount of exciting lung cancer abstracts. I know we're not going to discuss all of them on this podcast, but even exciting Plenary presentations coming up.  Dr. Vamsi Velcheti: So, one of the abstracts that caught my attention was Abstract 103, the LUMINOSITY trial, which will be presenting the primary analysis at the meeting. So, there's a lot of buzz and excitement around ADCs. Can you comment on this abstract, Nate, and what are your thoughts on key takeaways from this abstract?  Dr. Nathan Pennell: Absolutely, I agree. This is really an exciting new potential target for lung cancer. So historically, when we think about MET and lung cancer, we think about the MET exon 14 skipping mutations which are present in 3% or 4% of adenocarcinoma patients. And we have approved tyrosine kinase inhibitors, small molecule inhibitors that can be very effective for those. What we're talking about here is actually an antibody drug conjugate or ADC telisotuzumab vedotin, which is targeting the MET protein over expression in non-squamous EGFR wild type advanced non-small cell lung cancer. The LUMINOSITY was a single arm, phase 2 study of teliso, and first of all, I think we have to define the patient population. So, these were MET over expressing non-small cell lung cancer by immunohistochemical staining. So, it included both what they considered MET high expression and MET intermediate expression, both of which had to be 3+ IHC positive on 25% to 50% of cells in the intermediate and 50% or higher in the high expressing group. They were treated with the ADC and had pretty promising results, a response rate of 35% in the MET high group and 23% in the intermediate group. Duration of response at nine months and 7.2 months in those two groups, and the PFS was five and a half and six months. So I would say in a previously treated population, this was relatively promising and potentially defines a completely new and unique subgroup of biomarker defined patients. So, Vamsi, I'm curious, though, if this ends up moving forward to further development, what your thoughts are on adding yet another biomarker in non-small cell lung cancer? Dr. Vamsi Velcheti: Yeah, I think it's certainly exciting. I think for this population, we really don't have a lot of options beyond the second line, and even in the second line, docetaxels are low bar. So,I think having more options for our patients is certainly outcome development. And I think MET IHC is relatively easy to deploy in a clinical setting. I think we already test for MET PD-L1 IHC routinely, and now recently, as you know, HER2 IHC given approval for ADCs, HER2 ADCs there in that space. So, I think from a technical standpoint, I don't see a big barrier in terms of adding an additional IHC marker. And usually, the IHC testing is pretty quick. And I think if you have a therapeutic approval based on IHC positivity, I think certainly from an operational standpoint, it shouldn't be a very complicated issue. Dr. Nathan Pennell: Yeah, I agree. This is cheap. It's something that can be done everywhere in the world. And as you said, in addition to diagnostic IHC, we're already looking at PD-L1, and probably moving towards doing that for HER2. This is really wonderful that we're moving into kind of the era of the ADCs, which is opening up a whole new therapeutic group of options for patients. Dr. Vamsi Velcheti: So, the other abstract that caught my attention was like, the Abstract 8005. This is the molecular residual disease MRD analysis from the ADAURA trial. The ADAURA trial, as you all know, is the trial that led to the FDA approval of adjuvant use of osimertinib in patients with EGFR mutant stage 1B through 3A non-small cell lung cancer. And in this trial, osimertinib demonstrated significant improvements in DFS and OS. And in this particular study, Abstract 8005, the authors looked at the role of MRD in predicting DFS in the study. And after 682 patients who were randomized, 36% of the patients had samples to look at MRD post- surgery. And in the trial the MRD status predicted DFS or event free survival at 36 months with a hazard ratio of 0.23. And the MRD status had a median lead time of 4.7 months across both the arms, both osimertinib and the placebo arm. So, suggesting that MRD could potentially identify high risk subgroups of patients post-surgery to tailor personalized approaches potentially in this population. So, Nate, in your practice, of course, we don't have a clinically validated approach yet to kind of use MRD in this setting, but if we have an option to use an MRD based assay, do you think that would potentially be an opportunity to perhaps escalate or de-escalate adjuvant strategies with TKIs in the adjuvant setting? Do you see value in using MRI assays post- surgery? Dr. Nathan Pennell: Yeah, I think this is a really important study because this is such an important topic around adjuvant targeted treatment. So, of course, ADAURA really changed how we treated people with EGFR mutant lung cancer who underwent surgical resection, because we know that the three years of osimertinib significantly improved disease-free survival and overall survival. But there's still a lot of questions being asked about, is that affordable? Obviously, we're putting a lot of resources into three years of treatment, and not everyone necessarily needs it. There may well be people who are cured with surgery alone and adjuvant chemotherapy. And then what about duration? Is three years enough? Do we need even longer treatment, or do we need shorter treatment? And up to date, we haven't really been able to tell people at risk of recurrence other than the pure odds-based risk based on their stage.   And the assay that was used in the ADAURA study was a personalized tumor informed assay based on the resected tumor. It's unclear to me whether this was just a subgroup of people that had this done or whether they tried to do it in all 600 patients and only, it looks like they were successful in about 32% of people. Maybe about a third were able to successfully have a tumor informed assay. So, the first question is, “Can you use this to help guide who needs treatment or not?” And I think what they showed was only about 4% of people in osimertinib arm in 12% had MRD positive at baseline after surgery. So probably, upfront testing is not really going to be all that helpful at determining who's at high risk and needs to be treated.   Interestingly, of those who were positive, though, most of them, or 80% of them, did go MRD negative on osimertinib. And what I found really interesting is that of those who did have a recurrence, 65% of them did have the MRD test turn positive. And as you mentioned, that was about five months prior to being picked up radiographically, and so you can pick them up sooner. And it also looks like about two thirds of recurrences can be identified with the blood test. So that potentially could identify people who are recurring earlier that might be eligible for a more intensive treatment. The other thing that was really interesting is of those who recurred in the osimertinib arm, 68% of them happened after stopping the osimertinib, suggesting that for the majority of patients, even those not necessarily cured, they seem to have disease control while on the osimertinib, suggesting that maybe a longer duration of treatment for those patients could be helpful. The problem is it still isn't necessarily helpful at identifying who those people are who need the longer duration of treatment. So, definitely an important study. I think it could be useful in practice if this was available clinically, especially at monitoring those after completion of treatment. I think as the sensitivity of these MRD assays gets better, these will become more and more important. Dr. Vamsi Velcheti: I think it's a little bit of a challenge in terms of standardizing these assays, and they're like multiple assays, which are currently commercially available. And I think the field is getting really complicated in terms of how you incorporate different assays and different therapeutics in the adjuvant space, especially if you're kind of looking at de-escalating immunotherapeutic strategies at the adjuvant setting, I think, makes it even more challenging. I think exciting times. We definitely need more thoughtful and better studies to really define the role of MRD in the adjuvant space. So, I guess more to come in this space. Dr. Nathan Pennell: Vamsi, I wanted to ask you about another really interesting Abstract 8011. This is a subgroup of the AEGEAN perioperative study for early-stage resected non-small cell lung cancer. This abstract is specifically looking at baseline N2 lymph node involvement in stage 2A-3B with N2 positive patients in an exploratory subgroup analysis. What are your key takeaways from the study?   Dr. Vamsi Velcheti: I felt this was a very interesting abstract for a couple of reasons. As you know, this is the AEGEAN trial, the phase 3 trial that was reported earlier last year. This is a perioperative study of durvalumab plus new adjuvant chemotherapy versus new adjuvant chemotherapy alone and adjuvant durvalumab plus placebo. The study obviously met its primary endpoint, as we all saw, like the event-free survival. And here in this abstract, the authors present an exploratory subgroup analysis of patients who had N2 lymph node involvement prior to study enrollment. So, in this study, they were focusing on perioperative outcomes. And one of the issues that has come up multiple times, as you know, in a lot of these preoperative studies, is the impact of neoadjuvant chemo immunotherapy on surgery or surgical outcomes. And consistently, across a lot of these trials, including the CheckMate 816, about 20% of patients don't end up making it to surgery. So in that light, I think this study and the findings are very interesting. In this study, they looked at patients who had N2 nodal involvement and of the patients with N2 nodal involvement, the surgical operability or the number of patients who completed surgery was similar in both the groups. So, there was no significant difference between patients who received durva versus chemotherapy and also among patients who had N2 subgroup who had surgery, similar proportions of durvalumab and placebo arms had open versus minimally invasive versus pneumonectomy. So durvalumab didn't have a negative impact on the type of surgery that the patients had at the time of surgery. So overall, the findings were consistent with other trials, perioperative trials that we have seen. So, the surgical outcomes were not negatively impacted by adding immunotherapy in the neoadjuvant perioperative space. So, this is consistent with other trials that we have seen. And also, the other issue, Nate, I'd like to get your opinion on is, across the board, in all the perioperative trials we have seen that about 20% of the patients actually don't end up making it a surgery. And of course, most of these perioperative trials, a lot of these patients are stage 3 patients. And my take on this was that there's probably a little bit of a patient selection issue. We generally tend to err on the side of operability when we have a stage 3 patient discussed in the tumor board, sometimes feel like the patient may downstage and could potentially go to surgery. But even in the real world, in stage 3 operable patients, what proportion of patients do you think don't end up going to surgery? Dr. Nathan Pennell: That is such an important question that I don't think we have the best answer to. You're right. All of these perioperative studies have a relatively high- sort of 20% to 30% of people who enroll on the studies don't necessarily go to surgery. And I don't think that they've done as great a job as they could in all of these trials describing exactly what happens to these patients. So in the real world, obviously not everyone would be fit enough to go to surgery or might progress in the time between when they were diagnosed and the time as planned for surgery. But probably more of them would go to surgery if they weren't getting neoadjuvant treatment, because that would be their initial treatment. The question is, of course, is that the right choice? If someone gets 12 weeks or nine weeks of neoadjuvant treatment and then a restaging scan shows that they've had progression with metastatic disease, are those really the people that would have been optimally treated with surgery upfront, or would they just have had recurrence on their first postoperative scan? So, it's really an important question to answer. I think the bigger one is, is the treatment preventing them through toxicity from going to treatment? And I think the studies have generally felt that few patients are missing out on the option of surgery because of toxicity being caused by the IO. And in the AEGEAN study, for example, in this subgroup, a slightly numerically higher percentage of patients in the durvalumab arm actually underwent surgery compared to those who got neoadjuvant chemo. So, it doesn't seem like we're necessarily harming people with the neoadjuvant treatment. But I know that this is a concern for patients and doctors who are undergoing this approach. Dr. Vamsi Velcheti: Definitely, I think having multiple data sets from perioperative trials, looking at the relative impact of IO on the safety and the nature of the surgery is going to be important, and this is a very important study for that reason. Dr. Nathan Pennell: Can I ask you another thing that I thought really interesting about this particular one is they looked at the difference between those with single station N2 and multi station N2. And I know this is one of those, should we be operating on people who have multi station N2 disease? And the AEGEAN study did include people who had multiple N2 stations where perhaps in the pre-IO era, these would have been treated with definitive chemoradiation and not surgery at all. But the disease-free survival hazard ratio was essentially the same for multi station N2 as it was in the overall population. So, has that changed the way we're approaching these patients in these multidisciplinary discussions? Dr. Vamsi Velcheti: Absolutely, Nate. I think surgical operability is in the eye of the beholder. I think it depends on which surgeon sees the patient or how the discussion goes in the tumor boards, as you know. Certainly, I think with this optionality of having a chemo IO option and potential for downstaging, kind of pushes, at least in our practice, more of these patients who are multistation, who would have otherwise gone down the chemoradiation route are now actually going through neo adjuvant chemo IO and with the hope that they would make it to surgery. So, I think it's an interesting change in paradigm in managing our locally advanced patients. So, I think it's certainly interesting, but I guess to your point, there clearly are some patients who probably should just have chemoradiation upfront, and we may be kind of like delaying that definitive chemoradiation approach for at least a subset of patients. So, at the end of the day, I think it's a lot of clinical decision-making and I think there's going to be a little bit of art to managing these patients and it's going to be really hard to define that population for a clinical trial.  Dr. Nathan Pennell: Yeah, clearly, multidisciplinary discussion, still very important for earliest age non-small cell lung cancer patients. If we move back to metastatic lung cancer, let's talk about Abstract 8510 looking at one of our newer, exciting biomarkers, which are the KRASG12Cmutant non-small cell lung cancer. So this is a study of a second generation KRASG12Cinhibitor, olomorasib, which was combined with pembrolizumab, the anti PD-1 antibody, in patients with advanced KRASG12C mutant non-small cell lung cancer. This is something that has been tried before with first generation G12C inhibitors, with some concerns about how safe it was to do that. So, Vamsi, what did you learn from this abstract? Dr. Vamsi Velcheti: Definitely, I think one of the concerns that we've had in other trials is like the cumulative toxicity of adding checkpoint inhibition to G12C inhibitors, especially the sotorasib CodeBreaK trial, where we see increased rates of grade 3, 4 transaminitis. So, it is encouraging to see that some of the newer agents have less of those issues when it comes to combining the checkpoint inhibition. So especially with KRASG12C, as you know, these are patients who are smokers, and often these are patients who have high PDL-1 could potentially also benefit from immunotherapy. In order for these KRASG12C inhibitors, in order to move these targeted therapy options for these patients to the front line, I do think we need to have substantial comfort in combining the checkpoint inhibitors, which is a standard treatment approach for patients in the frontline setting. I think this is exciting, and I think they're also like, as you know, there are other KRASG12C inhibitors also looking to combine with checkpoint inhibition in the frontline settings. So, we'll have to kind of wait and see how the other agents will perform in the setting. Dr. Nathan Pennell: Yeah, I completely agree. I think this is such an important area to explore specifically because unlike our other targeted oncogenes like EGFR and ALK, we have multiple options for these patients, both immunotherapy and targeted treatments. And if we could think about sequencing them or even combining them and if it could be done safely, I think that would be well worth investigating. There still was significant toxicity in this trial; 30% of people had diarrhea, even at the reduced dose, and there was transaminitis at sort of about 20% or so, although probably at a manageable level. But the response rate was really quite promising. And these are all previously IO and mostly G12C TKI pre-treated patients still had a response rate of 63%. And in those who were naive to IO and TKIs, it was 78% response rate. So, if it could be done safely, I think it's definitely worth pursuing this in further trials. Dr. Vamsi Velcheti: And also, there's some data, preclinical data, like looking at G12C inhibition. And also we have known with MET inhibition for a long time that it could potentially augment immune responses and could be having some synergistic effect with IO. So, we'll have to wait and see, I think. But safety is really the top in mind when it comes to combining these agents with checkpoint inhibitors. So, it's really encouraging to see that some of the newer agents may be more combinable IO. Now moving on to the next abstract, and moving on to, again, the early-stage setting. So, Abstract 8052 from our colleagues in Princess Margaret reported outcomes in early-stage non- small cell lung cancer in patients with rare targetable mutation. This is actually becoming increasingly more relevant because we are seeing at least, like with the ALINA data, with the ALK and EGFR, now with ADAURA, we know that these patients don't benefit with adjuvant immunotherapy, especially some of these rare oncogene living mutations, other than like G12C. So I always struggle with this. When you have early-stage patients, with, let's say, a ROS or a RET, where we just don't have data, and we know that those are poor actors because biologically these are aggressive tumors. So, there's a really odd clinical question to ask in terms of, what is the role of adjuvant immunotherapy? Of course, this trial and this abstract are not really addressing that. But what is your take on this abstract? If you could just summarize the abstract for us. Dr. Nathan Pennell: Sure. Well, I think this is incredibly important, and this is an area near and dear to my own heart. And that is, of course, the whole landscape of how we manage early-stage patients has changed with both ADAURA, because we now have effective treatment in the adjuvant setting for EGFR mutant patients, and now more recently with the ALINA trial for adjuvant alectinib for ALK positive patients now being FDA-approved. So, what that means is we actually have to be testing people at diagnosis even before they would be getting adjuvant treatment, and potentially before even surgery to look for these targets. We need the PD-L1 status, we need EGFR and ALK. And if you're going to be looking at these biomarkers, I think there is a reasonable argument to be made that you should be doing broad testing for all of the targetable oncogenes in these patients. There are some studies suggesting that there's value to this and identifying them for treatment at the time of recurrence. But we also know that these patients are at high risk of recurrence and probably need to be investigated, at least in trials for the adjuvant setting. So, this particular study looked at 201 resected, mostly adenocarcinoma patients, and then they basically sequenced them for all of the targeted oncogenes. And they were quite common, perhaps even more common than you might expect in an advanced population. So, 43% of them had KRASG12C mutations, 13% had EGFR Exon 20 mutation, ERBB2 or HER2 mutations found in 11%, MET mutations in 10%, ALK in 7%, ROS1 in 6%, BRAF in 5%, and RET in 2%. So quite common to find these targetable oncogenes in this particular population, perhaps a somewhat biased population at Princess Margaret Hospital, but very common. And then they looked at the outcomes of these patients without targeted adjuvant treatment. And what they found was there was a very high rate of recurrence. So, relapse-free survival was pretty high in these patients across different stages, and generally their prognosis was worse than the more common KRASG12C patients. Most of these, in particular the HER2 mutant patients, seem to have a significantly worse relapse free survival. Interestingly enough, though, that did not carry over to overall survival. Overall survival was better in those who had targetable oncogenes. And my guess is that that probably had to do with the availability of targeted treatments at the time of recurrence that may have impacted overall survival. But I do think that this particularly highlights the need, the unmet need for effective adjuvant treatment in these patients. And most of them, with the exception of KRAS and perhaps BRAF, perhaps MET unlikely to benefit from adjuvant immunotherapy, as you mentioned. And so, I think we really need to be investing in trials of adjuvant targeted treatments in these populations.  Dr. Vamsi Velcheti: Yeah, this is an area that we really don't have a lot of data. But Nate, a question for you. So tomorrow you have a patient with RET fusion, stage 2, N1 disease. What would you do? Would you offer them an adjuvant RET inhibitor? Dr. Nathan Pennell: I think I would search really hard for a trial to give them access. But if you really want to know what I think, and I'm usually willing to tell people what I think, I think the proof of concept is there. I think we know that in the setting of highly effective and very tolerable adjuvant targeted treatment in the EGFR space with osimertinib, in the ALK space with alectinib, if anything, drugs like selpercatinib and pralsetinib in RET fusion positive lung cancer in the advanced setting are just as well tolerated and easily as effective and long lasting. And so, I think if you did a trial and they are doing trials looking at these drugs in the adjuvant space, almost certainly you're going to see the same really dramatic disease-free survival benefit from these treatments, which, at least in the EGFR space, seems to have translated into an improvement in overall survival. And so if I had a stage II or a resected stage 3, especially a RET fusion positive patient today, I would definitely talk to them about off-label use of a RET inhibitor if I could not find a trial. Now, I understand that there are going to be reimbursement issues and whatnot associated with that, but I think the extrapolation is worth discussing. Dr. Vamsi Velcheti: Yeah, I think it's really challenging because some of these fusions are so rare and it's hard to really do large adjuvant trials for some of these rarer subgroups. Nate, fascinating insights. Our listeners will find links to the abstracts we discussed today in the transcript of the episode. And Nate, I look forward to catching up with you at the Annual Meeting, and again after the meeting for our wrap up podcast to discuss the practice-changing lung cancer abstracts and highlights from the Plenary Session. Thank you so much for joining us and sharing your insights today. Dr. Nathan Pennell: Thanks for inviting me. Vamsi. I look forward to touching base after we get to see all the late-breaking abstracts. Like I said, this is, I think, a year for lung cancer with a lot of exciting data, and I know we'll have a lot to talk about. Dr. Vamsi Velcheti And thank you so much to all our listeners for your time. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate and review and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti   Dr. Nathan Pennell @n8pennell   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures: Dr. Vamsi Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

