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Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, 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. More on 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   ASCO on BlueSky   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 

Imagine if a single blood test could tell clinicians in real time how successful a cancer surgery has been. A recent study from the University of Brasília, published in Oncotarget, suggests that such an approach might soon be possible. By tracking changes in cell-free DNA (cfDNA) levels before, during, and after colorectal cancer (CRC) surgery, researchers have found a potential new way to monitor tumor removal and predict patient outcomes. Cell-Free DNA and Colorectal Cancer Surgery Cell-free DNA consists of tiny fragments of genetic material that are released into the bloodstream when cells break down. In healthy individuals, these fragments come from normal cell turnover, but in cancer patients, some of this DNA originates from tumor cells. cfDNA detection has been used to track cancer progression and treatment response in diseases like lung, breast, and CRC. What had not been investigated until now was how cfDNA levels fluctuate during cancer surgery itself. Since surgery is the primary treatment for CRC, understanding how cfDNA levels change during surgical intervention could provide valuable insights into whether the tumor has been fully removed and how the patient's body reacts to the procedure. The Study: Measuring Cell-Free DNA in Real-Time In the study, titled “Assessment of cfDNA release dynamics during colorectal cancer surgery,” led by first author Mailson Alves Lopes and corresponding author Fabio Pittella-Silva, scientists analyzed ​​blood plasma samples from 30 CRC patients at three critical time points—before, during, and after surgery. Using highly sensitive genetic tests, they measured changes in cfDNA concentration to determine whether surgery had a direct impact on its release. The goal was to check whether cfDNA could serve as a biomarker for evaluating surgical effectiveness and predicting the probability of cancer recurrence. Full blog - https://www.oncotarget.org/2025/02/26/how-a-simple-blood-test-could-predict-colorectal-cancer-surgery-success/ Paper DOI - https://doi.org/10.18632/oncotarget.28681 Correspondence to - Fabio Pittella-Silva - pittella@unb.br Video short - https://www.youtube.com/watch?v=jC5_xqIrbtA Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28681 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, colorectal cancer, cfDNA, surgery About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

In this episode of the Exploring Artificial Intelligence (AI) in Oncology series, Waqas Haque, MD, MPH, Hematology/Oncology Fellow at the University of Chicago, speaks with Osama Khan, MD, Staff Pathologist at Natera, a cell-free DNA (cfDNA) technology company that aims to make personalized genetic testing and diagnostics part of the standard of care. Dr. Khan shares insights into how digital pathology and emerging technologies like AI and measurable residual disease (MRD) testing are revolutionizing oncology, driving precision medicine, and enhancing patient care. Learn more at: https://oncdata.com/digital-pathology-osama-khan

BUFFALO, NY - January 27, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 21, 2025, titled “Assessment of cfDNA release dynamics during colorectal cancer surgery." Researchers from the University of Brasília investigated how cell-free DNA (cfDNA) levels in the blood change before, during, and after colorectal cancer surgery. The study found that cfDNA levels increase significantly during and after surgery. The findings suggest that cfDNA could help clinicians evaluate surgery effectiveness and monitor patient outcomes. cfDNA consists of small DNA fragments released into the bloodstream when cells die and break apart. In healthy individuals, cfDNA usually comes from normal cell turnover, while in cancer patients, some of it originates from tumor cells. Measuring cfDNA levels offers valuable insights into a patient's condition and is already being used to track disease progression and treatment response in cancers such as lung, breast, and colorectal cancer. Colorectal cancer is one of the most common cancers worldwide, affecting millions of people each year. Surgery is often the primary treatment, but up to 50% of patients experience cancer recurrence afterward. In this study, the research team, led by first author Mailson Alves Lopes and corresponding author Fabio Pittella-Silva, analyzed blood samples from 30 patients at three key time points: before, during, and after surgery. It was found that cfDNA levels increased nearly threefold during surgery and doubled after surgery compared to pre-surgery levels. The increases were even higher in individuals over 60, those with preexisting conditions such as diabetes or heart disease, and patients with elevated levels of carcinoembryonic antigen (CEA), a common cancer marker. Patients with the highest cfDNA levels were those with larger or more aggressive tumors, likely due to greater tissue damage during surgery. Additionally, longer surgeries were linked to higher cfDNA levels. “[...]we observed that cfDNA concentration may rise in correlation with the duration of the surgery, highlighting its potential as a marker of surgical quality.” These findings suggest that cfDNA could be a valuable, non-invasive biomarker for clinicians to monitor colorectal cancer patients. Tracking cfDNA levels may help better evaluate surgical outcomes and determine whether patients require closer follow-up care. While these findings are promising, further research is needed to standardize cfDNA testing and validate its usefulness. Larger studies could help establish cfDNA testing as a reliable tool for cancer care and postoperative monitoring, with the potential to become a routine part of clinical practice in the future. DOI - https://doi.org/10.18632/oncotarget.28681 Correspondence to - Fabio Pittella-Silva - pittella@unb.br Video short - https://www.youtube.com/watch?v=jC5_xqIrbtA About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Our immediate past episode summarized a validation study of cell-free DNA (cfDNA) isolated from maternal plasma for fetal RBC genotyping in alloimmunized patients. And now, in this episode, we will highlight a BRAND NEW ACOG Clinical Practice Update on this very subject! YEP... we now have new ACOG guidance regarding using maternal derived cfDNA for fetal RBC antigen detection as an option for care in alloimmunized pregnancies. This is how "medicine moves fast"! Listen in for details.

Organ transplantation is a modern marvel, with more than 157,000 solid organ, and more than 9,000 marrow and blood transplants occurring worldwide in 2022. Organ donor and recipient matching and compatibility screening has progressed significantly in recent decades as molecular methods have progressed rapidly to support this and other fields. Specifically, typing of human leukocyte antigens (HLAs) has expanded to consider ethnic population variation and cell free DNA (cfDNA) monitoring is now being used to monitor recipients for biomarkers that indicate organ rejection.  Our guest for this episode, Dr. Lee Ann Baxter-Lowe, Director of the HLA Laboratory at Children's Hospital Los Angeles has been working in the field of transplantation science for virtually her entire career. Join us for a great explanation of the science and a first-hand recounting of developing the assays, from decades ago, before thermal cyclers existed, to her cutting-edge work using digital PCR to progress the field even further. Lee Ann also shares very personal aspects of her career journey in her conversation with Cassie. This includes her describing the scientific “studies” of her and her cousin as children, her venturing into the world of HLA typing when it was emerging, and the role her family has played in her career, which gets personal quickly when she shares that her husband is currently dealing with a blood malignancy. Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

