Podcasts about mindact

In deze podcast, u aangeboden door oncologie.nu, spreekt Koos van der Hoeven met Laura van ‘t Veer naar aanleiding van de beslissing van Zorginstituut Nederland dat de MammaPrint voldoet aan de ‘stand van de wetenschap en praktijk'. Aan bod komen onder andere de ontstaansgeschiedenis van de MammaPrint, de RASTER- en de MINDACT-studie, en het proces tot voldaan werd aan de ‘stand van de wetenschap en praktijk'.

In this episode, we focus on the clinical value of gene expression profiling tests to analyze a number of different genes in breast cancer cells to predict the risk of cancer recurrence, and to provide insight into the biological natural history of the individual tumor. The results of gene expression profiling tests can help determine who may benefit from adjuvant treatment after surgery.Notably, this year is the 20th anniversary of the 2 seminal papers which showed that gene expression could predict clinical outcomes for breast cancer patients. That 70-gene signature, which later became Mammaprint, was published first in Nature, and then followed up a few months later with survival data in a publication in the New England Journal of Medicine. Today we speak with the first author of the most recent New England Journal of Medicine paper, from 2016, demonstrating the clinical value of MammaPrint as a decision aid for early breast cancer, Dr. Fatima Cardoso (Director Breast Unit Champalimaud Clinical Center Lisbon, Portugal). This result from the MINDACT study was followed up in a 2021 Lancet Oncology publication, which provided level 1 evidence of the validity of that 70-gene signature. We also interview Dr. William Audeh (Chief Medical Officer at Agendia BV, CA) to discuss the implications of the MINDACT trial and the added value of the genomic profiling tools MammaPrint and Blueprint. Dr. Audeh also touches upon the FLEX study, which provides whole transcriptome data linked with a clinical database annotated with over 800 clinical characteristics, over 90 sites in USA and > 9K patients enrolled with the ambition to enroll 30K. We also touch upon new data from the I-SPY trial, which indicates that within the high-risk region, there is also information to be gained by stratifying patients into High Risk 1 and 2 categories. Enjoy listening!Let us know what you thought of this week's episode on Twitter: @physicianswkly Want to share your medical expertise, research, or unique experience in medicine on the PW podcast? Email us at editorial@physweekly.com! Thanks for listening!