In this podcast episode, Sara M. Tolaney, MD, MPH, and Melinda Telli, MD, delve into the critical aspects of the current therapeutic landscape for patients with unresectable or metastatic HER2-low, hormone receptor–positive, and triple-negative breast cancer, including:Challenges with the pathologic testing for HER2-low expressionOptimal treatment of patients with HER2-low advanced breast cancerRole of TROP-2–targeted therapiesManagement of ADC-associated adverse events to optimize treatment outcomesADCs on the horizon for patients with advanced breast cancerPresenters:Sara M. Tolaney, MD, MPHChief, Division of Breast OncologyDana-Farber Cancer InstituteAssociate Professor of MedicineHarvard Medical SchoolBoston, MassachusettsMelinda Telli, MDProfessor of MedicineStanford University School of MedicineDirector, Breast Cancer ProgramStanford Cancer InstitutePalo Alto, CaliforniaContent based on an online CME program supported by educational grants from AstraZeneca and Daiichi Sankyo, Inc.Link to full program:https://bit.ly/49WxRBM

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. ASCO's first clinical trial is the Targeted Agent and Profiling Utilization Registry, or TAPUR Study. This clinical trial is intended for people with advanced cancer without other treatment options available, and whose cancer has at least one genomic variation that can be targeted with specific drugs. In this podcast, Dr. Richard Schilsky discusses the TAPUR study and explains why it is significant. He also discusses what participants can expect. Dr. Schilsky is the Principal Investigator for the TAPUR study. He is also the former Chief Medical Officer for ASCO and Professor Emeritus at University of Chicago. View Dr. Schilsky's disclosures at Cancer.Net. Dr. Schilsky: Hi, everyone. My name is Richard Schilsky and I'm the principal investigator of the ASCO TAPUR Study and the former Chief Medical Officer of ASCO. I'm happy to give you an overview and update about the study today. By the way, TAPUR is an acronym that stands for Targeted Agent and Profiling Utilization Registry. Hopefully, the reason for naming it that will become clear as you listen. The TAPUR study was conceived in 2013 and launched in 2016, and was based on the observation that there was a rapid increase in testing the tumors of patients with advanced cancer for gene mutations that might be contributing to the growth of the tumor, so-called genomic profiling, in the hope of finding a genomic alteration that could potentially be treated by a drug that was already FDA-approved for a different tumor type than what the patient had. Meaning, in order for the patient to receive the drug, it would have to be prescribed off-label. The challenge with prescribing the off-label use of a drug is that most insurance plans don't cover the cost of treatment. Additionally, even if the patient were able to receive the drug, there was no mechanism for the oncology community to learn from the patient's treatment experience. The TAPUR study has managed to address these challenges by providing access to FDA-approved drugs at no cost to the patient and providing treatment results to the oncology community regarding the effects of off-label use of the treatments being studied. Now, TAPUR is a clinical trial, and its primary objective is to describe the anti-tumor activity and toxicity of commercially available targeted anti-cancer drugs prescribed for treatment of patients whose tumors have a genomic alteration known to be a drug target or to predict sensitivity to a drug. TAPUR was designed to be simple for providers and patients. It's a phase 2 study, meaning that we're aiming to learn about efficacy and safety. It's prospective, that is, it enrolls patients going forward. It is not randomized. Everybody gets a treatment based on the genomic profile of their tumor and the available treatments in the study. It's a multi-basket study. That is to say, multiple therapies are available on the study that are targeting multiple genomic alterations. And it's a pragmatic study. TAPUR attempts to replicate routine clinical care. It's exempt from FDA oversight. It provides oral drugs that can be shipped directly to the patient's home after the first visit. Now, as I said, the TAPUR study was launched in March of 2016. And as of this month, it's still going strong, with more than 2,700 patients having been enrolled at 267 locations in 28 states. So how does the study work? Well, a patient's physician has results of a genomic profile of the patient's tumor and determines that a study drug might benefit the patient. The patient then decides to participate in TAPUR and gives their informed consent. A molecular tumor board, which is a group of experts convened by ASCO, is available to consult regarding the proposed treatment or to provide alternative treatment options for the patient. A participating pharmaceutical company, and there are 10 right now, provides the study treatments at no cost to the patient. The patient is cared for by their own oncologist, receives a standard dose of the drug, and is evaluated at standard intervals to see if the treatment is working and if they're having any side effects. ASCO has convened an independent data and safety monitoring board of cancer experts that periodically reviews results and determines whether treatment is promising for a particular cancer type and genomic alteration. That's what we call a cohort in the study. Once the data are finalized, ASCO publishes the study findings in peer-reviewed journals to inform clinical practice and future research. So let me give you an example. There are specific molecular alterations that often appear in tumor cells that are important for driving the growth and progression of the cancer and can be targeted with specific drugs that interrupt those abnormal molecular pathways. Many of these alterations occur at low frequency, meaning in less than 5% of tumors of any given type. The benefit of the TAPUR trial having a basket design is our ability to evaluate multiple therapies simultaneously to target multiple low-frequency alterations, which ultimately offers more treatment options to patients who wish to participate in the study. If the TAPUR study were set up looking to target only a single genomic alteration, we would potentially have to screen hundreds of patients in order to find one who is appropriate for the trial, which also means hundreds more would still be left without treatment options. But because TAPUR evaluates multiple treatments and multiple genomic alterations simultaneously, we found that about two-thirds of patients who were screened for the trial ultimately enroll. A specific example of a drug and targeted gene alteration on TAPUR is the use of the treatment combination pertuzumab plus trastuzumab in tumors with ErbB2 amplification or mutation. Now, you may be aware that ErbB2 is a gene that is synonymous with the HER2 gene that is frequently amplified or overexpressed in patients with breast cancer. And this drug combination, pertuzumab and trastuzumab, is FDA-approved for treatment of patients with breast cancer. But in the TAPUR study, we found multiple tumor types outside the FDA-approved label that can benefit from this treatment if an ErbB2 alteration is detected, including patients with colorectal cancer, endometrial [uterine] cancer, biliary tract cancer, and lung cancer. To learn more about TAPUR, please follow our progress at the ASCO website. In an effort to provide up-to-date information about cohorts that are available for enrollment on the TAPUR study, ASCO launched a public-facing status report in March of 2023. So first click on www.tapur.org. Click on the link to the ASCO website. From there, select study participation at the bottom of the page. Once at the study participation page, click on the link to see a list of study cohorts that are currently enrolling. The report updates daily, providing viewers with an up-to-date list of available study cohorts based on their genomic alterations. It's important to note that study cohorts are available on a first-to-enroll basis. You can also find information about current results from the TAPUR study on the study results page. So what have we learned so far? Thus far, we've publicly reported results on 29 cohorts of patients. 17 gave a positive signal of treatment activity, 12 were negative. Now we feel it's just as important to report on the negative results as the positive results. If the treatment is unlikely to be effective for patients, it's important to inform the oncology community because all of the drugs in the study are commercially available and could be prescribed to a patient. Enrollment to patients on TAPUR is very representative of the U.S. population. The study has broad eligibility criteria that allows more patients to enroll, including patients with an ECOG performance status of 0 to 2 and younger patients. Some treatments allow for adolescent patients as young as age 12 to be enrolled in the study. We hope the oncology community finds value in the TAPUR study. Physicians have the opportunity to contribute to research and participate in publications and to contribute more knowledge in the field of oncology. TAPUR provides guidance on interpreting genomic reports via the molecular tumor board and provides additional treatment options for patients. Institutions obtain insights on potential new uses of existing drugs and their side effects, and TAPUR data can inform updates to clinical practice guidelines. And patients receive access to drugs not available as standard of care. Patients may be able to receive oral drugs at their home and limit their commute to clinic. And of course, participation in the study provides an opportunity for patients themselves to contribute to knowledge about cancer treatments. To find a clinical site offering the TAPUR study, please visit the TAPUR website again, www.tapur.org and select “Participating Centers.” This will lead to a searchable map of participating sites and includes the site-specific contacts. Contact the primary contact listed for that site. Thank you for listening to this update on the ASCO TAPUR study and enjoy the rest of your day. ASCO: Thank you, Dr. Schilsky. Learn more about clinical trials, including the TAPUR Study, at www.cancer.net/clinicaltrials. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