Drs. Shaalan Beg and Rachna Shroff discuss key abstracts on GI cancers that were featured at the 2024 ASCO Gastrointestinal Cancers Symposium, including SKYSCRAPER-08, EMERALD-1, and NEST-1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, and colorectal cancer, respectively. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. Today, we'll be discussing key abstracts and other exciting highlights from the 2024 ASCO Gastrointestinal Cancers Symposium. Joining me to discuss some key takeaways from the meeting is the chair of this year's Symposium, Dr. Rachna Shroff. Dr. Shroff is the division chief of Hematology Oncology and chief of GI Medical Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for clinical and translational research at the University of Arizona College of Medicine – Tucson. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Shroff, welcome back to the ASCO Daily News Podcast, and congratulations on a great Symposium. The scientific advances and innovative, multidisciplinary approaches that were featured throughout the meeting were really inspiring and reflect the incredible strides we're making in GI cancer research. Dr. Rachna Shroff: Thank you so much for having me back. I am delighted to be here.  Dr. Shaalan Beg: Dr. Shroff, the theme of this year's symposium was "Taking Personalized Care to the Next Level." I'd love to hear your reflections on the sessions that you found most exciting and really resonated with the attendees.  Dr. Rachna Shroff: Yes, thank you. We were really excited about this theme because we really felt that “Taking Personalized Care to the Next Level” translated to thinking through personalized approaches to patient care, not just in the traditional ways that we think of with precision oncology and genomics driving our care, but also how we can think through multidisciplinary approaches and an individualized care plan. Thinking through how artificial intelligence and novel clinical trial designs can and should be implemented to meet the needs of our individual patients. And so we really highlighted that in what was a somewhat new reboot of a session called “Intersections,” which were every day and were really more cross-tumor; they were tumor agnostic but were thematic focused. As I mentioned, those themes were really based on feedback that we had from prior attendees, as well as from the program committee's feeling on what are really the questions that we are dealing with and that are burning in the clinic today and that includes the emerging role of artificial intelligence and machine learning and how we integrate that into our clinical care, approaches to oligometastatic disease, and it's not really just something that we think of in colorectal cancer but haven't fully used that paradigm to really apply it to other GI malignancies. And then the art and science of clinical trial design where, again, traditional randomized phase 3 trials might not be the best and most innovative and most expedient way of bringing novel therapeutics to our patients. And so, I thought that all of those sessions were really highlighting different important topics that we deal with day to day. Additionally, we had a really fantastic keynote lecture from Dr. Kimmie Ng of the Dana-Farber Cancer Institute. She is a world-renowned expert in the early-onset colorectal cancer space, and the timing of her keynote was perfect with the new cancer statistics that came out literally days before GI ASCO that demonstrated this just dramatic rise in early onset GI malignancies as a whole, not just colorectal. And she spoke really in a comprehensive manner not just on clinical approaches, screening approaches, and how to find these patients at an earlier stage, but also kind of gave us a call to action, if you will, in terms of public health initiatives, as well as like I said, clinical care and really thinking outside of the box for how to reach these patients.  And then, of course, we always have what I think is one of my favorite aspects of the meeting, which are the networking opportunities that include the Trainee and Early Career Networking Luncheon, the Women's Networking Reception, and the Meet the Experts Luncheon where, especially as junior career investigators, you have an opportunity to meet what we think of as the “big names” in GI cancer. Dr. Shaalan Beg: Absolutely, I remember my first couple of GI ASCO meetings and those were probably the most memorable sessions that I attended as junior faculty as well.   So let's take a deeper dive into some key abstracts from the meeting. I'd like to begin with Abstract 245. This is the SKYSCRAPER-08 study. It's first-line tiragolumab and atezolizumab with chemotherapy in an Asian patient population with esophageal squamous cell carcinoma. What are your key takeaways from this study?  Dr. Rachna Shroff: Yeah. This was an exciting study in my opinion in the sense that thinking through how we can build on immunotherapy backbones is obviously a pressing question across the GI cancer space. So this was a phase 3 randomized, double-blinded, placebo-controlled trial that looked specifically at patients with esophageal squamous cell carcinomas. And the study was enrolled fully with an Asian population. It looked at taking the traditional chemotherapy backbone and adding to it an anti-PD-L1 with atezolizumab and an anti-TIGIT with tiragolumab. Again, that proof of principle of using anti-TIGIT and PD-L1 has been looked at across a lot of different GI cancer spaces and we know that the esophageal squamous cell cancers tend to be very immunotherapy responsive. So this was a really important question.  This involved a number of patients, a little over 460 patients, who were randomized one-to-one to receive the tiragolumab with atezolizumab with the standard paclitaxel and cisplatin, that's used for esophageal squamous versus chemotherapy alone with placebo. And the primary endpoint was independent review of progression-free survival, and overall survival. And so, out of the 461 patients randomized, there was at the primary analysis, a median improvement in progression free survival, from 5.4 months in the control arm to 6.2 months with a tira-paclitaxel plus chemo arm with a hazard ratio of 0.56, highly statistically significant. Similarly the median overall survival was also improved from 11.1 months to 15.7 months again with a hazard ratio of 0.7 and some of the other key efficacy endpoints were also improved with the addition of the anti-TIGIT PD-L1 approach. And importantly, there was not really safety signals that jumped out at us.  And so, to me, what this means is that, in our patients with esophageal squamous cell carcinoma, we really should be thinking about chemotherapy with immunotherapy as a backbone and how we can build on it. And, you know, I would imagine that it's hard to argue with both the PFS and OS endpoint that adding anti-TIGIT won't necessarily be kind of the new approach to these patients. And importantly, I'll point out that it seems to be a benefit across the subgroups, including PD-1 status, which is always our big question here. I think the only thing to keep in mind is this was an all-Asian population and whether or not that kind of immune profile of the immune responsiveness is different in those patients, but regardless, a positive phase 3 trial. Dr. Shaalan Beg: It's really exciting to see immune checkpoint inhibitors or immunotherapy beyond PD-1 targeted, CTLA-4 targeted treatments making their way into GI Cancers.  Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: Sticking with the immunotherapy theme, let's focus on hepatocellular carcinoma. So LBA432, the EMERALD-1 study of transarterial chemoembolization combined with durva with or without bevacizumab looked at people with unresectable hepatocellular carcinoma eligible for embolization. So really a highly anticipated study, I'm wondering what your thoughts are and whether it'll be practice-changing for this field.  Dr. Rachna Shroff: I was excited to see the press release when it showed that the study was positive, and I think it's because now that we're using immunotherapy in the advanced HCC space, our obvious question is, can we integrate it into multimodality approaches? There are a lot of smaller studies looking at neoadjuvant IO approaches, and in this intermediate stage, unresectable hepatocellular carcinoma patients. We wanted to know if there was a utility to liver directed therapy with immunotherapy.  So, this was a large study. It was a global study looking at unresectable HCC with preserved Child-Pugh function. But it was Child-Pugh A and up to B7, importantly. And there were 616 patients randomized in a 1:1:1 fashion, with the control arm being just TACE alone. But then, there was also an opportunity for durvalumab with TACE, as well as durvalumab plus bevacizumab with TACE. The patients would receive durvalumab during their TACE treatments and could receive up to four TACE treatments and then subsequently were either continued on durvalumab alone, durvalumab plus bevacizumab, or the placebo. The primary endpoint was progression-free survival, powered specifically to look at TACE versus durvalumab plus TACE. In this study, the primary endpoint was met with a significant improvement in PFS. Median PFS was 15 months versus 8.2 months, with a hazard ratio of 0.77. Most prespecified subgroups demonstrated this benefit.  Importantly, there was a secondary endpoint looking at durvalumab plus TACE versus TACE alone, and that actually did not show a statistically significant improvement in median PFS from 8.2 months in the control arm to 10.0 months. The overall response rates were slightly higher with the durvalumab plus bevacizumab approach at 43.6%. And importantly in these patients, who oftentimes have a higher burden of disease in the liver, median time to progression is a really important and clinically meaningful endpoint. That was 22 months with the durvalumab plus bevacizumab and TACE versus 10 months for TACE alone. I would just point out that the overall concern we always have with bevacizumab is the increased risk of bleeding and the treatment-related adverse event profile. Overall, there were no safety signals that emerged from this, with nothing that really, especially in that bleeding risk category, jumped out at us. Of course, we haven't seen the overall survival data yet because we have not seen enough follow-up to really see that number.  I do think that this is potentially practice-changing, and I think it just demonstrates that there's probably some synergy between anti-VEGF with anti-PD-1, and then the liver-directed treatments. The obvious question for us in the United States is that the vast majority of people are moving away from TACE and towards more radioembolization and what can we extrapolate from this? Does this really tell us much if people are using more of a Y90-based approach? I think those are a lot of the burning questions that most of us have.  Dr. Shaalan Beg: Yeah, and it's a very interesting direction that the HCC space is taking because we heard in previous meetings, the role of PD-1 inhibition as adjuvant therapy after resection. Now, we have data for local-regionally advanced disease over local-regional treatments. And of course, you already mentioned the data for more advanced disease. So it sounds like immunotherapy may be impacting the management of anyone diagnosed with hepatocellular carcinoma.  