In this episode of the Epigenetics Podcast, we talked with Jason Carroll from the Cambridge Research Institute about his work on contribution of estrogen receptor to breast cancer progression. The Podcast centers around the crucial role of the forkhead protein FOXA1 in breast cancer. FOXA1 acts as a pioneer transcription factor, facilitating gene regulation by recruiting nuclear receptors to chromatin, profoundly influencing gene expression in various breast cancer subtypes. The FOXA1-positive subtype of triple-negative breast cancer, despite being estrogen receptor-negative, shares gene expression profiles with estrogen receptor-positive breast cancer, shedding light on the importance of targeting the androgen receptor for treatment. The challenges of studying transcription factor mappings from clinical samples are explored, with a focus on the ChIP-seq method's success in mapping estrogen receptor binding sites. Various techniques for transcription factor mapping, including CUT&RUN, CUT&Tag, and ChIP-exo, are discussed, as well as the potential of mass spec techniques like the RIME method in analyzing protein interactions. An intriguing experiment involving the purification of multiple proteins to identify interactions is highlighted.   References Carroll, J. S., Meyer, C. A., Song, J., Li, W., Geistlinger, T. R., Eeckhoute, J., Brodsky, A. S., Keeton, E. K., Fertuck, K. C., Hall, G. F., Wang, Q., Bekiranov, S., Sementchenko, V., Fox, E. A., Silver, P. A., Gingeras, T. R., Liu, X. S., & Brown, M. (2006). Genome-wide analysis of estrogen receptor binding sites. Nature genetics, 38(11), 1289–1297. https://doi.org/10.1038/ng1901 Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., Jiang, J., Howat, W. J., Ali, S., & Carroll, J. S. (2008). Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature, 456(7222), 663–666. https://doi.org/10.1038/nature07483 Ross-Innes, C. S., Stark, R., Teschendorff, A. E., Holmes, K. A., Ali, H. R., Dunning, M. J., Brown, G. D., Gojis, O., Ellis, I. O., Green, A. R., Ali, S., Chin, S. F., Palmieri, C., Caldas, C., & Carroll, J. S. (2012). Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature, 481(7381), 389–393. https://doi.org/10.1038/nature10730 Mohammed, H., Russell, I. A., Stark, R., Rueda, O. M., Hickey, T. E., Tarulli, G. A., Serandour, A. A., Birrell, S. N., Bruna, A., Saadi, A., Menon, S., Hadfield, J., Pugh, M., Raj, G. V., Brown, G. D., D'Santos, C., Robinson, J. L., Silva, G., Launchbury, R., Perou, C. M., … Carroll, J. S. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313–317. https://doi.org/10.1038/nature14583   Related Episodes Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret) The Role of Pioneer Factors Zelda and Grainyhead at the Maternal-to-Zygotic Transition (Melissa Harrison)   Contact Epigenetics Podcast on Twitter Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Active Motif on Twitter Active Motif on LinkedIn Email: podcast@activemotif.com

JCO PO author Dr. Apar K. Ganti shares insights into his JCO PO article, “Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.” Host Dr. Rafeh Naqash and Dr. Ganti discuss clinical decision-making regarding biopsy; HER2 amplification, mutation, and targeted therapy; drug combinations; and aspects of the TAPUR and DESTINY-Lung studies. Click here to read the article!   TRANSCRIPT Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the University of Oklahoma Stephenson Cancer Center.  Today we are joined by Dr. Apar Kishor Ganti. Dr. Ganti is a Professor of Medicine and associate director of clinical research at the Fred and Pamela Buffett Cancer Center at the University of Nebraska Medical Center. He's also a staff physician at the VA Nebraska Western Iowa Healthcare System. Dr. Ganti is the lead author of the JCO Precision Oncology article titled "Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study," which is also the TAPUR Study.  Dr. Ganti, thank you so much for joining us today. Dr. Apar Kishor Ganti: Thank you for having me. I'm happy to be here. Dr. Abdul Rafeh Naqash: For starters, Dr. Ganti, this is one of the trials from the TAPUR Basket study. So I wanted to take this opportunity since this is an ASCO initiative that has been there for a few years now. Could you tell us a little bit of background about the TAPUR initiative, what kind of trials are being run or have been run, and how it all started, basically?  Dr. Apar Kishor Ganti: The TAPUR Study or the Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial which evaluates the anti-tumor activity of commercially available targeted agents in patients with advanced cancers and tumors that have potentially actionable genomic alterations, like mutations, amplifications, etc. And this has multiple arms in multiple malignancies, using drugs that are currently approved in different indications and not necessarily approved for the indication that's being studied. But there's preclinical data that suggests that that particular drug may potentially be active in patients whose tumors harbor those mutations. For example, this present study that we conducted utilized a combination of pertuzumab and trastuzumab, both of which are FDA-approved for the treatment of patients with HER2-positive breast cancers. And we analyzed the efficacy of the combination of these two drugs in patients with lung cancer who had either a HER2 mutation or an amplification of HER2.  Dr. Abdul Rafeh Naqash: Thank you so much for giving us that background. Going to this study specifically, which is one of the very interesting TAPUR studies, what I'm reminded of especially is NCI-MATCH, for example, which runs on a similar premise to this study, where we've seen some successes and some not as exciting combination approach successes that is what we would have wanted to see.  For lung cancer specifically, as you and I both know and perhaps many of the listeners know, there's a lot of actionable drivers that have target therapies that are approved, could you touch on some of those to give a background on where the field currently lies and what are some of the important steps with respect to obtaining next generation sequencing, perhaps in patients. So what your practice is and what you would recommend for these individuals? Dr. Apar Kishor Ganti: Certainly, non-small cell lung cancer, or non-squamous non-small cell lung cancer, to be more precise, seems to be the poster child for next-generation sequencing. And the importance of NGS testing cannot be overemphasized in these patients. For example, right now we have multiple different drivers that have drugs approved for the management of these patients. The first among them, obviously, was EGFR or epidermal growth factor receptor. And that has been followed fairly successfully by targeting ALK, ROS1, now, more recently, RET, MET, KRAS, and HER2. So if you look at lung adenocarcinomas, almost half of the patients will have a tumor with a mutation that is targetable. And so it's very important to make sure that these patients are tested for, before initiating any therapy. What makes it more important is that the standard of care for patients with non-small cell lung cancer without driver mutations is either immunotherapy or chemoimmunotherapy. And we have found that if a patient has a driver mutation, especially EGFR or ALK, even if their PD-L1 expression is extremely high, their response to checkpoint inhibitors is negligible. And so it is important to make sure that we understand what their molecular status is before starting any treatment in these patients. And I think the key point here is that every patient with advanced non-small cell lung cancer should have next generation sequencing studies done prior to initiation of treatment. Dr. Abdul Rafeh Naqash: Absolutely. And in your practice, Dr. Ganti, do you tend to do liquid biopsies concurrently when you get a new individual with a diagnosis of lung cancer, or do you do it at some other time point?  Dr. Apar Kishor Ganti: Liquid biopsies, I tend to get them, but not as frequently as some would like. I tend to believe more in tumor biopsies, and I would get liquid biopsies only in the setting where a tumor biopsy is not feasible or if I feel that the patient needs treatment more rapidly than can be expected if I got a tissue biopsy. Liquid biopsies, in my opinion, are good, but they're very dependent on the tumor fraction that is present in the sample that you send. As you very well know, not all patients who have a driver mutation necessarily shed the mutation into the blood. And therefore, even if a patient has a driver mutation in a tumor, there is a small chance that the liquid biopsy may not detect it. So I tend to be more in favor of getting tumor biopsies for next-generation sequencing. In situations where the tumor fraction is high, the concordance between tumor biopsies and liquid biopsies is fairly good. Dr. Abdul Rafeh Naqash: Thank you so much for that very important clinical decision-making thought process. At least in my practice, when tissue is often the issue, as you very well know, where you don't either have enough tumor cells or the biopsy is just enough to tell you whether it is squamous or non-squamous and not enough for any further sequencing, I try to get liquid biopsies whenever feasible and appropriate so that at least we can rule out some of the driver alterations before I put a patient on immunotherapies, due to the concern for subsequent toxicities if there are driver alterations. But I totally agree, I think tissue is definitely the standard, gold standard. And if you have overlapping mutations in tissue and liquid, then obviously it increases your confidence of treating that individual with that targeted therapy. But in general, tissue definitely, at least we should try to emphasize, and I try to do this often when I get a call from a community oncologist. I'm pretty sure you do the same where we ask for multigene broad gene testing NGS, so that especially when you have HER2 mutations, for example, you won't necessarily capture those as you show on your study here.   Now, going to your study, Dr. Ganti, could you tell us a little bit more about HER2 mutations and amplifications? And there's different levels of evidence where amplification may not lead to expression or expression may not lead to amplification. And then there is a separate category of HER2 mutations. And a lot of what we know for HER2 is from breast cancer. And recently, in the last two to three years now, is for lung cancer also. Could you tell us about how the field is shaping from a HER2 mutational landscape, an amplification landscape, in the lung cancer field?  Dr. Apar Kishor Ganti: As you rightly said, most of our knowledge from HER2 is from the breast cancer world. And frankly, I think we've been spoiled by the data on breast cancer. So, unlike in breast cancer, lung cancer seems to have a much lower frequency of HER2 alterations. And while in breast cancer, HER2 amplification seems to be important and predictive for response to HER2-targeted agents, in lung cancer, we see a combination of mutations and amplifications. So, in a large TCGA study, mutations in HER2 seem to occur in about 2% of all lung cancers. And amplification seems to be occurring in approximately a similar proportion of different patients. So, they seem to be mutually exclusive as best as we can tell.  And, unlike in breast cancer, where HER2 amplification seems to be directly associated with protein over-expression and response to tumor, the data in lung are much less robust. And so, it is not necessarily that an amplification will translate into a prediction of response to a HER2-targeted agent. And we and certain other studies have shown that patients who have HER2 amplification may not respond as well to HER2-targeted therapy as opposed to, for example, patients with HER2 mutations. So, that seems to be the discrepancy in HER2 amplification and HER2 mutations when you look at lung cancer versus breast cancer. And that's another reason why we are doing the TAPUR study at the various arms because what works in one specific cancer with the same mutation or same abnormality may not necessarily work in other cancers. Dr. Abdul Rafeh Naqash: Absolutely. Thank you for indulging into that side of things. Now, going back to your trial, could you tell us a little bit of background on the eligibility criteria, how you chose some of the different mutations? What were the levels of evidence for some of those mutations from a pathogenicity standpoint, and then what were your endpoints, since this is a clinical trial with a Simon two-stage design?  Dr. Apar Kishor Ganti: Patients who were eligible for the trial included all patients with advanced lung cancer who did not have another FDA-approved treatment or were not candidates for another treatment. They all should have been 18 years or older at the time of diagnosis and have lung cancer with either ERBB2 amplification or we looked at 13 specific mutations, insertions, or deletions, and, if the patient had any of those abnormalities identified by any clear approved next-generation sequencing testing platform, then they would be eligible for the study. We chose these because of how frequently these specific mutations occurred in lung cancer and other cancers. And so, these 13 abnormalities were chosen from the host of HER2 mutations that you can see. Patients should not have received a previous HER2 inhibitor, obviously, and their LV ejection fraction should be normal because of the known risk of decreasing cardiac function with HER2-targeted therapy. They were treated with pertuzumab every three weeks and then combined with trastuzumab. Trastuzumab was given at a loading dose, initially of 8 milligrams per kilogram, and in subsequent cycles, we used 6 milligrams per kilogram. The dose of pertuzumab was a flat dose of 840 milligrams for the first dose and 420 milligrams for subsequent doses.  We continued the treatment till progression or excessive toxicity or patient withdrawal of consent. The endpoints were disease control, which we defined as objective response or stable disease for at least 16 weeks duration. Other endpoints were progression-free survival, overall survival, duration of response, and, of course, safety. We used a Simon two-stage design, as you said. The null hypothesis was that the disease control rate would be 15%, alternative hypothesis was 35%, the power was 85%, alpha was at 10%. So, if in the first stage, less than two out of ten patients had disease control, then the cohort would be closed for futility. If two patients or more had disease control of the first 10, then we expanded to an additional 18 patients for a total study size of 28. So, as far as safety analysis, any patient who received even a single dose of treatment was included in that safety analysis.  Dr. Abdul Rafeh Naqash: Thank you so much for giving us those details about the cohort. Going to the mutation or the amplifications, I'm looking at the cohort, so it seems like more or less, to some extent, there was an equal distribution of the mutations. 50% of individuals had mutations and then around 45%, 43% had amplifications. Did that play into your expectation of how the cohort did in terms of responses or the primary endpoints that you had set? Did you see differences based on those findings of mutations versus amplifications.  Dr. Apar Kishor Ganti: Yes, we did. The disease control rate was 37%, with an overall response rate of 11%. And when you looked at patients who had a partial response, which is three patients, all of them had ERBB2 mutation. And of the patients who had stable disease, only two patients out of seven had an amplification. Five patients had the mutation. So, again, this was similar to what we had expected, that based on previous studies, patients with mutation tend to respond better than patients with alterations. Dr. Abdul Rafeh Naqash: Definitely. And going to one of the striking figures that you have in this manuscript, of course, you have the waterfall plot, and then you have the swimmer's plot and the spider plot. I'm very intrigued personally by the spider plot, which is the Figure 3 in your paper, especially with this individual that had this long, durable partial response. I believe this was the same individual with the mutation. I believe it was this 776 insertion. Was there anything, any other aspect that could have contributed to this response, or does this mutation, does it have any strong preclinical data of why the activity offer to direct therapy might be more pronounced in this mutation that you came across?  Dr. Apar Kishor Ganti: Not to my knowledge. I don't think we found anything specific or different about this particular patient compared to the others. So, as far as the mutation itself is concerned, it's a fairly common mutation, the G776 insertion. It is one of the most common mutations seen in lung cancer, and studies have shown that patients with the mutation tend to respond. But why this patient responded so long, it's difficult to say. I wish we were able to find out, but unfortunately, we were not able to. Dr. Abdul Rafeh Naqash: Sure. Another question that I wanted to ask you since this falls into the precision medicine basket study questions. Does TAPUR have a different endpoint for different sub-studies? Because I vaguely remember coming across another paper where I believe a 16-week disease control was also the endpoint. So, is that something universal in TAPUR, or is it specific for specific tumor types and different combination approaches? Dr. Apar Kishor Ganti: I believe that this is a more generalized feature of the TAPUR study, the stable disease for 16 weeks as a marker of response. Of course, different arms have additional endpoints, but I think this is one of the more common ones. Dr. Abdul Rafeh Naqash: Now, there has been some work, as you very well pointed out in your paper as well, from others related to HER2 mutations, especially the DESTINY-Lung study. Could you tell us a little bit about that for listeners who may not be well aware of the DESTINY study with trastuzumab deruxtecan targeting the HER2 mutations? Dr. Apar Kishor Ganti: So, DESTINY-Lung01 was a study of patients with ERBB2 mutated lung cancer. That study just looked at mutation-positive patients as opposed to what we did, looking at both mutation and amplification. And that study showed an overall response rate of 55%, which was much higher and led to the approval of fam- trastuzumab-deruxtecan in this group of patients. And so, one of the differences between our study and trastuzumab deruxtecan DESTINY-Lung01 study, is that our study included patients with both mutations and amplification and our study did not include any cytotoxic drug. And I believe that was one of the big differences, which may make the results of our study intriguing and potentially useful to patients who may not be able to tolerate a cytotoxic agent. Because, as you know, fam-trastuzumab-deruxtecan has the cytotoxic binder. It's an ADC and has been known to have some toxicities. And the thing about lung cancer is that these patients are relatively frail and may not be able to tolerate it. And so, that's one of the major differences, a portion at least for this combination, even though the response rates are much smaller than what we see with fam-trastuzumab-deruxtecan. Dr. Abdul Rafeh Naqash: And from your practice, have you started using this combination from your study as a potential approach for individuals who may not be candidates for trastuzumab deruxtecan in your clinic? Dr. Apar Kishor Ganti: I have not as yet because I have not come across a patient who would be eligible for this combination. In my practice, as we have TAPUR open, we have the tucatinib-trastuzumab arm that opened after this arm closed. So my priority is to try and enroll patients onto that cohort. And so I currently have one patient on that. And as you know, this is not a very common alteration, so we don't have as many patients with this. But definitely, this would be a combination that I would put patients on if I felt that they were not a candidate for fam-trastuzumab-deruxtecan.  Dr. Abdul Rafeh Naqash: So, Dr. Ganti, what's the next step after this since your study didn't meet some of its endpoints? What are you planning, or is there a plan to expand on this through the TAPUR mechanism?   Dr. Apar Kishor Ganti: Right now, I don't think that there's a mechanism through TAPUR to expand this particular cohort because there is also another cohort that opened subsequently with tucatinib and trastuzumab. But I think it would not be unreasonable to study this combination in patients who are not candidates for fam-trastuzumab because of the differences in toxicity. So that would be where I would potentially see a role for this particular combination, and I think it should be studied in that setting. Dr. Abdul Rafeh Naqash: Excellent. Now, I try to dedicate a section of this conversation for provocative discussions that may not be addressed in your paper, but I still like to get insights from experts in the field such as yourself. So comparing it to the NCI-MATCH or some other precision medicine-based initiatives, we do often see that mutations that we think might be driving the process don't necessarily lead to really high or really promising responses to targeted therapies. So in this case, do you think, from a futuristic standpoint, a proteomic-based assay, since I think you work in the proteomic space as well, that would be an interesting way to look at whether signaling actually is altered from a mutation or an amplification, suggesting that that is driving the process, so would be a more attractive target than just looking at a mutational signature?  Dr. Apar Kishor Ganti: I think definitely that should be the way we should be looking at these kinds of studies, because even in this study, even if you look at fam-trastuzumab-deruxtecan and the DESTINY-Lung01 study, we have patients who have definite, identified drivers, and even there, only about half of the patients responded. It was much smaller in our study. But basically what I'm getting at is with the best of the drugs that we have today, only half of our patients respond with HER-2 mutations, for example. So I would definitely favor a more integrated approach to identifying those patients who would be candidates for these targeted agents and not just simply relying on a specific mutation.  Since we are being provocative, I would go one step further and say, “Hey, we have AI. And there are currently AI-based technologies which look at the entire next-generation sequencing profile and try to identify which drugs could potentially be effective in those patients based on a complete understanding of their entire tumor genetic profile, rather than just looking at one or two, or three mutations.” So that, I think, would be a much more robust approach through precision medicine. So, like you just said, that patient that we had who had a prolonged response, we don't know why he or she had a prolonged response. And maybe if we identified a pathway or pathways which were overexpressed or more active in that particular tumor setting, we would be able to identify better targets and better approaches for those patients. So I think that is the way to go in the future. Dr. Abdul Rafeh Naqash: Excellent. Thanks for indulging into that provocative discussion and hopefully maybe five years down the line when we meet again or run across each other at ASCO, we will say, “Oh, it did actually happen, that multiomics is being used in a way that is suited for the need of the patient.” So matching the right patient to the right therapy at the right time.  So, Dr. Ganti, the last section is going to be dedicated to you as an individual. So you've had a very successful, brilliant career as a clinical trialist and as a lung cancer expert. Tell us, for the sake of our listeners and perhaps some of the early career junior investigators, what your career trajectory has been briefly, and what are some of the things that you felt were successful that could provide advice and insights to people who are earlier in their careers and trying to emulate what perhaps you have done or you are doing?  Dr. Apar Kishor Ganti: Well, that is a big one. I never thought of myself as being a role model for anyone, far less someone who's at the beginning of their career. But what I have always mentioned to students and residents and fellows is basically there is no substitute for hard work. Luck plays some role in this because you need to be at the right place at the right time for some of it, but hard work definitely will pay off. And the other thing that is important is not to get disheartened if your first clinical trial gets rejected or concept gets rejected, or if your first grant gets unscored. That is part of life, and persisting is probably the best way to continue.   Also, continuing to believe in yourself. I've seen a lot of folks, especially once they get into their second or third year after fellowship when things are not going the way they want to, they start to wonder, “Am I suited for this job? Am I the right person? Am I doing this correctly? Should I be doing something else?” And I think it's just a matter of time before they will find success. And also, the other thing is, if one particular approach does not work, there are always other ways that you can look at. So, for example, if you extend a bunch of clinical trial concepts that do not work out, you could potentially look at other ways of answering questions. For example, you could do retrospective analyses, come up with provocative, hypothetical generating questions that could be answered in the future in a prospective study. So there are lots of avenues to do that. And I think I was benefited by my mentors who helped me see this relatively early in my career. Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Ganti, for all those valuable insights that you've learned over your career and hopefully will help some of the listeners. Before we finish, I'm going to ask you three rapid-fire questions that hopefully will let our listeners--give them a little bit of a sneak peek into you as a person. And you get like five seconds for each question. And they're not complicated questions. My first question to you is what is your favorite food? Dr. Apar Kishor Ganti: Thai food. Dr. Abdul Rafeh Naqash: What is your favorite place to go for vacation?  Dr. Apar Kishor Ganti: South Africa.  Dr. Abdul Rafeh Naqash: And what is your favorite hobby?  Dr. Apar Kishor Ganti: Reading.  Dr. Abdul Rafeh Naqash: Well, thank you so much again, Dr. Ganti. This was a very interesting conversation and hopefully, when you or others have other TAPUR-related trial results, perhaps they will again choose JCO PO as a destination for that work.  Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Guest Bio: Dr. Apar Kishor Ganti, MD, MS, is professor of medicine and Associate Director of Clinical Research, Fred & Pamela Buffett Cancer Center at the University of Nebraska Medical Center and Staff Physician at VA Nebraska Western Iowa Health Care System.   Guest COIs: Apar Kishor Ganti, MD, MS Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Flagship Biosciences, Cardinal Health, Sanofi Genzyme, Regeneron, Eisai Research Funding: Apexigen (Inst), NEKTAR Pharmaceuticals (Inst), TopAlliance BioSciences Inc (Inst), Novartis (Inst), Iovance (Inst), Mirati Therapeutics (Inst), Chimeric Therapeutics (Inst)  