Let's talk about the MONET trial, Abstract 249, which compared thoracoscopic esophagectomy and open esophagectomy for thoracic esophageal cancer. Do you think this is a study which may influence the treatment of patients with thoracic esophageal cancer? Dr. Rachna Shroff: So, this was, again, I think, a really important question. It was a randomized, controlled phase 3 trial comparing a more minimally invasive approach with TE — thoracoscopic esophagectomy — versus an open approach. This had patients with clinical stage 1-3, excluding T4 thoracic esophageal squamous cell carcinomas. They were randomized 1:1 to the open versus the TE approach, with a primary endpoint of overall survival and an important secondary endpoint of relapse-free survival. 300 patients were randomized, and at the second planned interim analysis, the median follow-up was a little over two and a half years. The 3-year overall survival was 82% in the TE group versus 70.9% in the open group. The DSMC of this trial actually recommended early termination based on the non-inferiority, which is what they were specifically looking at. There was a very statistically significant one-sided p-value for non-inferiority.  Importantly, the 3-year recurrence-free survival was also markedly better in the TE group versus the open group, with no real notable differences in R0 resection, or a large percentage of patients who needed to be converted from a TE to an open approach, and really not any significant difference in overall postoperative morbidity. I think this just supports the concept that minimally invasive approaches for our patients with GI malignancies can and should be considered. Again, esophageal squamous because they tend to be seen a lot more in Asia, this study was conducted in Japan, but I think that being said, a lot of our surgeons in Europe and in the U.S. are also very amenable to minimally invasive approaches. And I think this just supports the fact that an open approach is not necessary. So, I would think again, that this is something that is implementable and I think will affect the field.  Dr. Shaalan Beg: Moving on to metastatic cholangiocarcinoma, there have been many FGFR inhibitors that have shown activity and promise and are approved for the management of cholangiocarcinoma with FGFR alteration. But at this ASCO GI, we heard the results of the safety and efficacy of an FGFR1, 2, and 3 inhibitor, tinengotinib, as monotherapy for advanced metastatic cholangiocarcinoma (Abstract 434). How do you see this fitting into the broad picture? Dr. Rachna Shroff: Yeah, so this was highly anticipated data, primarily because at this point, the FGFR space in cholangiocarcinoma is quite crowded. And so a lot of us were getting sick of the "me-too" drugs. What is really unique about tinengotinib is that, not only is it a selective multikinase inhibitor, but it also, in preclinical models as well as in early phase one trials, demonstrated potent inhibition of patients with FGFR2 fusions and rearrangements who had acquired resistance mutations. So, as we better understand the first generation of FGFR inhibitors and note the resistance mechanisms, these drugs are now being developed to try to circumvent or overcome those.  This study looked at 4 different cohorts: 1 cohort with FGFR2 fusion patients who had primary progression who never responded to FGFR inhibitors, a second cohort with FGFR2 fusion patients who had progression after primary response, so those with acquired resistance, and then there was non-fusion FGFR alterations because we do know that a number of cholangiocarcinoma patients have other FGFR alterations that are not fusions, and then those with FGFR wild-type. The primary endpoint was objective response rate, with a total of 48 patients enrolled across the four cohorts. And so the 40 patients who were evaluable in the group that had primary resistance, which was the first cohort, there was a response rate was 9.1% and that was partial response, and 31% had tumor reduction with tinengotinib. And similarly in those with acquired resistance, 37.5%, 3 out of 8 patients had a partial response and tumor reductions were noted with an overall disease control rate between those patients with FGFR2 fusions of 94.7%, between those with primary and secondary resistance.  In the patients who had FGFR alterations, there was 3 out of 9 patients with a partial response and again, tumor reductions were notable across the board and the disease control rate was 88.9%. The FGFR wild-type group, not surprisingly, did not see any partial responses, but interestingly, 75% of these patients had at least disease control, and the median progression-free survival was 5.26 months, again, kind of most notably impressive in the 2 cohorts that included FGFR2 fusions. The toxicity profiles are what we come to expect for FGFR inhibitors and we've gotten better at managing those and mitigating some of those so there was really nothing to jump out there. So there is now an ongoing randomized phase III trial specifically looking at tinengotinib versus physician's choice in patients with FGFR2-altered cholangiocarcinoma after having received prior FGFR inhibitors. So that's where I think it's in is for those of us who know that there are multiple drugs in the space, our big question is can we sequence through that? Can we offer multiple FGFR inhibitors in these patients? And I think we are all eagerly anticipating this data as well as the subsequent data to really justify the use of these novel second generation FGFR inhibitors.  Dr. Shaalan Beg: It's been fantastic to see the evolution of these compounds in precision medicine, or precision oncology at its finest, in terms of understanding mechanisms of resistance and treating refractory disease.   Let's focus on colorectal cancer. I'll tell you, there has been a lot of discussion, Dr. Shroff, on social media, on insurance companies sometimes rejecting one biologic or the other based on tumor sidedness. We have talked about tumor sidedness predicting response on this podcast based on data from previous studies. But this year in GI ASCO, Abstract 207 explored the role of tumor genomics and tumor sidedness and they said that it's tumor genomics, that tumor genomics better explains the differences on outcomes, and it explains it better than sidedness. What does this mean to the field? Because a lot of professional organizations have guidelines that are asking people to now incorporate sidedness. So how does that change based on these results? Dr. Rachna Shroff: I really commend these authors on leveraging real-world data, and I think we're getting better and better at recognizing that real world data actually informs our clinical decision making, possibly better than sometimes some of these studies that lead to the guidelines and algorithms that we develop. So this is a perfect example of a little bit cart before horse in trying to understand the way that sidedness and genomics may interplay.   So this was a study that basically leveraged both the Foundation Medicine and Flatiron Health clinical genomic database and looked at patients with microsatellite stable metastatic colorectal cancer. There were a total of 3,845 patients included in a kind of two-thirds one-third split between left sided and right-sided colorectal cancer. And they found the typical genomic alterations that historically have been thought of more with left-sided colorectal cancer like APC and then more of the RAS BRAF alterations in the right-sided patients. But I think what they really thought and what I think was remarkable is they really looked at the patients and how they received chemotherapy with anti-EGFR or bevacizumab therapies, and they did a multivariate analysis to really see what is driving outcomes. And like you mentioned, what they found was patients in the RAS pathway, those classified as having alterations in the RAS pathway, had less favorable outcomes, while those with APC altered group had more favorable outcomes. And that was regardless of treatment received and sidedness.  And so when they did an analysis of what was called a “likelihood ratio test,” they found that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction, but not when sidedness was added to genomics. Like you said, it kind of demonstrates, at least in this mining of real-world data from Flatiron that tumor genomics is probably a better driver and a more important driver in determining outcomes than sidedness.  I totally agree with you. I would push for us to really kind of bring a little bit of noise to this and to make insurance companies and other companies that are looking at this to think through this a little bit more and make sure that we're putting all of the data together in a comprehensive passion before making the treatment plans and determinations. Dr. Shaalan Beg: The last abstract I'd like to ask you about is Abstract 117, the NEST-1 trial. This study looked at neoadjuvant botensilimab and balstilimab for resectable mismatch repair proficient and deficient colorectal cancer, both MSS and MSI. What are your key takeaways from this study?  Dr. Rachna Shroff: This is another study that is demonstrating that there may potentially be a role for immunotherapy in microsatellite stable patients. I will make the caveat that this was a single-arm study that really was looking at feasibility safety, with efficacy as a secondary endpoint. The combination of bot-bal in the neoadjuvant space for colorectal cancer patients, they received one dose of boten and two fixed doses of bal two weeks apart and then were taken to surgery. They limited the number of patients and out of the 12 patients that were enrolled, they limited the number of mismatch repair deficient patients. So to your point, they allowed both, but they wanted to make sure it was not just MSI-high patients. What they basically found is that it was safe and did not delay surgery or increase risks of adverse events. But importantly, there was significant regression of tumor noted. And some interesting spatial biology analyses demonstrated potentially novel mechanisms of action, especially in the MSS population, and that ctDNA reductions correlated with pathologic response. There were a lot of different things that they were looking at, basically suggesting that bot-bal is safe and can be used in both mismatch repair–deficient and proficient patients with colorectal cancer. And now importantly, they've added some additional cohorts and expanding the study. As I mentioned, this is right now just 12 patients, but does definitely have a provocative result.  Dr. Shaalan Beg: Thanks so much, Dr. Shroff.  Finally, the role of cell-free DNA (cfDNA) in GI cancers has been an exciting and important development in our field. There's tremendous data that emerged at the GI meeting, and we have decided to do a separate ASCO Daily News Podcast dedicated to ctDNA. So listeners, please look out for our coverage of key studies on ctDNA in GI cancers very soon here on the ASCO Daily News Podcast.  Many thanks, Dr. Shroff, for sharing your insights with us today and for your great work in building a robust GI meeting this year. Thank you very much. Dr. Rachna Shroff: Thank you so much. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed on the transcript of this episode. Finally, if you value the insights that you hear on the 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 inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Our guests on this podcast express their own opinions, experiences, and conclusions. These statements do not necessarily reflect the views of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.   Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics

NIPT is a prenatal SCREENING method that involves analysis of cell-free fetal DNA (cfDNA) in maternal blood. Prenatal screening for sex chromosome aneuploidies (SCAs) has become readily available through expanded non-invasive prenatal testing (NIPT). NIPTs became commercially available in 2011 and has since been introduced in more than 60 countries around the world and is now part of mainstream obstetrical practice. Initially offered as a secondary screen for pregnancies with a high probability of a fetal chromosomal anomaly, NIPT is now often offered and recommended as a first-line screening test for the main chromosomal aneuploidies. Initially, NIPT was available to screen for fetal trisomies 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome). This has expanded of course to include (separately) fetal sex chromosome aneuploidy (SCA) screening. However, there are some VERY important points we must remember when seeing an “atypical sex chromosome” NIPT result. What is the PPV of a SCA found on NIPT? In this episode we will highlight a recent NIPT atypical sex chromosome result from our practice and review what this may and may not actually mean, and review why NIPT screening for SCA is actually VERY controversial with some potential ETHICAL concerns, with some countries recommending AGAINST ordering it. Lots to cover here….so listen in.

Cancer is the number two cause of death worldwide, and despite 100s of billions invested, there is still no cure, only treatments. The treatments we do have such as chemotherapy, radiation, and surgery, while extremely aggressive, work very well if detection is early. Since there are dozens of types of cancer, screening and detection has proven challenging–but that might be changing. My guest on this week's podcast is on the forefront of genomic medicine and hopes to make early screen accessible to everyone. Listen and learn: How new technology allows for blood plasma scanning of cell-free DNA (cfDNA) to find tiny particles from cancers The role of full body MRI in cancer screening Why it currently costs thousands per year but could end up costing a fraction of this in the future Links GetSerenity.live ABOUT OUR GUEST Jo Bhakdi is the Founder and CEO of Quantgene, a precision genomics and oncology company founded in 2015. Quantgene's goal is to build the future of medicine by utilizing advanced scientific and technological innovations. Like the Show? Leave us a review Check out our YouTube channel Visit www.yogabody.com

FDA 批准降钙素基因相关肽单抗用于预防偏头痛和丛集性头痛的发作JAMA Neurology 妊娠与临床孤立综合征发病的关系J Am Coll Cardiol 复杂的颈动脉斑块是引起隐源性卒中的一个原因Nature子刊 颅内恶性肿瘤的无创检测Nature子刊 合成纳米颗粒治疗胶质母细胞瘤加那珠单抗（galcanezumab）降钙素基因相关肽（CGRP）受体位于疼痛信号通路、颅内动脉和肥大细胞中，其活化被认为在偏头痛的病理生理学中起着因果作用。加那珠单抗（galcanezumab）是一种CGRP单克隆抗体。和此前在《神经科星期四 Episode 4》中介绍的治疗急性偏头痛的CGRP受体拮抗剂包括：瑞美吉泮（rimegepant）和乌布吉泮（ubrogepant）；以及《神经科星期四 Episode 14》中介绍的预防偏头痛发作的依替尼单抗（eptinezumab）属于一类药物。2018年9月，FDA批准加那珠单抗用于预防偏头痛发作；2019年6月，FDA批准加那珠单抗用于预防丛集性头痛发作。《CONQUER研究：加那珠单抗预防偏头痛的安全性和有效性的3b期临床研究》Lancet Neurology，2020年10月 (1)这项多中心、随机、双盲、安慰剂对照的3b期研究，纳入2到4类偏头痛预防药物无效的患者655例，患者年龄在18-75岁之间，有发作性或慢性偏头痛，在50岁之前发生偏头痛，入组后随机接受安慰剂或加那珠单抗（120mg q1m * 3m）。在1-3个月期间，加那珠单抗治疗的患者偏头痛发作天数比安慰剂显著减少。与基线相比，加那珠单抗组每月平均少4·1天，而安慰剂组每月平均少1·0天（p < 0·0001）。加那珠单抗和安慰剂之间治疗紧急不良事件的类型和数量相似。结论：加那珠单抗在偏头痛的预防治疗方面优于安慰剂，并且在以前的多个标准预防治疗失败的患者中有良好的耐受性。 《加那珠单抗预防发作性丛集性头痛的临床研究》New England Journal of Medicine，2019年7月(2)阵发性丛集性头痛是一种神经功能障碍，其特征是每天头痛发作，持续数周或数月。共招募患者106人，随机分配接受加那珠单抗（300mg）或安慰剂组。基线期每周丛集性头痛的平均发作次数，加那珠单抗组为17.8，安慰剂组为17.3。在第1至3周中，加那珠单抗组每周平均减少为8.7次，而安慰剂组为5.2次（P =0.04）。在第3周，头痛频率降低≥50%的患者，加那珠单抗组为71%，安慰剂组为53%。除了加那珠单抗组8%的患者有注射部位疼痛外，不良事件发生率在组间没有实质性差异。结论：与安慰剂相比，在首次注射后的1-3周内，加那珠单抗300mg ip降低了偶发性丛集性头痛的发作频率。多发性硬化多发性硬化（multiple sclerosis，MS）是以中枢神经系统白质炎性脱髓鞘病变为主要特点的自身免疫病。本病最常累及的部位为脑室周围白质、视神经、脊髓、脑干和小脑，主要临床特点为中枢神经系统白质散在分布的多病灶与病程中呈现的缓解复发，症状和体征的空间多发性和病程的时间多发性。 多发性硬化症主要的模式和病程可以分为以下几种临床亚型：临床孤立综合征（CIS）、复发缓解型（RR）、继发进展型（SP）、和原发进展型（PP）。 《前瞻性队列研究：妊娠与临床孤立综合征发病的关系》JAMA Neurology，2020年12月 (3)多发性硬化症常诊断于育龄妇女，但妊娠是否能延迟脱髓鞘或临床孤立综合征（CIS）的首次发作尚无共识。研究的目的是探讨妊娠与CIS发病时间的关系。这个国际、多中心、前瞻性研究纳入2557名女性，CIS发病的平均年龄为31岁，发病前46%至少有1次怀孕，43%至少有1次分娩。首次怀孕的平均年龄为23.3岁，首次分娩的平均年龄为23.8岁。与从未怀孕过的女性相比，有过怀孕和分娩经历的女性发生CIS的时间较晚，延迟3.3年（P < 0.001）。与从未分娩过的女性相比，分娩过的女性发病年龄也较晚，延迟3.4年（P < 0.001）。孕产次数与发病延迟无关。结论：发病前怀孕和分娩与CIS发病时间之间存在关联，但与次数无关。需要进一步的研究来帮助解释怀孕和多发性硬化症发病之间关联的机制。《前瞻性观察性队列研究：持续免疫治疗与活动性继发进展性多发性硬化症患者残疾结果的相关性》JAMA Neurology，2020年11月 (4)研究旨在评价继发进展性多发性硬化的患者中残疾累计发生率，及是否能够通过治疗延缓残疾累积的进展。这项观察性队列研究中， 招募53680例多发性硬化的患者，其中4997例继发进展型，在1621例符合纳入条件的患者中，女性患者68.0%，发病时的平均年龄为33.9岁。共有661例（40.8%）患者在继发进展性多发性硬化期间经历了叠加性复发。早期治疗方案和残疾累计发生无关。继发进展期的高复发率与轮椅依赖的残疾风险增加有关（P = 0.009）。在继发进展性多发性硬化期间经历反复复发的患者中，抑制疾病进展的治疗与残疾进展率的降低和轮椅依赖风险的降低显著相关。结论： 继发进展型多发性硬化症患者中，残疾进展率与早期病程和治疗方案无关，但是与疾病复发相关。多发性硬化的治疗多发性硬化治疗的主要目的是抑制炎性脱髓鞘病变进展，防止急性期病变恶化及缓解期复发，晚期采取对症和支持疗法，减轻神经功能障碍带来的痛苦。疾病修正治疗（disease-modifying therapy，DMT）主要包括：抗整合素α-4单抗（那他珠单抗 natalizumab），抗CD20单抗（奥瑞珠单抗 ocrelizumab、奥法木单抗 ofatumumab、利妥昔单抗 rituximab），抗CD52单抗（阿伦单抗 alemtuzumab）、干扰素（干扰素β-1a、干扰素β1-b）、富马酸类（富马酸二甲酯 dimethyl fumarate、富马酸单甲酯 monomethyl fumarate）、鞘氨醇调节剂（芬戈莫德 fingolimod、西尼莫德 siponimod、奥扎莫德 ozanimod）、免疫抑制剂（克拉屈滨 cladribine），还可使用其他免疫抑制剂如特立氟胺（teriflunomide）、硫唑嘌呤、环磷酰胺、米托蒽醌等。《OPERA I和OPERA II研究：复发相关的恶化与复发无关的进展对典型复发性多发性硬化症总体确认残疾积累的贡献》JAMA Neurology，2020年9月 (5)奥瑞珠单抗（ocrelizumab）是一种靶向CD20+B细胞的单克隆抗体，于2017年被批准用于多发性硬化的治疗。研究旨在评价复发相关的恶化（relapse-associated worsening，RAW）和复发无关的进展（progression independent of relapse，PIRA）对证实的残疾累积（confirmed disability accumulation，CDA）的影响，并评估两种治疗方法对预后的影响。这2个相同的、3期、多中心、双盲随机临床试验中，1656人纳入分析，两组平均年龄37.2-37.1岁，随机奥瑞珠单抗组（奥瑞珠单抗 600mg ivgtt q24w）或干扰素组（干扰素 ip q3w）共96周。12周后，干扰素组和奥瑞珠单抗组的残疾累积事件发生率分别为29.6%和21.1%；24周发生率分别为22.7%和16.2%。复发无关的进展事件是12周和24周复合残疾累积事件的主要影响因素，分别占干扰素组的78.0%和80.6%，占奥瑞珠单抗组的88.0%和89.1%。结论：大部分的残疾积累事件与明显的疾病复发无关，这挑战了目前多发性硬化复发和进展形式的临床区别。《ORATORIO研究的事后分析：奥瑞珠单抗治疗原发性进行性多发性硬化症的长期随访》Lancet Neurology，2020年12月 (6)ORATORIO研究是一项国际、多中心、双盲、随机对照的3期试验，招募年龄18-55岁的、原发性进行性多发性硬化症患者，随机分配奥瑞珠单抗（600mg ivgtt q24w）或安慰剂，至少120周，之后可以选择进入开放标签阶段。共451人进入完成6.5年的随访。在早期使用奥瑞珠单抗的患者，残疾进展比例较低（51.7% vs 64.8%，P=0.0018），复合进展率较低（73.2% vs 83.3%；p = 0.0023）；需要轮椅的比例较低（11.5% vs 18.9%；p = 0.0274）。在研究结束时，奥瑞珠单抗组患者T2病变体积更小（0.45% vs 13.00%， p