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers: Dr. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

This week we discuss heart dedifferentiation and regeneration with Avraham Shakked @abingtonSA a final year PhD student, at the Weizmann Institute of Science, @WeizmannScience. We speak about their ingenious mouse model which uses transient and temporarily controlled ERBB2 expression which allows dedifferentiation and redifferentiation of cardiomyocytes. Using this model they examined the difference in RNA, protein and heart function in the redifferentiated the cells with and without heart injury. We also speak about preprints, publishing and alternative careers for scientists. Read the full preprint: https://www.biorxiv.org/content/10.1101/2022.02.22.481415v1.full This episode was produced by Emma Wilson and edited by John D Howard . If you enjoyed this show then hit that subscribe button and leave a review. If you love what we are trying to do then buy us a coffee https://www.buymeacoffee.com/preprints! For the latest podcast news and updates follow us on Twitter @MotionPod or visit our website; www.preprintsinmotion.com. Produced by JEmJ Productions (find us on Twitter: Jonny @JACoates, Emma @ELWilson92, John @JohnDHoward8) and generously supported by ASAPbio (https://asapbio.org | @asapbio_).

CME credits: 0.25 Valid until: 19-04-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-emerging-role-of-her2-erbb2-mutations-in-nsclc/13695/ HER2-targeted therapies have demonstrated substantial survival benefits for patients with HER2-positive breast cancer. So can we use those agents for HER2-positive NSCLC? Join Dr. Lyudmila Bazhenova and Dr. Benjamin Levy as they discuss the latest data around emerging agents for HER2-positive NSCLC and the best way to identify these mutations in clinical practice.

CME credits: 0.25 Valid until: 19-04-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-emerging-role-of-her2-erbb2-mutations-in-nsclc/13695/ Since the release of this activity, the FDA has approved the use of trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 HER2 (ERBB2) mutations, as determined by an FDA-approved test, for those who have received prior systemic therapy. Visit the FDA statement dated August 11, 2022 to learn more. HER2-targeted therapies have demonstrated substantial survival benefits for patients with HER2-positive breast cancer. So can we use those agents for HER2-positive NSCLC? Join Dr. Lyudmila Bazhenova and Dr. Benjamin Levy as they discuss the latest data around emerging agents for HER2-positive NSCLC and the best way to identify these mutations in clinical practice.

On this episode we hear from Thoracic Medical oncologist Dr. Thomas Stinchcombe. Dr. Stinchcombe is a member of Duke Cancer Institute, and Thoracic Oncology Program at Duke University in Durham, North Carolina. Dr. Stinchcombe explains whether or not they would recommend RET inhibitors as first line therapy for a RET-fusion positive metastatic Non-Small Cell Lung Cancer patient, what drugs are available to treat patients with Non-Small Lung Cancer and MET exon 14 skipping alterations, the significance of a metastatic Non-Small Cell Lung Cancer patient with a ERBB2 or HER2 alteration & whether there are specific mutations that are targetable for HER2. We conclude with a breakdown of the role of immune check point inhibitors in patients with resected Non-Small Cell Lung Cancer & the role of adjuvant therapy with atezolizumab. Visit www.precisca.com for more resources, content, and access to our entire catalogue of educational content. There you will have access to our complete library of educational videos. New episodes of the PrecisCa Oncology Podcast are released weekly. Please consider sharing our podcast, subscribing & turning on notifications to be the first to know about new releases. Together, we can raise the level of cancer care from diagnosis to recovery.

Nov 21The papers behind the pod:1. A non-human primate in vitro functional assay for the early evaluation of TB vaccine candidates. npj Vaccines, January 2021. https://doi.org/10.1038/s41541-020-00263-72. Inducible dominant negative ErbB2 rat spermatogonial line for generation of transgenic rat model and dissecting ERBB2 tyrosine kinase mediated pathways. Experimental Oncology, June 2019. https://doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-2.130263. Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response. Cancer Communications, September 2018. https://doi.org/10.1186/s40880-018-0329-5Visit the AAALAC website to learn more about this year's Global 3Rs Award winners: https://www.aaalac.org/awards/global-3rs-winners/It's the third Thursday of November, and you're listening to 3 Minute 3Rs, your monthly recap of efforts to replace, reduce and refine the use of animals in research. This month, we're celebrating our fourth birthday, and we're also celebrating this year's Global AAALAC/IQ Award winners. Three papers were recognized this year, by scientists in Europe, North America and the Pacific Rim. First let's hear about the European winner: Dr Rachel Tanner at the University of Oxford.Tuberculosis is a serious global health problem with rising cases and deaths, in part, due to the current vaccine being insufficient. To develop a new vaccine, non-human primates are necessary relevant animal model, but efforts to refine their use are needed. Recently, a team has developed an in vitro assay to refine and expedite early tuberculosis vaccine testing. This assay uses non-human primate blood or cell samples to measure the ability to control mycobacterial replication. Importantly, it allows vaccine candidates to be tested without infecting non-human primates with tuberculosis directly. Rather, blood samples can be taken before and after vaccination and tested in vitro to examine efficacy. This work is a promising 3Rs tool to facilitate early testing of new vaccine candidates.To learn more, read the full paper online. Next, let's move to North America and Dr Andrew Syvyk from Texas A&M University, who won the prize for work on a simpler way to generate transgenic animal models. Such models can be tailored to study specific genes, for example by introducing a gene construct into a zygote or embryonic stem cell, but this is a long process that requires numerous steps and manipulations, and therefore a lot of animals.In his winning paper, Syvyk describes a simpler approach using immature sperm cells, or spermatogonia. The model involves manipulating spermatogonial stem cells from a donor male, which are then transplanted into recipient males. These can be used to breed transgenic animals directly, eliminating mosaicism and reducing the number of animals required.The paper discusses using this approach to study ERBB2, a protein involved in multiple biological processes and forms of cancer. As well as being used to generate transgenic animals, the cells can be used for in vitro research, further reducing reliance on in vivo models for investigating molecular pathways.Want to learn more about the model? Find the paper in Experimental Oncology via the link in the description.And finally, the winner... See acast.com/privacy for privacy and opt-out information.

Featuring an interview with Dr Kathleen Moore, including the following topics: Optimal treatment duration of bevacizumab in combination with paclitaxel/carboplatin for advanced ovarian cancer (0:00) Phase III PAOLA-1 trial subgroup analysis: Progression-free survival outcomes by disease stage in patients with newly diagnosed, homologous recombination-deficient advanced ovarian cancer (4:44) Efficacy and safety results from the randomized Phase II NEOPEMBROV study assessing neoadjuvant chemotherapy with or without pembrolizumab for patients with advanced high-grade serous carcinoma not eligible for front-line debulking surgery (6:50) Combined analysis of Phase III studies assessing the efficacy and safety of niraparib in patients with ovarian cancer with BRCA mutations (11:28) Rucaparib versus chemotherapy for relapsed ovarian carcinoma with BRCA mutation in the platinum-sensitive subgroup of patients: Results from the Phase III ARIEL4 study (13:45) Clinical activity of olaparib combinations in patients with recurrent PARP inhibitor-resistant cancer: Results from the Phase II CAPRI and EFFORT trials (17:55) Efficacy of the combination of mirvetuximab soravtansine and bevacizumab for platinum-agnostic ovarian cancer (25:34) Results from the Phase III OUTBACK trial comparing adjuvant chemotherapy after chemoradiation therapy to chemoradiation therapy alone for locally advanced cervical cancer (27:55) Clinical data with immunotherapeutic agents for cervical cancer; ongoing Phase III innovaTV 301 study assessing tisotumab vedotin versus chemotherapy for recurrent metastatic cervical cancer (31:14) Role of surveillance in the management of endometrial cancer: Results from the TOTEM study (34:51) Antitumor activity of dostarlimab alone or in combination with a PARP inhibitor for recurrent endometrial carcinoma (36:51) Comparison of health-related quality of life with lenvatinib/pembrolizumab versus chemotherapy for patients with advanced endometrial cancer (39:48) Biomarkers of response to immune checkpoint inhibitors; Results from the TAPUR study of dual HER2-targeted therapy for patients with uterine cancer and ERBB2 or ERBB3 abnormalities (41:17) CME information and select publications

Interview with Thomas Hatschek, MD, PhD, author of Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial

Interview with Thomas Hatschek, MD, PhD, author of Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial

Pek Lum, co-founder, and CEO of Auransa believes that a lot fewer drugs would fail in Phase 2 clinical trials if they were tested on patients predisposed to respond. The problem is finding the sub-populations of likely high-responders in advance and matching them up with promising drug compounds. That’s Auransa's specialty.The Palo Alto, CA-based drug discovery startup, formerly known as Capella Biosciences, has a pipeline of novel compounds for treating cancer and other conditions identified through machine learning analysis of genomic data and other kinds of data. It’s closest to the clinical trial stage with a DNA-binding drug for liver cancer (AU-409) and is also working on drugs for prostate cancer and for protecting the heart against chemotherapy drugs. The company says it discovered AU-409 as part of a broad evaluation of data sets on a range of close to 30 diseases. The company’s discovery process uses a platform called the SMarTR Engine that uses hypothesis-free machine learning to identify druggable targets and compounds as well as likely high-responder patients. Lum  calls it “interrogating gene expression profiles to identify patient sub-populations.” The company believes this approach can identify unexpected connections between diverse molecular pathways to disease, and that it will lead to progress in drug development for intractable conditions with poorly understood biology, including cancer and autoimmune, metabolic, infectious, and neurological diseases.Lum co-founded Auransa with Viwat Visuthikraisee in 2014 and is the chief architect behind its technology. Before Auransa, she was VP of Product, VP of Solutions, and Chief Data Scientist at Ayasdi (now SymphonyAyasdiAI), a Stanford spinout known for building hypothesis-free machine learning models to detect patterns in business data. Before that, she spent 10 years as a scientific director at Rosetta Inpharmatics, a microarray and genomics company that was acquired by Merck. She has bachelor's and master's of science degrees in biochemistry from Hokkaido University in Japan and a Ph.D. in molecular biology from the University of Washington, where she studied yeast genetics.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:• Launch the “Podcasts” app on your device. If you can’t find this app, swipe all the way to the left on your home screen until you’re on the Search page. Tap the search field at the top and type in “Podcasts.” Apple’s Podcasts app should show up in the search results.• Tap the Podcasts app icon, and after it opens, tap the Search field at the top, or the little magnifying glass icon in the lower right corner.• Type MoneyBall Medicine into the search field and press the Search button.• In the search results, click on the MoneyBall Medicine logo.• On the next page, scroll down until you see the Ratings & Reviews section. Below that, you’ll see five purple stars.• Tap the stars to rate the show.• Scroll down a little farther. You’ll see a purple link saying “Write a Review.”• On the next screen, you’ll see the stars again. You can tap them to leave a rating if you haven’t already.• In the Title field, type a summary for your review.• In the Review field, type your review.• When you’re finished, click Send.• That’s it, you’re done. Thanks!TRANSCRIPTHarry Glorikian: I’m Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market. If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.For every drug candidate that makes it all the way through the three phases of clinical trials to win FDA approval, there are about 20 others that fail along the way. Phase 2, where drug makers have to prove that a new drug is safer or more effective than existing treatments, is where a lot of drugs falter.But often, it’s not because the drugs don’t work. Sometimes it’s just because they weren’t tested on the right patients. Meaning, the people in the treatment group didn’t happen have the right genes or gene expression profiles to respond. If you could find enough patients who were likely high-responders and try your new drug just on them, your chances of approval might go way up. The tough part is identifying those subpopulations in advance and matching them up with promising drug compounds.That’s where a company like Auransa comes in. It’s a Palo Alto startup that has built an AI platform called the SMarTR Engine. The engine uses public datasets on gene expression to identify subtypes of molecular diseases and predict what kinds of compounds might work against specific subtypes. Auransa used the engine to discover a drug for liver cancer that’s about to enter clinical trials. And it’s licensing out other drugs it discovered for prostate cancer and for protecting the heart against the effects of cancer chemotherapy.Some of the ideas baked into the SMarTR Engine come from a sub-field of artificial intelligence called hypothesis-free machine learning. And joining us this week to explain exactly what that means is our guest Pek Lum. She’s a biochemist and molecular biologist who worked at the microarray maker Rosetta Inpharmatics and the software company Ayasdi before founding Auransa in 2014. And she says one of the real revolutions in drug development is that almost every disease can be divided up into molecular subtypes that can best be treated using targeted drugs.Harry Glorikian: Pek, welcome to the show.Pek Lum: Thank you. Pleasure to be here.Harry Glorikian: You know, I always try to ask this opening question when I start the show to give the listeners a good idea of of what your company does. But you guys are in in drug discovery. What tell us how people understand what is the basic approach that you guys have. And I'll get into the special sauce later. But what do you guys do in the drug discovery space?Pek Lum: No, that's a really great question in the sense that when we first started in about five years ago, we... I've always been in the drug discovery field in the sense that I worked for over 20 years ago at that time in a company called Rosetta Inpharmatics, which is really pushing the cutting edge of thinking about using molecular data. Right. And to solve the mysteries of biology. And I was extremely lucky to be one of the core members in when we were very small. And then that really kind of put me in the sense put me in the stage where I could think about more than just one gene. Right. Because the technology was just kind of getting really kind of I would say not rolling forward, like propelling forward, with microarrays.Harry Glorikian: Yes.Pek Lum: So I was part of the whole movement and it was really amazing to be kind of like, you know, in the show as it runs, so to speak. And so and then Merck bought us after we went public and worked for Merck and Co. for another eight years, really learning how technology, how we should apply technology, how we can apply technology, molecular data, RNA data, DNA data to a drug discovery pipeline. And really kind of figured out that there are many things that the pharmaceutical world does very well, but there are many things that it also fails in and that how can we do it better? So I've always been in the mindset of, when starting Auransa with my co-founder, How do we do it better? And not only just do it better, but do it very differently so that we can address the most, I would say critical problems. So Auransa is really a company started by us to address the problem of why drugs actually fail a lot when we go into a Phase II efficacy trial. Right. Is not like the drug is bad or toxic. And most of the time is you can find enough responders to make your clinical trial a success.Pek Lum: And that cause, I guess, drugs actually made to maybe against one target. You don't really think about the biology that much at the beginning or the biology responders. So Auransa was really created to think about first, the heterogeneity of the disease and the heterogeneity of patient response. So we start from looking at molecular data of the disease from the get go. We take RNA, is really the RNA world is coming back with the vaccines.Harry Glorikian: Right.Pek Lum: And the RNA has always been fascinating because it tells you about the activity of the cell, of a normal cell versus a disease cell. So we use RNA transcriptomes right, transcriptomics to study the biology and the heterogeneity. So our algorithms, there are many algorithms, one of the first algorithms of the engine is really to look at the biology of heterogeneity, whether we can subdivide a disease into more homogeneous categories before doing anything.Harry Glorikian: Right. Yeah, I remember when, because when I was at Applied Biosystems, I remember Applied Biosystems, Affymetrix and then Stephen Friend starting this and like, you know, it was all starting back then. And I want to say we sort of had an idea of what we were doing, but compared to now, it's like, wow, how naive we were back then compared to how much this whole space has evolved. And it's interesting you mention, you know, RNA and its activity because in a couple of weeks, I'm actually going to be talking to a spatial genomics company so that you get a better idea from a visual standpoint of which cells are actually activating and which aren't.Harry Glorikian: But so, you've got an interesting professional career, and I say that because you were working at a big data analytics company for a while that was utilizing an approach that was hypothesis-free machine learning, where the machine was sort of identifying unique or aspects that you should be paying attention to. Maybe that it was seeing that instead of you going in there saying, let's just look over here, you could see what the machine was seeing for you. How much can you tell us a little bit about that experience? And then how did that influence what you're doing now? Because I have to believe that they superimpose at some level.Pek Lum: Right. I think, you know, ever since my first job at Rosetta and then my subsequent jobs really kind of culminated into this into this tech, as you see today. Right. All this experience and certainly experience while being a founding member of a small team at that time of Ayasdi, which is the software company, has been also an eye-opening experience for me because we were trying to create, using a very old mathematical idea called topology, or TDA, really start to figure out whether there's maybe there's some things that can't be learned. Right. And so typical machine learning methods need a training set or a test. But there are just some things where you don't really know what the ground truth is. So how do you do that? So that's the idea of like I say, the hypothesis-free approach. And the approach that that that the tech company, the software company that we built is really around the idea that not everything can be learned. But you can actually adapt some very interesting ideas around a hypothesis-free approach and then use it in a machine learning AI framework. So I definitely have been influenced by that thinking, you know, as I as we built the software.Harry Glorikian: Right.Pek Lum: And also, when we were Rosetta, we were generating in parallel, data on thousands of genes. And often at that time we were called, "Oh, you're just going fishing," you know, but fishing is not a bad idea because you don't really know which part of the ocean you need to go to catch your Blue Marlin, for example, right?Harry Glorikian: Yeah, no, no, absolutely.Pek Lum: Fish a little bit, not the whole ocean, but, you know, to get some, I would say, boundaries. Right. So in that sense, to me, a hypothesis-free approach gives you the boundaries where you can look. So, you know, so the experience, definitely the idea that you can use methods or thinking, algorithms, that could help you in a field where you do not know the ground truth. Like patient heterogeneity, I would say nobody really can pinpoint and say, OK, I can say that, oh, this is THE subtype, these are THE markers. And therefore, I'm going to go after this. And there are many. I guess, for example, you can think of a Herceptin as a great example, right, but when you first started, you know, it was like, wow, OK, you're going to go after a target. And then the idea of really kind of subtyping breast cancer, you know, I don't know, 20, 30 years ago. Right. And we're still learning about, you know, in a patient heterogeneity and we're just beginning to scratch the surface. So for Auransa, we wanted to use a method very much like the thinking that and the idea that we had, you know, when we were when I was at Ayasdi, is that you could search with some parameters, you know, a very complex space without needing to say, this is my hypothesis. This is that one gene, because we all know that if you have a target, you know ... to have to respond you need the target. But if you have the target, it doesn't mean you're going to respond. Because things below the target or above the target are much more complex than that.Harry Glorikian: Correct. And I always feel that there's, you know, I always call them low hanging fruit. Like the first one is, OK, well, it's either luck or skill, but I got to one level. But then you start to see people that are not responding. So that means something else is going on and there's subtypes. Right. So it's funny how we always also call it "rare diseases" in these smaller population. I'm pretty convinced that at some point everything is going to be a rare disease. Right. Because of the subtypes that we're going to start to see. I mean, even we're seeing in a neurological now, or Alzheimer's. There's subtypes of Alzheimer’s. No! Really? Shocking. Amazing to me that there's subtypes. Right. We've been dealing with this for ages. And I do believe that these technologies are so good at highlighting something where a human might not have seen it, might not have understood it. You know, I was I was interviewing actually I just posted it today on imaging and agriculture. And they were saying that sometimes the machine sees things that we don't fully understand how it sees it, but it sees it and points it out, which allows us now to dig into it and be able to sort of identify what that unique feature is that the machine has pulled out. I'm not sure I want drug discovery and drugs being based on something we don't fully understand, but the machine highlighting something for us that then we can go dig into, I think is an interesting greenfield space that that we need to explore more.Pek Lum: Right. I think you're absolutely right. You know, when we first started Auransa, that was the idea that we had. And then my co-founder and I thought, what if we find like hundreds of subtypes? We're never going to be able to make a drug again a hundred subtypes. So let's hope we find a small enough number of buckets that we can say this is approximately what it looks like, to be able to be practical to find drugs against those subtypes. So when we talk about subtypes, we are talking about you're absolutely right, it's like a leaf on a tree and that we have to cut it off at one point. Enough that things that, OK, this is homogeneous enough that actually makes sense out of it. And that's where the engine, that's what the engine does. Basically, it takes data, very, very complex data, things that we could never figure that out ourselves and say this approximately five, six buckets. So we've actually not found hundreds of subtypes, otherwise we probably would not have started Auransan, because it would have been impossible. But instead, we find n of one, but maybe a five to seven subtypes at most. That is enough for us to say, the machine says, OK, it is homogeneous enough, go for this. So that's kind of where we are, where we start at Auransa. And I think that's an important concept because people often thought about precision medicine as being, oh, I'm going to make a medicine for you and you only. But actually you could learn from, say, breast cancer, and that's approximately people with estrogen-receptor-positive tumors. And then you will likely respond to a drug like Tamoxifen. And even though we know that the response rate is only about, I think maybe 30, 40 percent. Right. But that's really good. At least at this poibt. So that's where we how we think about the engine as a shining light on a homogeneous enough population that we can actually make a drug against that.Harry Glorikian: Yeah. So that sort of leads us into you have this technology that you've termed SMarTR, S-M-A-R-T-R engine. Right. What does that stand for?Pek Lum: You know, that's my one of my rare occasion where I put my marketing hat on. I don't like marketing all. And we so and you notice the Mar is big-M, little-a-r. So S is for Subpopulation. Markers. Targets. And Redefining. Because I needed it to be Smartr.Harry Glorikian: Ok, ok. So and when you like when you've described this in the papers that I've looked at it, it's a machine learning mathematical statistical approaches, highly automated and totally runs in the cloud. So can you give us a little more color on the sort of the highly automated, and why is that so important?Pek Lum: Right. It's important because it comes from my own experience of working with, like, amazingly talented implementations and data scientist at the at Merck or I know how it goes where biologists will often ask them for something and they would run their magic and they'd give us an Excel sheet or a PowerPoint. Right. It's always a one-off one of those and one of that because you know, biologists are kind of one-off. So the idea of of us building this engine is not just equipping it with algorithms. So first of all, we don't have one algorithm, a hammer looking for a nail. We have a problem to solve. The problem is how to find novel drugs, drugs that people have never thought about, for patient populations that will respond.Pek Lum: So with that in mind, we built a pipeline of algorithms that starting from thinking about heterogeneity, to understanding preclinical models that reflect the biology of human subtypes, to predicting drugs and targets for those, and getting biomarkers for the patients when we go to the clinic. And we have different algorithms for each step of the pathway. So instead of having my team do a one-off thing, we know that if we don't do good software engineering it's going to be problematic because first it's going to take a really long time. This will be kind of higgledy piggledy in Excel sheets and we might be able to solve one thing. But to do this as a platform and as a pipeline builder, it would be impossible without good engineering practices. So we wanted to put this in, like I say, in a framework where everything is connected, so where it gets to run faster and faster through better algorithms, through better software engineering. And this really kind of came from my experience to at Ayasdi, a software engineering, a software firm. And also my co-founder who is a physicist and a software engineer, that we need to have good software practices. So what we did was we built first. We don't want any servers. Everything is done on AWS and is done in modules. So we create algorithms for each part of the pipeline, of the in silico pipeline. And then we have in such a way that when we take data in, when we ingest data, that we also automate it, and then by the time it ingest data and it spits out, I would say, what subtypes of disease, what biomarkers could be used in the clinic, what targets are interesting to you, what compounds from our digital library of compounds may be effective for that. Everything is more or less connected and could be done up in the cloud and now it finishes in about 24 hours.Harry Glorikian: When do humans look at it to say hmmm, makes sense. Or maybe we need to tweak the model a little. Right. Because it's not making sense. When does that happen?Pek Lum: So we, it happens at several steps. So within our engine we actually have benchmarks in there that we run periodically. You know, for example we have about about eight to ten data sets that we have for breast cancer, thousands of patient tumors. And we know approximately that it should be discovering, and it has discovered ER+ flavored subtypes, ERBB2, HER2+ subtypes, triple negative subtypes. So that is kind of like the rails that we put into our engine as well to make sure that when we actually do tweak an algorithm, it still has its wheels. But what we do is at this point, we generate out all the in-between data, but it's kept on the cloud. And once it's up, when it outputs the the list of things, the biologists actually, I would say the biologists with a knack for computation, we look at it and I myself look at it. I love to do data analysis in my spare time when I'm not doing CEO stuff. And we can see that we will look at once it's done that it also allows you...Ok, so this is an interesting one. The engine on the cloud outputs all of this. And right now, let's say my CSO, who is not a computational person, or me, or whoever really would be kind of a big pain to kind of go up and install the stuff and look at the things, some things you can't see. So what we did as a company is to build another kind of software, which is the visualization software on top of that.Pek Lum: So we have on our other end a visualization software that we call Polo because it's exploring that basically connects everything the SMarTR engine has done into something that's visualizable. It has a URL, we go to it and let's say, for example, my CSO wants to know, OK, the last one you did on head and neck cancer, you know, how many subtypes did you find? What is the biology, what's the pathway? And it could do all of that by him just going then looking at things. Or he can actually type in his favorite gene and then see what the favorite gene actually is predicted for how it behaves across over 30 diseases, and you can do that all at his fingertips, so we have that part of the engine as well, which is not the engine. We call it Polo, which is our visualization platform.Harry Glorikian: Right. It's funny because one of the first times I interviewed Berg Pharma and they were talking about their system, I was like, if you put on a pair of VR glasses, could you see the interconnectivity and be able to look in a spatial.... I was on another planet at the time, but it was a lot of fun sort of thinking about how you could visualize how these things interact to make it easy. Because human beings I mean, you see a picture. Somehow we're able to process a picture a lot faster than all this individual data. I think it... I just slow down. I rather look at a visual if it's possible.Pek Lum: It is so important because, you know, even though the engine is extremely powerful now, takes it 24 hours to finish from data input to kind of spitting out this information that we need. Visualization and also like the interpretation and just kind of making sure kind of like the human intelligence. Can I keep an eye on things. The visualization platform is so, so important. That's why I feel like that we did the right thing in making and taking time, putting a bit of resources to make this visualization platform for our preclinical team who actually then needs to look at it and go, OK, these are the drugs that are that are predicted by the engine. Can we actually have an analog of it or does it have development legs? Does it make sense? Does the biology makes sense. And so now we're basically connected everything. So you can click on a, you can find a drug in a database and it will pop up, you know, the structure and then it will tell you, hey, this one has a furan ring. So maybe you might want to be careful about that. This one has a reactive oxygen moiety. You might want to be careful about that. As we grew the visualization platform, we got feedback from the users. So we put more and more things in there, such that now it has a little visualization module that you can go to. And if you ever want to know something, I can just, I don't have to email my data scientist at 1:00 am in the morning saying, hey, can you send me that Excel sheet that has that that particular thing on it that I want to know from two weeks ago? I can just go to Auransa's Polo, right? As long as I have wi-fi. Right. And be able to be self-sufficient and look at things and then ask them questions if things look weird or, you know, talk to my CEO and say, hey, look at this. This is actually pretty interesting. And this one gets accessed by anybody in Auransa as long as you have Wi-Fi.Harry Glorikian: So so it's software development and drug development at the same time. Right. It's interesting because I always think to myself, if we ever, like, went back and thought about how to redo pharma, you'd probably tear apart the existing big pharma. Other than maybe the marketing group, right, marketing and sales group, you tear apart the rest of it and build it completely differently from the ground up? It was funny, I was talking to someone yesterday at a financial firm, a good friend of mine, and it's her new job and she's like, my job is to fully automate the back to the back end and the middle and go from 200 people down to 30 people because we're fully automating it. I'm like, well, that sounds really cool. I'm not really thrilled about losing the other 170 people. But with today's technology, you can make some of these processes much more automated and efficient. So where do you get your data sets that you feed your programs?Pek Lum: Yeah, let me tell you this. We are asked this a lot of times. And just kind of coming back again for my background as an RNA person. Right. One thing that I think NIH and CBI did really well over 20 years ago is to say, guys, now we no longer doing a one gene thing. We have microarrays and we're going to have sequencing. There's going to be a ton of data. We need to start a national database. Right. And it will enable, for anybody that publishes, to put the data into a coherent place. And even with big projects like TCGA, they need things that could be accessed. Right. So I think it is really cool that we have this kind of, I would say, repository. That unfortunately is not used by a lot of people because, you know, everything goes in. That's a ton of heterogeneity. So when we first started the company, before we even started the company, we thought about, OK, where is it that we can get data? We could spend billions of dollars generating data on cells, pristine data, but then it would never represent what's in the clinical trials without what's out there in the human the human world, which is the wild, wild west. Right. Heterogeneity is abundant. So we thought, aha, a repository like, you know, like GEO, the Gene Expression Omnibus, right, and ANBO or TCGA allows this kind of heterogeneity to come in and allows us the opportunity to actually use the algorithms which actually have algorithms that we look for. We actually use to look for heterogeneity and put them into homogeneity. These kind of data sets. So we love the public data sets. So because it's free, is generated by a ton of money. It is just sitting there and it's got heterogeneity like nobody's business. Like you could find a cohort of patients that came from India, a cohort of patients that came from North Carolina, and group of patients that came from Singapore and from different places in the US and different platforms. So because the algorithms at first that studied heterogeneity is actually, I would say, platform independent, platform agnostic, we don't use things that are done 20 years ago. They were done yesterday. And what we do is we look at each one of them individually and then we look for recurrent biological signals. So that's the idea behind looking for true signals, because people always say, you go fishing, you may be getting junk out. Right?Pek Lum: So let's say, for example, we go to, the engine points to a spot in the sea, in the ocean, and five people go, then you're always fishing out the same thing, the Blue Marlin, then you know that there is something there. So what we do is we take each data set, runs it through an engine and say these are the subtypes that I find. It does the same thing again in another data set and say these are the things that I find. And then it looks for recurrence signals, which is if you are a artifact that came from this one lab over here, or some kind of something that is unique to this other code over there, you can never find it to be recurrent. And that's a very weird, systematic bias, you know, so so because of that, we are able to then very quickly, I would say, get the wheat and throw away the chaff. Right. And basically by just looking by the engine, looking at looking for recurring signals. So public data sets is like a a treasure trove for Auransa because we can use it.Harry Glorikian: So you guys use your engine to I think you identified something unexpected, a correlation between plant-derived flavonoid compound and the heart. I think it was, you found that it helps mitigate toxic effects in a chemotherapy drug, you know. Can you say more about how the system figured that out, because that sounds not necessarily like a brand-new opportunity, but identifying something that works in a different way than what we thought originally.Pek Lum: Right, exactly. So in our digital library, let me explain a little bit about that. We have collected probably close to half a million gene expression profiles. So it's all RNA gene expression based, representing about 22,000 unique compounds. And these are things that we might generate ourselves or they are in the public domain. So any compound that has seen a live cell is fair game to our algorithms. So basically you put a compound, could be Merck's compound, could be a tool compound, could be a natural compound, could be a compound from somewhere. And it's put on a cell and gene expression was captured. And those are the profiles or the signatures that we gather. And then the idea is that, because remember, we have this part of the engine where we say we're going to take the biology and study it and then we're going to match it or we're going to look for compounds or targets. When you knock it down, who's gene expression actually goes the opposite way of the the disease. Now, this is a concept that is not new, right. In the sense that over 20 years ago, I think Rosetta probably was one of the first companies that say, look, if you have a compound that affects the living cell and it affects biology in a way that is the opposite of your disease, it's a good thing. Right thing. So that's the concept. But, you know, the idea then is to do this in such a way that you don't have to test thousands of compounds.Harry Glorikian: Right.Pek Lum: That is accurate enough for you to test a handful. And that's what we do. And by putting the heterogeneity concept together with this is something extremely novel and extremely important for the engine. And so with this kind of toxicity is actually an interesting story. We have a bunch of friends who are spun off a company from Stanford and they were building cardiomyocytes from IPS cells to print stem cells. And they wanted to do work with us, saying that why do we work together on a cool project? We were just starting out together and we thought about this project where it is a highly unmet medical need, even though chemotherapy works extremely well. Anthracyclines, it actually takes heart, takes a toll. There is toxicity and is it's a known fact. And there's only one drug in the market and a very old drug in the market today. And there is not much attention paid to this very critical aspect. So we thought we can marry the engine. At that time were starting up with oncology. We still we still are in oncology, and they were in cardiomyocytes. So we decided to tackle this extremely difficult biology where we say, what is a how does chemotherapy affect heart cells and what does the toxicity look like? So the engine took all kinds of data sets, heart failure data sets, its key stroke and cells that's been treated with anthracyclines. So a ton of data and look for homogeneity and signals of the of the toxicity.Pek Lum: So this is a little bit different from the disease biology, but it is studying toxicity. And we then ask the engine to find compounds that we have in our digital library, that says that what is the, I would say the biology of these compounds when they hit a living cell that goes the opposite way of the toxicity. And that's how we found, actually we gave the company probably about seven, I forget, maybe seven to 10 compounds to test. The one thing that's really great about our engine is that you don't have to test thousands of compounds and it's not a screen because you screened it in silico. And then it would choose a small number of compounds, usually not usually fewer than 30. And then we able to test and get at least a handful of those that are worth looking into and have what they call development legs. So this I would say this IPSC cardiomyocyte system is actually quite complex. You can imagine that to screen a drug that protects against, say, doxorubicin is going to be a pretty complicated screen that can probably very, very hard to do in a high throughput screen because you have to hit it with docs and then you have to hit it with the compounds you want to test and see whether it protects against a readout that is quite complex, like the beating heart.Pek Lum: And so we give them about, I think, seven to 10 and actually four of them came out to be positive. Pretty amazing. Out of the four, one of them, the engine, noticed that it belonged to a family of other compounds that looked like it. So so that was really another hint for the the developers to say, oh, the developers I mean, drug developers to say, this is interesting. So we tested then a whole bunch of compounds that look like it. And then one of them became the lead compound that we actually licensed to a a pharma company in China to develop it for the Chinese market first. We still have the worldwide rights to that. So that's how we tackled toxicity. And I think you might have read about another project with Genentech, actually, Roche. We have a poster together. And that is also the same idea, that if you can do that for cardio tox, perhaps you can do it for other kinds of toxicity. And one of them is actually GI tox, which is a very common toxicity. Some of them are rate limiting, you might have to pull a drug from clinical trials because there's too much GI tox or it could be rate limiting to that. So we are tackling the idea that you can use to use machine, our engine, to create drugs for an adjuvant for a disease, a life-saving drug that otherwise could not be used properly, for example. So that's kind of one way that we have to use the engine just starting from this little project that we did with the spin out, basically.Pek Lum: So basically, you're sort of, the engine is going in two directions. One is to identify new things, but one is to, I dare say, repurpose something for something that wasn't expected or wasn't known.Pek Lum: That is right. Because it doesn't really know. It doesn't read papers and know is it's a repurposed drug or something. You just put in it basically, you know, the gene expression profiles or patterns of all kinds of drugs. And then from there, as a company, we decided on two things. We want to be practical, right. And then we want to find novel things, things that, and it doesn't matter where that comes from, as long as the drug could be used to do something novel or something that nobody has ever thought of or it could help save lives, we go for it. However, you know, we could find something. We were lucky to find something like this flavanol that has never been in humans before. So it still qualifies as an NCE, actually, and because it's just a natural compound. So so in that sense, I would say maybe is not repurposing, but it's repositioning. I don't know from it being a natural compound to being something maybe useful for heart protection. Pek Lum: Now for our liver cancer compound, it is a total, totally brand-new compound. The initial compound that the engine found is actually a very, very old drug. But it was just a completely different thing and definitely not suitable for cancer patients the way it is delivered.Harry Glorikian: This is the AU 409?Pek Lum: Correct? Entirely new entity. New composition of matter. But the engine gave us the first lead, the first hit, and told us that we analyzed over a thousand liver tumors and probably over a thousand normal controls, found actually three subtypes, two of them the main subtypes and very interesting biology. And the engine predicted this compound that it thinks will work on both big subtypes. We thought this is interesting. But we look at the compound. You know, it's been in humans. It's been used. It's an old drug. But it could never be given to a cancer patient. And so and so our team, our preclinical development team basically took that and say, can we actually make this into a cancer drug? So we evaluated that and thought, yes, we can. So we can basically, we analogged it. It becomes a new chemical. Now it's water-soluble. We want to be given as a pill once a day for liver cancer patients. So so that's how we kind of, as each of the drug programs move forward, we make a decision, the humans make a decision, after the leadds us to that and say can we make it into a drug that can be given to patients?Harry Glorikian: So where does that program stand now? I mean, where is it in its process or its in its lifecycle?Pek Lum: Yeah, it's actually we are GMP manufacturing right now. It's already gone through a pre-IND meeting, so it's very exciting for us and it's got a superior toxicity profile. We think it's very well tolerated, let's put it that way. It could be very well tolerated. And it's it's at the the stage where we are in the GMP manufacturing phase, thinking about how to make that product and so on.Harry Glorikian: So that that begs the question of do you see the company as a standalone pharma company? Do you see it as a drug discovery partner that that works with somebody else? I'm you know, it's interesting because I've talked to other groups and they start out one place and then they they migrate someplace else. Right. Because they want the bigger opportunities. And so I'm wondering where you guys are.Pek Lum: Yeah, we've always wanted to be, I say we describe ourselves as a technology company, deep tech company with the killer app. And the killer app is drug discovery and development especially. And we've always thought about our company as a platform company, and we were never shy about partnering with others from the get go. So with our O18 our team, which is a cardioprotection drug, we out-licensed that really early, and it's found a home and now is being developed. And then we moved on to our liver cancer product, which we brought a little bit further. Now it's in GMP manufacturing. And we're actually looking for partners for that. And we have a prostate cancer compound in lead optimization that will probably pan out as well. So we see ourselves as being partners. Either we co-develop, or we out-license it and maybe one day, hopefully not too far in the future, we might bring one or two of our favorite ones into later stage clinical trials. But we are not shy about partnering at different stages. So we are going to be opportunistic because we really have a lot to offer. And also one thing that we've been talking to other partners, entrepreneurs, is that using our engine to form actually other companies, to really make sure the engine gets used and properly leveraged for other things that Auransa may not do because we just can't do everything.Harry Glorikian: No, that's impossible. And the conversation I have with entrepreneurs all the time, yes, I know you can do it all, but can we just pick one thing and get it across the finish line? And it also dramatically changes valuation, being able to get what I have people that tell me, you know, one of these days I have to see one of these A.I. systems get something out. And I always tell them, like, if you wait that long, you'll be too late.Harry Glorikian: So here's an interesting question, though. And jumping back to almost the beginning. The company was named Capella. And you change the name to Auransa.Pek Lum: That's right.Harry Glorikian: And so what's the story behind that? Gosh, you know.Harry Glorikian: When somebody woke up one morning and said, I don't like that name.Pek Lum: It's actually pretty funny. So we so we like to go to the Palo Alto foothills and watch the stars with the kids. And then one day we saw Capella. From afar, you look at it, it's actually one star. You look at closer, it's two stars. Then closer, it's four stars. It's pretty remarkable. And I thought, OK, we should name it Capella Biosciences. Thinking we are the only ones on the planet that are named. So we got Capella Biosciences and then probably, we never actually had a website yet. So we were just kind of chugging along early days and then we realized that there was a Capella Bioscience across the pond in the U.K. We said what? How can somebody be named Capella Bioscience without an S? So I actually called up the company and said, “Hey, we are like your twin across the pond. We're doing something a little different, actually completely different. But you are Capella Bioscience and I am Capella Biosciences. What should we do?” And they're like, “Well, we like the name.” We're like, “Well, we like it too.” So we kind of waited for a while. And but in the meantime, I started to think about a new name in case we need to change it. And then we realized that one day we were trying to buy a table, one of those cool tables that you can use as a ping pong table that also doubles as a as a conference room table. So we called up this New York City company and they said, oh, yeah, when are you going to launch the rockets into space. We're like what? So apparently, there's a Capella Space.Harry Glorikian: Yeah, OK.Pek Lum: Well, that's the last straw, because we get people tweeting about using our Twitter handle for something else. And so it's just a mess. So we've been thinking about this other name, and I thought this is a good name. Au means gold. And ansa is actually Latin for opportunity, which we found out. So we're like oh, golden opportunity. Golden answer. That kind of fits into the platform idea. Auransa sounds feminine. I like it. I'm female CEO. And I can get auransa.com. Nobody has Auransa. So that is how Auransa came to be.Harry Glorikian: Well, you got to love the…I love the Latin dictionary when I'm going through there and when I'm looking for names for a company, I've done that a number of times, so. Well, I can only wish you incredible success in your journey and what you're doing, it's such a fascinating area. I mean, I always have this dream that one day everybody is going to share all this data and we're going to move even faster. But I'm not holding my breath on that one when it comes to private companies. But it was great to talk to you. And I hope that we can continue the conversation in the future and watch the watch the progression of the company.Pek Lum: Thank you, Harry. This has been really fun.Harry Glorikian: That’s it for this week’s show. We’ve made more than 50 episodes of MoneyBall Medicine, and you can find all of them at glorikian.com under the tab “Podcast.” You can follow me on Twitter at hglorikian. If you like the show, please do us a favor and leave a rating and review at Apple Podcasts. Thanks, and we’ll be back soon with our next interview.  