FDA 批准降钙素基因相关肽单抗用于预防偏头痛和丛集性头痛的发作JAMA Neurology 妊娠与临床孤立综合征发病的关系J Am Coll Cardiol 复杂的颈动脉斑块是引起隐源性卒中的一个原因Nature子刊 颅内恶性肿瘤的无创检测Nature子刊 合成纳米颗粒治疗胶质母细胞瘤加那珠单抗（galcanezumab）降钙素基因相关肽（CGRP）受体位于疼痛信号通路、颅内动脉和肥大细胞中，其活化被认为在偏头痛的病理生理学中起着因果作用。加那珠单抗（galcanezumab）是一种CGRP单克隆抗体。和此前在《神经科星期四 Episode 4》中介绍的治疗急性偏头痛的CGRP受体拮抗剂包括：瑞美吉泮（rimegepant）和乌布吉泮（ubrogepant）；以及《神经科星期四 Episode 14》中介绍的预防偏头痛发作的依替尼单抗（eptinezumab）属于一类药物。2018年9月，FDA批准加那珠单抗用于预防偏头痛发作；2019年6月，FDA批准加那珠单抗用于预防丛集性头痛发作。《CONQUER研究：加那珠单抗预防偏头痛的安全性和有效性的3b期临床研究》Lancet Neurology，2020年10月 (1)这项多中心、随机、双盲、安慰剂对照的3b期研究，纳入2到4类偏头痛预防药物无效的患者655例，患者年龄在18-75岁之间，有发作性或慢性偏头痛，在50岁之前发生偏头痛，入组后随机接受安慰剂或加那珠单抗（120mg q1m * 3m）。在1-3个月期间，加那珠单抗治疗的患者偏头痛发作天数比安慰剂显著减少。与基线相比，加那珠单抗组每月平均少4·1天，而安慰剂组每月平均少1·0天（p < 0·0001）。加那珠单抗和安慰剂之间治疗紧急不良事件的类型和数量相似。结论：加那珠单抗在偏头痛的预防治疗方面优于安慰剂，并且在以前的多个标准预防治疗失败的患者中有良好的耐受性。 《加那珠单抗预防发作性丛集性头痛的临床研究》New England Journal of Medicine，2019年7月(2)阵发性丛集性头痛是一种神经功能障碍，其特征是每天头痛发作，持续数周或数月。共招募患者106人，随机分配接受加那珠单抗（300mg）或安慰剂组。基线期每周丛集性头痛的平均发作次数，加那珠单抗组为17.8，安慰剂组为17.3。在第1至3周中，加那珠单抗组每周平均减少为8.7次，而安慰剂组为5.2次（P =0.04）。在第3周，头痛频率降低≥50%的患者，加那珠单抗组为71%，安慰剂组为53%。除了加那珠单抗组8%的患者有注射部位疼痛外，不良事件发生率在组间没有实质性差异。结论：与安慰剂相比，在首次注射后的1-3周内，加那珠单抗300mg ip降低了偶发性丛集性头痛的发作频率。多发性硬化多发性硬化（multiple sclerosis，MS）是以中枢神经系统白质炎性脱髓鞘病变为主要特点的自身免疫病。本病最常累及的部位为脑室周围白质、视神经、脊髓、脑干和小脑，主要临床特点为中枢神经系统白质散在分布的多病灶与病程中呈现的缓解复发，症状和体征的空间多发性和病程的时间多发性。 多发性硬化症主要的模式和病程可以分为以下几种临床亚型：临床孤立综合征（CIS）、复发缓解型（RR）、继发进展型（SP）、和原发进展型（PP）。 《前瞻性队列研究：妊娠与临床孤立综合征发病的关系》JAMA Neurology，2020年12月 (3)多发性硬化症常诊断于育龄妇女，但妊娠是否能延迟脱髓鞘或临床孤立综合征（CIS）的首次发作尚无共识。研究的目的是探讨妊娠与CIS发病时间的关系。这个国际、多中心、前瞻性研究纳入2557名女性，CIS发病的平均年龄为31岁，发病前46%至少有1次怀孕，43%至少有1次分娩。首次怀孕的平均年龄为23.3岁，首次分娩的平均年龄为23.8岁。与从未怀孕过的女性相比，有过怀孕和分娩经历的女性发生CIS的时间较晚，延迟3.3年（P < 0.001）。与从未分娩过的女性相比，分娩过的女性发病年龄也较晚，延迟3.4年（P < 0.001）。孕产次数与发病延迟无关。结论：发病前怀孕和分娩与CIS发病时间之间存在关联，但与次数无关。需要进一步的研究来帮助解释怀孕和多发性硬化症发病之间关联的机制。《前瞻性观察性队列研究：持续免疫治疗与活动性继发进展性多发性硬化症患者残疾结果的相关性》JAMA Neurology，2020年11月 (4)研究旨在评价继发进展性多发性硬化的患者中残疾累计发生率，及是否能够通过治疗延缓残疾累积的进展。这项观察性队列研究中， 招募53680例多发性硬化的患者，其中4997例继发进展型，在1621例符合纳入条件的患者中，女性患者68.0%，发病时的平均年龄为33.9岁。共有661例（40.8%）患者在继发进展性多发性硬化期间经历了叠加性复发。早期治疗方案和残疾累计发生无关。继发进展期的高复发率与轮椅依赖的残疾风险增加有关（P = 0.009）。在继发进展性多发性硬化期间经历反复复发的患者中，抑制疾病进展的治疗与残疾进展率的降低和轮椅依赖风险的降低显著相关。结论： 继发进展型多发性硬化症患者中，残疾进展率与早期病程和治疗方案无关，但是与疾病复发相关。多发性硬化的治疗多发性硬化治疗的主要目的是抑制炎性脱髓鞘病变进展，防止急性期病变恶化及缓解期复发，晚期采取对症和支持疗法，减轻神经功能障碍带来的痛苦。疾病修正治疗（disease-modifying therapy，DMT）主要包括：抗整合素α-4单抗（那他珠单抗 natalizumab），抗CD20单抗（奥瑞珠单抗 ocrelizumab、奥法木单抗 ofatumumab、利妥昔单抗 rituximab），抗CD52单抗（阿伦单抗 alemtuzumab）、干扰素（干扰素β-1a、干扰素β1-b）、富马酸类（富马酸二甲酯 dimethyl fumarate、富马酸单甲酯 monomethyl fumarate）、鞘氨醇调节剂（芬戈莫德 fingolimod、西尼莫德 siponimod、奥扎莫德 ozanimod）、免疫抑制剂（克拉屈滨 cladribine），还可使用其他免疫抑制剂如特立氟胺（teriflunomide）、硫唑嘌呤、环磷酰胺、米托蒽醌等。《OPERA I和OPERA II研究：复发相关的恶化与复发无关的进展对典型复发性多发性硬化症总体确认残疾积累的贡献》JAMA Neurology，2020年9月 (5)奥瑞珠单抗（ocrelizumab）是一种靶向CD20+B细胞的单克隆抗体，于2017年被批准用于多发性硬化的治疗。研究旨在评价复发相关的恶化（relapse-associated worsening，RAW）和复发无关的进展（progression independent of relapse，PIRA）对证实的残疾累积（confirmed disability accumulation，CDA）的影响，并评估两种治疗方法对预后的影响。这2个相同的、3期、多中心、双盲随机临床试验中，1656人纳入分析，两组平均年龄37.2-37.1岁，随机奥瑞珠单抗组（奥瑞珠单抗 600mg ivgtt q24w）或干扰素组（干扰素 ip q3w）共96周。12周后，干扰素组和奥瑞珠单抗组的残疾累积事件发生率分别为29.6%和21.1%；24周发生率分别为22.7%和16.2%。复发无关的进展事件是12周和24周复合残疾累积事件的主要影响因素，分别占干扰素组的78.0%和80.6%，占奥瑞珠单抗组的88.0%和89.1%。结论：大部分的残疾积累事件与明显的疾病复发无关，这挑战了目前多发性硬化复发和进展形式的临床区别。《ORATORIO研究的事后分析：奥瑞珠单抗治疗原发性进行性多发性硬化症的长期随访》Lancet Neurology，2020年12月 (6)ORATORIO研究是一项国际、多中心、双盲、随机对照的3期试验，招募年龄18-55岁的、原发性进行性多发性硬化症患者，随机分配奥瑞珠单抗（600mg ivgtt q24w）或安慰剂，至少120周，之后可以选择进入开放标签阶段。共451人进入完成6.5年的随访。在早期使用奥瑞珠单抗的患者，残疾进展比例较低（51.7% vs 64.8%，P=0.0018），复合进展率较低（73.2% vs 83.3%；p = 0.0023）；需要轮椅的比例较低（11.5% vs 18.9%；p = 0.0274）。在研究结束时，奥瑞珠单抗组患者T2病变体积更小（0.45% vs 13.00%， p

FDA 批准靶向PDL1抑制剂成为尿路上皮癌的一线治疗Clin J Am Soc Nephr 老年捐赠者单肾和双肾移植的应用和结果LANCET 供氧冷灌注与标准冷灌注保存肾脏的临床研究Am J Kidney Dis ABO血型不匹配的活体肾移植对患者生存的影响Nature子刊 使用血浆和尿液无细胞DNA甲基化模式识别肾细胞癌阿维鲁单抗（avelumab）2020年7月，FDA批准PD-L1抑制剂阿维鲁单抗（avelumab）用于局部晚期或转移性尿路上皮癌患者的一线维持治疗。《JAVELIN Bladder 100研究：阿维鲁单抗用于晚期或转移性尿路上皮细胞癌的维持治疗》New England Journal of Medicine，2020年9月 (1)这项3期试验的目的是阿维鲁单抗用于化疗后尿路上皮癌患者的维持治疗的疗效。研究纳入局部晚期或转移性尿路上皮细胞癌，并且一线化疗（吉西他滨+顺铂或卡铂治疗4~6个周期）后未出现疾病进展的患者共700人，随机分入支持治疗组、或阿维鲁单抗维持治疗组。阿维鲁单抗维持性治疗显著延长了总生存期和无进展生存期。阿维鲁单抗与对照组相比，1年总生存率分别为71.3%和58.4%（中位总生存期，21.4个月vs. 14.3个月；风险比，0.69；P=0.001）；在PD-L1阳性人群中，阿维鲁单抗组和对照组相比，1年总生存率分别为79.1%和60.4%（风险比，0.56；P

FDA 批准靶向PDL1抑制剂成为尿路上皮癌的一线治疗Clin J Am Soc Nephr 老年捐赠者单肾和双肾移植的应用和结果LANCET 供氧冷灌注与标准冷灌注保存肾脏的临床研究Am J Kidney Dis ABO血型不匹配的活体肾移植对患者生存的影响Nature子刊 使用血浆和尿液无细胞DNA甲基化模式识别肾细胞癌阿维鲁单抗（avelumab）2020年7月，FDA批准PD-L1抑制剂阿维鲁单抗（avelumab）用于局部晚期或转移性尿路上皮癌患者的一线维持治疗。《JAVELIN Bladder 100研究：阿维鲁单抗用于晚期或转移性尿路上皮细胞癌的维持治疗》New England Journal of Medicine，2020年9月 (1)这项3期试验的目的是阿维鲁单抗用于化疗后尿路上皮癌患者的维持治疗的疗效。研究纳入局部晚期或转移性尿路上皮细胞癌，并且一线化疗（吉西他滨+顺铂或卡铂治疗4~6个周期）后未出现疾病进展的患者共700人，随机分入支持治疗组、或阿维鲁单抗维持治疗组。阿维鲁单抗维持性治疗显著延长了总生存期和无进展生存期。阿维鲁单抗与对照组相比，1年总生存率分别为71.3%和58.4%（中位总生存期，21.4个月vs. 14.3个月；风险比，0.69；P=0.001）；在PD-L1阳性人群中，阿维鲁单抗组和对照组相比，1年总生存率分别为79.1%和60.4%（风险比，0.56；P