Dr. Millie Das discusses treatment options for patients with advanced non small cell lung cancer and a HER2-ERBB2 mutation.

Dr Cristina Sánchez, Vice Dean of Research at the School of Biology at the Complutense University in Madrid, is a world renowned molecular biologist specialising in the study of compounds in the cannabis plant as anticancer agents in breast cancer. Cristina has been involved in researching the antitumoral properties of cannabinoids for over twenty years, and played a key role in discovering how THC kills cancer cells while working alongside colleague Professor Manuel Guzmán.These days, while many research groups around the world focussing on isolated or synthetic cannabinoids as potential anticancer drugs, Cristina's group stands out as trying to understand and replicate the experiences of actual patients who are reporting extraordinary results using whole plant cannabis for their cancer.In her paper, 'Appraising the ''entourage effect'': Antitumor action of pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer,' Sánchez found that in mice at least and across all types of breast cancer, a whole plant cannabis extract was more efficacious and potent than THC alone. As Cristina says: "This is not a hippie fashion or energy from the plant. No, this is science. This is molecules activating and deactivating. So the same thing as for opioids or for any of the drugs that they use."Resources:Appraising the "entourage effect": Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancerCannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibitionTherapeutic targeting of HER2-CB 2 R heteromers in HER2-positive breast cancer Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancerTargeting CB2-GPR55 receptor heteromers modulates cancer cell signalingSupport the show (https://www.paypal.com/paypalme/marybiles71)

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.20.344556v1?rss=1 Authors: Osmak, G., Kiselev, I., Baulina, N., Favorova, O. Abstract: MicroRNAs (miRNAs) are short single-stranded non-coding RNA molecules, which are involved in regulation of main biological processes, such as apoptosis, cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases and data on its function in myocardium are mostly unclear. We identified PIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, and CDC42 as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signalling pathways. We implemented our algorithm for miRNA function prediction into Python module, which is available at GitHub (https://github.com/GJOsmak/miRNET). Copy rights belong to original authors. Visit the link for more info

Proceedings from the second in a 3-part webinar series. Featuring perspectives from Drs Alexander E Drilon, Andrew McKenzie and Milan Radovich, including on the following topics: Part 1: Case Presentations Introduction (00:00) Case: A woman in her early 70s with metastatic adenocarcinoma of the lung (ERBB2, PALB2) — Milan Radovich, PhD (2:50) Case: A man in his mid-70s with metastatic adenocarcinoma of the lung (BRAF V600E) — Andrew McKenzie, PhD (8:55) Case: A woman in her mid-70s with metastatic NSCLC (EGFR exon 19 insertion) — Sulfi Ibrahim, MD (12:38) Case: A man in his mid-60s with recurrent SCCHN (TMB 215 mut/Mb) — Dr Radovich (16:52) Case: A man in his early 60s with metastatic adenocarcinoma of the lung (STK11, BRCA) — Dr Ibrahim (20:55) Case: A woman in her early 30s with metastatic adenocarcinoma of the lung (EML4-RET fusion) — Alexander E Drilon, MD (25:52) Part 2: Beyond EGFR, BRAF and ALK — Actionable Biomarkers in NSCLC Faculty Presentation — Dr Drilon (27:49) Part 3: Case Presentations Case: A woman in her mid-60s with metastatic adenocarcinoma of the lung (RET fusion) — Dr McKenzie (40:15) Case: A man in his late 50s with metastatic adenocarcinoma of the lung (RET fusion) — Dr Ibrahim (44:59) Case: A man in his late 60s with metastatic pancreatic cancer (ERC1/RET fusion) — Dr Radovich (48:02) Case: A woman in her mid-70s with metastatic adenocarcinoma of the lung (EPS15-NTRK1) — Dr Drilon (50:28) Case: A man in his early 80s with metastatic adenocarcinoma of the lung (MET exon 14) — Dr McKenzie (52:14) Case: A woman in her mid-80s with Stage IIIB NSCLC (MET exon 14 skipping mutation) — Dr Ibrahim (55:43) Case: A man in his early 70s with metastatic NSCLC (MET exon 14 splice site mutation) — Dr Radovich (58:41) CME information and select publications