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.255885v1?rss=1 Authors: Zheng, H., Zhu, M. S., Liu, Y. Abstract: Circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation pat-terns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns. Availability and implementation: FinaleDB service: http://finaledb.research.cchmc.org/. FinaleDB source code: https://github.com/epifluidlab/finaledb_portal and https://github.com/epifluidlab/finaledb_workflow. Copy rights belong to original authors. Visit the link for more info

A liquid biopsy is a minimally invasive alternative to a more traditional surgical solid tumor biopsy. In this episode, Dr. Stephanie Hastings, genomics product lead at Q Squared Solutions, lays out the considerations for liquid biopsy collection and the type of information that can be gathered from circulating free DNA (cfDNA). The main approaches comprise for evaluating cfDNA are: specific mutation detection to help support targeted therapies broader sequencing technologies to enable biomarker evaluations custom sequencing panels to support clinical trial assay development She describes the typical panels for each of the approaches, the sample collection requirements and how these analyses are implemented on a global scale.

Dr. Kathryn Lang, vice president of Health Outcomes and Evidence at Guardant Health discusses research highlighting the significance of its LUNAR-2 liquid biopsy test in detecting early-stage colorectal cancer (CRC) with clinically meaningful accuracy. These data were presented during the American Cancer Association for Cancer Research (AACR) Virtual Meeting II in Abstract #2316: "Integrated genomic and epigenomic cell-free DNA (cfDNA) analysis for the detection of early-stage colorectal cancer".

Guest: Carrie Guy, MS QNatal® Advanced is a noninvasive, prenatal, cell-free DNA (cfDNA) screen that can be ordered as early as 10 weeks gestation. This test utilizes Next-Generation Sequencing (NGS) technology and superior bioinformatics to ensure high sensitivity, specificity, and PPV. Here to walk us through the QNatal Advanced screening test and how the results are reported is Carrie Guy, a Certified Genetic Counselor and the Product Manager for Women's Health at Quest Diagnostics.

Guest: Carrie Guy QNatal® Advanced is a noninvasive, prenatal, cell-free DNA (cfDNA) screen that can be ordered as early as 10 weeks gestation. This test utilizes Next-Generation Sequencing (NGS) technology and superior bioinformatics to ensure high sensitivity, specificity, and PPV. Here to walk us through the QNatal Advanced screening test and how the results are reported is Carrie Guy, a Certified Genetic Counselor and the Product Manager for Women's Health at Quest Diagnostics.

In episode 9 we dive deep into the topic that could not be more relevant today - diagnosis of infectious diseases. Our guest on this episode is Tim Blauwkamp, the co-founder and Chief Scientific Officer of Karius, a company that leverages genomics and AI to develop highly-accurate diagnostic tests based on cell-free DNA sequencing. Karius has recently raised a stunning Series B round of $165 million to further the transition of their test to clinic.Tim did his PhD in Biochemistry at the University of Michigan, where he studied genes involved in nitrogen assimilation in bacteria. He then continued as a PostDoc first in Michigan and then at Stanford researching the mechanisms behind WNT signaling and its role in cell differentiation. He then joined Moleculo as a Head of Molecular biology. Moleculo was acquired by Illumina and Tim was responsible for bringing to life the technologies that made it possible to generate long and accurate sequencing reads. About six years ago, Tim co-founded Karius together with Mickey Kertesz. Tim and his team have achieved enormous progress during the last years, bringing the diagnostic tests to clinics that are already changing the lives of patients. Together with Tim, we have talked about:: ◦ The story behind Karius ◦ Cell-free DNA (cfDNA) as a blood biomarker of infection ◦ Why DNA sequencing has an edge over classical microbiology methods ◦ The challenge of isolating microbial cfDNA from blood ◦ Untangling cfDNA sequencing data with AI ◦ Why Coronavirus (SARS-CoV-2) is hard to detect using NGS ◦ Diagnosing sepsis based on microbial cfDNA ◦ Clinical evidence as a key to healthcare innovation ◦ Working with payers to spread the use of innovative diagnostic tests ◦ How cfDNA screening can become a cornerstone of next-generation medicineGet in touch with Tim: ◦ LinkedIn: Tim Blauwkamp ◦ Twitter: @timblauwkamp ◦ Web (Karius): http://kariusdx.com/ ◦ Email: tim.blauwkamp@kariusdx.comMake sure to download the full show notes with our guest's bio, links to their most notable work and our recommendations for further reads on the topic of the episode at pmedcast.com

Dr Salomon Manier speaks with ecancer at the 16th International Myeloma Workshop about cell-free DNA (cfDNA) and circulating tumour cells (CTCs) sequencing that enable serial temporal sampling. The team looked at whole-exome sequencing (WES) and ultra low pass-whole genome sequencing (ULP-WGS) of cfDNA and CTCs in multiple myeloma. The study demonstrated that WES and ULP-WGS of cfDNA and CTCs are consistently representative of tumour DNA alterations in terms of CNAs and SNVs. This approach could therefore be used to longitudinally follow clonal evolution and minimal residual disease in MM, personalising and improving treatment. It also reduces the need for bone marrow biopsy, greatly improving the patient experience.

Dr Chandarlapaty talks to ecancertv at SABCS 2015 about the results of a study looking at two genetic mutations in the estrogen receptor 1 gene (ESR1) and how this affected the outcomes of women with estrogen receptor-positive metastatic breast cancer. The Y537S and D538G mutations in ESR1 are common alterations seen in metastatic breast cancer and result in making the receptor estrogen independent and can results in resistance to estrogen deprivation therapy such as an aromatase inhibitor. Using blood samples from the BOLERO-2 study, Dr Chandarlapaty and colleagues hypothesized that cell free DNA (cfDNA) analysis of a patient’s plasma could be used to detect the presence of the mutations. The mutations were found in about 30% of women and women with these mutations had a shorter OS than women who did not have these mutations. Dr Chandarlapaty says that one major implication of these data is that it shows a blood sample could be taken to test for these mutations and provide important prognostic information.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.

Dr. Jack West reviews new techniques for evaluating mutations from blood, including detection of circulating tumor cells (CTCs) or mutations in circulating free DNA (cfDNA) that can replace at least some tissue biopsies.