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Go online to PeerView.com/VJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, oncology experts explore the potential of the next wave of novel HER2-targeting therapies in various HER2-altered cancers, including breast, gastrointestinal, lung, and other tumors. Watch as the panel share their insights into the data that support therapeutic targeting of HER2 and consider other critical research questions and future directions. Upon completion of this activity, participants should be better able to: Review evidence-based guidelines and expert recommendations regarding HER2 testing and interpretation of results in breast, gastric, colorectal, and non–small cell lung cancers, Evaluate the characteristics, mechanisms of action, and efficacy/safety evidence of established and emerging HER2-targeted agents for the management of patients with advanced HER2-expressing or ERBB2-mutant cancers, Identify novel approaches to overcome mechanisms of resistance to HER2-targeted therapies, Integrate the latest HER2-targeted therapies into individualized treatment plans for patients with advanced HER2-expressing or ERBB2-mutant breast, gastric, colorectal, and non–small cell lung cancers, either in the context of clinical practice or through clinical trial participation.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.290122v1?rss=1 Authors: Pinet, L., Wang, Y., Deville, C., Lescop, E., Badache, A., Bontems, F., Morellet, N., Durand, D., Guerlesquin, F., Assrir, N., van Heijenoort, C. Abstract: ErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poor prognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in the last twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding of the receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains very poorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction is triggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the first description of ErbB2 disordered tail at atomic resolution, using NMR and SAXS. We show that although no part of CtErbB2 has any stable secondary or tertiary structure, it has around 20% propensity for a N-terminal helix that is suspected to interact with the kinase domain, and many PPII stretches distributed all along the sequence, forming potential SH3 and WW domains binding sites. Moreover, we identified a long-range transient contact involving CtErbB2 termini. These characteristics suggest new potential mechanisms of auto-regulation and protein-protein interaction. Copy rights belong to original authors. Visit the link for more info

The cover for issue 29 of Oncotarget features Figure 5, "In vivo effects of treatment with L-Grb2 in combination with anti-angiogenic therapy in an ovarian tumor model," by Lara, et al. which reported that adaptor proteins such as growth factor receptor-bound protein-2 play important roles in cancer cell signaling. In the present study, the authors examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression in gynecologic cancer models. Murine orthotopic models of ovarian and uterine cancer were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2. Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Reverse-phase protein array analysis identified significant dysregulation of metabolites in ovarian cancer cells after Grb2 downregulation. L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. Dr. Anil K. Sood and Dr. Cristian Rodriguez-Aguayo from The University of Texas MD Anderson Cancer Center said, "Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation." Druggable targets have often been proteins with enzymatically active sites to which small molecules could bind. However, the ability to target previously undruggable targets is evolving. Small-molecule inhibitors rely on intracellular targets or antibodies to inhibit the activity of growth factors, cell surface receptors, and cytokines. The development of nucleic acid interference-based therapeutics has allowed for regulation of gene expression to inhibit elusive targets. Nucleic acid-based therapeutics involves a process in which RNA molecules or antisense oligonucleotides inhibit gene expression or translation by neutralizing targeted mRNA molecules. After crossing the cell membrane, ASOs target mRNA directly through complementary base pair interactions, in the nucleus or cytosol, thus blocking and neutralizing targeted mRNAs. The Sood/Rodriguez-Aguayo Research Team concluded in their Oncotarget Research Paper, "we report that L-Grb2 has promising antitumor activity in preclinical models of ovarian and uterine carcinoma. Whereas the evidence of L-Grb2's activity against hematological malignancies is promising, whether it is active in clinical trials against solid tumors has yet to be tested. Therapies targeting the ErbB2 receptor have had limited success in ovarian cancer, but L-Grb2 may be a better target given its status as an important converging point for cancer cell signaling pathways." Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27667 Full text - https://www.oncotarget.com/article/27667/text/ Correspondence to - Anil K. Sood - asood@mdanderson.org and Cristian Rodriguez-Aguayo - CRodriguez2@mdanderson.org Keywords - ovarian cancer, nucleic-acid based therapeutics, therapeutic approaches, uterine cancer About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

Volume 11 Issue 25 of @Oncotarget reported that this study aimed to define the mutation profile of SUM in Caucasians. Next-generation sequencing-based genomic analysis was used to identify frequently mutated loci in 50 cancer-related genes in 31 SUM primary tumors. The most abundant mutations in SUM were found in KIT – in 13% of cases and NRAS – also in 13%, while BRAF - only in 3% of cases. The authors' findings confirmed a high frequency of KIT and NRAS mutations in SUM, as well as a low incidence of BRAF mutations. They reported novel KRAS, CTNNB1, TP53, ERBB2, and SMAD4 mutations in SUM. Dr. Aneta Borkowska from The Maria Sklodowska-Curie National Research Institute of Oncology said "Across all human cancers, cutaneous malignant melanoma (MM) genome has one of the highest prevalence of somatic mutations." At the same time, NRAS mutations are detected in approximately 20% of MM and are more commonly reported in melanomas developing in the skin with chronic sun exposure. WHO Classification of Skin Tumours recognizes the most common acral melanoma histotype is acral lentiginous melanoma, followed by nodular cutaneous melanoma and superficial spreading melanoma. Cutaneous MM located on the acral part of extremities - hand and foot melanoma - comprises a rare group within all melanomas in Caucasians. Whole-genome sequencing study shown that structural changes and mutational signature of acral melanomas were dominated by different than other MMs sites. SUM seems to be not related to sun exposure, however, in Australian Melanoma Genome Project UVR signatures on acral melanomas occurred most frequently in subungual parts. The Borkowska Research Team concluded in their Oncotarget Research Paper, "Our study offers new insights into the genetics SUM subtype, for understanding pathogenesis and providing potential biomarkers for future studies. Molecular testing is now widely used in patients with advanced melanoma in the process of therapeutic decisions. Mutations reported in melanoma cells provide starting points for the development of the rational design of novel therapies, including immunotherapy agents. They also may provide to find the molecular pathogenesis and natural history of subtypes of this heterogeneous disease. We confirmed that SUM have different than other cutaneous melanomas genetic profile, which due to its rareness and lack of studies should be subjected to further analyzes in multicenter studies." Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27642 Full text - https://www.oncotarget.com/article/27642/text/ Correspondence to - Aneta Borkowska - anetame@gmail.com Keywords - melanoma, acral melanoma, subungual melanoma, nail apparatus melanoma, SMAD4 About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

Featuring perspectives from Dr Shirish M Gadgeel on the later-line management of metastatic squamous cell carcinoma of the lung. Recent advances in the management of advanced non-small cell lung cancer (NSCLC) (0:00) Case: A woman in her early 70s with metastatic squamous cell carcinoma (SCC) of the lung receives carboplatin/paclitaxel and pembrolizumab as first-line therapy on the KEYNOTE-021 trial (02:25) Response to pembrolizumab and chemotherapy in advanced SCC of the lung (04:34) Efficacy of pembrolizumab alone or in combination with chemotherapy for advanced NSCLC (07:41) Choice of immune checkpoint inhibitor/chemotherapy regimen as first-line therapy for metastatic SCC of the lung (12:22) Results of the Phase III CheckMate 227 trial evaluating nivolumab alone, with ipilimumab or with chemotherapy as first-line therapy for metastatic NSCLC (15:43) Interim overall survival analysis of the Phase III IMpower110 study investigating atezolizumab versus platinum-based chemotherapy for metastatic NSCLC in the first-line setting (18:32) Cancer site and adverse events induced by immune checkpoint inhibitors (20:05) Genetic alterations in patients with SCC of the lung; rationale for targeting the ERBB signaling pathway (22:18) Results of the Phase III LUX-Lung 8 trial of afatinib versus erlotinib as second-line treatment for advanced SCC of the lung (25:53) Secondary analysis of LUX-Lung 8: Association of ERBB mutations with clinical outcomes among patients with afatinib- or erlotinib-treated SCC of the lung (28:04) Role of HER2 mutations and HER2 amplification in patients with NSCLC; incidence of HER2 alterations in patients with SCC of the lung (30:14) Targeting HER2 alterations with the tyrosine kinase inhibitors afatinib and dacomitinib in patients with NSCLC (34:15) Efficacy of the antibody-drug conjugate trastuzumab deruxtecan (DS-8201) in patients with NSCLC and HER2 alterations (36:11) Activity of T-DM1 in patients with NSCLC and HER2 mutations (38:04) Management of gastrointestinal side effects associated with afatinib (40:22) Activity of afatinib in heavily pretreated ERBB2 mutation-positive advanced NSCLC (43:01) Afatinib in patients with metastatic or recurrent lung cancer with HER2 mutations  (45:15) Case: A man in his early 80s develops metastases to the liver during treatment with durvalumab after chemoradiation therapy for Stage III SCC of the lung and is found to have FGFR1 amplification (47:15) FGFR signaling as a target for NSCLC therapy; outcomes with the FGFR inhibitor AZD4547 in patients with metastatic SCC of the lung and FGFR alterations (51:04) SWOG-S1400 Lung Cancer Master Protocol (Lung-MAP) — Biomarker-targeted therapy for patients with previously treated Stage IV SCC of the lung (56:02) Case: A woman in her early 50s with ALK-rearranged metastatic lung adenocarcinoma experiences a dramatic response to crizotinib on the PROFILE 1014 study (1:02:39) Response to ALK inhibitors for ALK-rearranged metastatic NSCLC (1:06:54) CME information and select publications

Dr Li talks to ecancer at ASCO 2017 about results from a phase II basket trial looking at Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers. Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 2% of lung cancers, resulting in receptor dimerisation and kinase activation with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine. Ado-trastuzumab emtansine is active and well tolerated in pts with HER2 mutant lung cancers.

Interview with Ahmad Awada, MD, PhD, author of Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial, and Mark D. Pegram, MD, author of Neratinib in ERBB2-Positive Brain Metastases

Breast Cancer

T cells directed against brain antigens are generally held to play a crucial role in the initiation of multiple sclerosis (MS). This was deduced from experimental autoimmune encephalomyelitis (EAE). In this model for MS, T cells reactive for myelin antigens induced a severe paralytic disease upon transfer to healthy syngeneic recipients. Intriguingly, the disease does not start immediately upon transfer of the pathogenic effector T cells. Instead, as earlier studies have shown, the effector T cells attack their target organ only after having migrated in the periphery through secondary lymphoid organs. The aim of the project was to characterize the functional properties of these migrating encephalitogenic T cells during the course of EAE and to identify biological pathways which determine their migratory behaviour and pathogenic potential. To this end, average linkage hierarchical clustering, pathway and gene ontology (GO) analyses of transcriptomes from cultured and ex vivo-isolated myelin basic protein-reactive T cells (TMBP cells) were performed. At the time of transfer, encephalitogenic T cells in vitro are maximally activated, i.e. they exhibit a prominent upregulation of cell cycle genes such as cyclin A2 (CCNA2) and cyclin B2 (CCNB2) among others. In contrast, T cells isolated from spleen 3 days post transfer, downregulated activation markers such as interleukin 2 receptor (IL2R) and interferon γ (IFNγ), and at the same time upregulated migration specific genes such as CC-chemokine receptor 1 (CCR1), CC-chemokine receptor 2 (CCR2) and CC-chemokine receptor 5 (CCR5). Hierarchical cluster analysis revealed that several transcription regulators known for inhibiting cell cycle progression such as krüppel-like factor 4 (KLF4), B-cell translocation gene 2 (BTG2) and transducer of ERBB2, 1 (TOB1) were clustered together with cell cycle and migration genes. Overexpression of KLF4 in T cells not only inhibited G1/S phase progression of the cell cycle but additionally induced upregulation of CCR2 and CCR5. A novel tetraspan membrane protein called epithelial membrane protein (EMP1), was found to be up regulated in ex vivo-isolated effector T cells. Overexpression of EMP1 in encephalitogenic T cells influenced the migratory behaviour of effector T cells both in vitro and in vivo. EMP1 enhanced T cell motility within the extracellular matrix milieu in vitro and promoted T cell migration from the connective tissue to lymph nodes in vivo resulting in an accelerated onset of EAE. In conclusion, gene expression profiling of encephalitogenic T cells revealed interesting genome wide transcriptomic changes and established a correlation between cell cycle progression and cell migration. As a result, in silico analysis put forth several interesting candidate genes that hold promise as potential targets for therapeutic intervention.

In women with estrogen receptor(ER)- and ErbB2(HER2)-positive breast cancer, a vicious cycle is established between ER mechanisms of action and the growth factor receptor network, leading to enhanced cell proliferation and endocrine resistance. As such, co-targeting ErbB1 and ErbB2 with lapatinib in combination with hormonal therapy is an attractive approach to enhance the efficacy of either tamoxifen or estrogen deprivation. As demonstrated in the EGF30008 trial, a combined targeted strategy with letrozole and lapatinib significantly increased progression-free survival and clinical benefit rates in patients with metastatic breast cancer that co-expresses ER and ErbB2. Therefore, women who are not in an acutely life-threatening situation should be considered for upfront treatment with hormonal therapy (e. g. aromatase inhibitors) in combination with an anti-ErbB2 therapy.

Tue, 1 Jan 2008 12:00:00 +0100 https://epub.ub.uni-muenchen.de/17073/1/10_1159_000119747.pdf Nitz, Ulrike; Möbus, Volker; Minckwitz, Gunter von; Janni, Wolfgang

Tue, 1 Jan 2008 12:00:00 +0100 https://epub.ub.uni-muenchen.de/17072/1/10_1159_000119744.pdf Untch, Michael; Loibl, Sibylle; Heinemann, Volker; Harbeck, Nadia

Alterations in oncogenes are critical steps in the development of endometrial cancer. To investigate the potential clinical relevance of the amplification of the oncogenes c-erbB2, c-myc, and int-2 and the mutation of K-ras in endometrial cancer, 112 tumors were examined using PCR-based fluorescent DNA technology. Amplification of the three oncogenes and the mutation of K-ras were correlated with age, tumor size, lymph node status, metastases, stage, histological types, grade, steroid hormone receptor expression (estrogen receptor, ER; progesterone receptor, PgR), family history of cancer, previous history of cancer or precursor lesions, and previous history of hormone replacement therapy. Oncogene amplification of c-erbB2 was detected in 18.9%, of c-myc in 2.7% and of int-2 in 4.2%, and K-ras mutation in 11.6%. No significant correlations could be detected between amplification of c-erbB2 and any of the other parameters. Mutation of K-ras is associated with positive expression of PgR. This might indicate that mutation and activation of K-ras are involved in the development of hormonal independence in endometrial cancer.