Dr. Hope Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, highlights key studies in breast cancer featured at the 2021 ASCO Annual Meeting.   Transcript: ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Hope Rugo. She is a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. Dr. Rugo joins me to discuss key advances in the breast cancer field featured at the 2021 ASCO Annual Meeting. Dr. Rugo has received research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Roche, and other organizations. Her full disclosures are available on the transcript of this episode at asco.org/podcasts. Dr. Rugo, it's great to have you on the podcast today. Dr. Hope Rugo: Oh, it's great to be here. ASCO Daily News: There were many interesting studies in breast cancer featured at the Annual Meeting. Thank you for being here to highlight some of them. Let's start with the OlympiA trial. This is LBA1. This remarkable study found that adjuvant olaparib extends disease-free survival in BRCA-mutated early stage HER2-negative breast cancer. What can you tell us about this trial? Dr. Hope Rugo: Well, this is really such an amazing study, in terms of the results and its practice-changing impact. The study actually kind of interestingly was published in the New England Journal [of Medicine] 2 days before it was presented. And even though we had all seen the data, it was really such a, I think, moving presentation in terms of really changing the face of treatment for women and men with BRCA1 and BRCA2 associated breast cancer. Of course, olaparib and talazoparib are both PARP inhibitors that are approved to treat metastatic breast cancer associated with BRCA1 and BRCA2 mutations. And in those randomized trials, they showed improvement in response and progression-free survival, but not clear differences in overall survival. So, of course, when we have an impact in the metastatic setting, the next step is to move into early-stage breast cancer. But that's quite a challenge given the fact that you have to test and find the mutation, which is challenging in some parts of the world. And then you have to decide which group of patients need more than standard therapy. So the OlympiA trial randomly assigned patients who had pathogenic BRCA1 or BRCA2 mutations and HER2-negative, either hormone receptor-positive or triple negative breast cancer, to receive a year of olaparib or a placebo. And the patient eligibility was further defined. If you had triple negative breast cancer, you could have had any residual disease after neoadjuvant therapy, or you had to have a tumor greater than two centimeters or a positive node. If you have hormone receptor-positive disease keeping in mind the benefit of adjuvant endocrine therapy. If you didn't have a pathologic complete response to neoadjuvant therapy, you had to have a few other high-risk features using the CPS plus EG score. And if you received adjuvant therapy, you had to have four or more positive nodes, so stage III disease. All patients had to have received at least six cycles of chemotherapy, radiation as indicated, and of course, hormone therapy was given for hormone receptor-positive disease. There were over 1,800 patients randomly assigned, which was pretty, I think, impressive given the fact that everybody had to be tested. And the whole idea behind the trial is that you would enroll a group of patients who still had a high residual risk of recurrence, even though you got standard and reasonable adjuvant or neoadjuvant therapy. It's important to keep in mind when you think about the results of this trial is that having a BRCA mutation, and in particular BRCA1, increases sensitivity to chemotherapy. So the pathologic complete response rates, for example, in the neoadjuvant setting for triple negative breast cancer with the BRCA1 gene mutation, are higher than in patients who don't have a germline mutation. And so you're really looking at a group of patients who have high-risk disease because they didn't have a pathologic complete response if it was the neoadjuvant setting. Now, of the patient population, a little over 70% had BRCA1 mutations. The rest had BRCA2 mutations. And for the triple negative group, that represented a large portion of the population, about 80%. Again, the rest, a little under 20%, had hormone receptor-positive disease. As you would expect, more than 50%, about 60%, were premenopausal. And about 50% received neoadjuvant therapy. There's always a question about whether or not treatment with prior platinum-based therapy, which is also effective when you have DNA repair deficiency, such as in the germline BRCA mutations, whether or not that would affect sensitivity. A little more than a quarter of the patients had received a platinum chemotherapy agents. And the invasive disease-free survival, the primary endpoint of this trial, was really remarkable. There was an 8.8% improvement in a 3-year invasive disease-free survival rate in patients taking olaparib versus placebo, a very big p-value, and a hazard ratio 0.58. This is really dramatic. The curves separated early, and they remained separated. So that it was the IDFS was 77% for patients on placebo and about 86% in patients who were receiving olaparib, just really very impressive. And one of the things you want to find out about is are you changing the rate of distant recurrence. And indeed, not only were there less distant recurrences, but if you look at distant excluding the brain, that's where you really saw the biggest difference. There was a small difference--hard to know if it really is significant--1.5% less brain recurrence is a big issue for patients, particularly with triple negative disease. It was a little less contralateral invasive disease, but it wasn't anything significant. So really, what you were preventing was the kind of recurrence we don't want to see, which is distant recurrence. And then if you looked at the distant disease-free survival, the absolute improvement for metastatic disease was 7.1%. Again, the curve separated early and stayed separated over time. Now, overall survival, of course, is the golden endpoint that you want to look at. There were numerically less deaths in the olaparib arm, 59 versus 86 in the placebo arm. Most of these deaths were due to breast cancer. And the hazard ratio is 0.68. Although the p-value was 0.024, that didn't meet the statistical plan, which was a p less than 0.01 in terms of how the statistics can be balanced in this trial. But the overall difference was 3.7%. And of course, there were subgroup analyses done, which showed that everybody benefited. It was impossible to see a difference. And again, only a small number of patients relatively receive platinum, so it's hard to know whether or not that changed the response. In terms of the side effects--you always want to think about side effects--it was exactly what you would have expected from what we [expect] in the metastatic setting. Not a lot of grade III or greater toxicities. Mainly anemia was the most common at 9%, and 5% neutropenia, a little bit increase of grade III fatigue, but only 2%. The rest of the toxicities were all grade I and II. And of note, olaparib does cause nausea, 57% of patients versus 23% reported nausea with olaparib versus placebo. But normally, you can manage this nausea and the anemia by actually dose reducing and first holding and then dose reducing. One of the big questions, of course, with PARP inhibitors is if you're inhibiting repair of DNA, are you causing leukemia--new primary cancers? And it was very encouraging. Again, it's 3 years, so we need to be followed a little bit longer, maybe 5, but it was 0.2% or 0.3%. There was no increase in myelodysplasia or myeloleukemias with the use of the PARP inhibitor, which is really important. And the global quality of life scores were identical. So even with these side effects, they could be managed and didn't impact global quality of life. And then in terms of the paper, the additional information the paper gave is that most of the people who required a transfusion received only one transfusion of red blood cells. So I think with the caveat that there are some additional side effects, they are generally able to be managed well. Quality of life is maintained. And there's a huge early difference in the most important endpoints that we look for in these trials--invasive disease-free survival and most importantly, distant disease-free survival. So definitely history in the making. ASCO Daily News: Excellent. Thank you for sharing these fantastic results from the OlympiA trial. The ECOG-ACRIN Research Group presented EA1131, a study of platinum-based chemotherapy or capecitabine in patients with residual triple negative basal-like breast cancer following neoadjuvant chemotherapy (Abstract 605). This interim analysis really highlighted the need for better therapies for this patient population. What are your thoughts on this trial? Dr. Hope Rugo: Well, this, I think, is an important trial. Ingrid Mayer from Vanderbilt designed the trial with ECOG and actually presented the data. There will be a lot more data coming from this study because they collected tumor tissue and are doing a lot of different analyses, which might help us understand the benefits of different treatments in different subgroups of patients with triple negative breast cancer. Now, this trial really focused on patients who have the highest risk disease after neoadjuvant therapy, clinical stage II or III triple negative breast cancer diagnosis. They received the standard neoadjuvant chemotherapy. And they had to have tumors that were greater than one centimeter in the breast at the time of surgery or any positive lymph nodes. So this is actually a group of patients who we already know have a high-risk of distant recurrence. They did do an analysis of the tissue using a PAM50 assay to understand which tumors were basal or non-basal like. And patients were randomly assigned to receive capecitabine by the CREATE-X trial, which showed an improvement in overall survival when capecitabine was given to patients with residual triple negative breast cancer after neoadjuvant chemotherapy in Japan and Korea, versus carboplatin or cisplatin by treating physician discretion (DOI: 10.1056/NEJMoa1612645). The patients received four cycles every 3 weeks of carbo or cisplatin. Now, one thing that's important to keep in mind is in Japan where the CREATE-X trial was designed in Korea where it also participated, the capecitabine dose was the original U.S. Food and Drug Administration (FDA)-approved dose, where it was a little bit higher, 1,200 milligrams per meter squared twice a day, 2 weeks on, 1 week off. In the U.S., patients don't tolerate this very well. And there is a different metabolism in Asian patients, where they can tolerate a higher dose of 5FU and capecitabine with not as much toxicity due to pharmacogenomics. The patients in the ECOG-ACRIN trial received capecitabine at 1,000 milligrams per meter squared twice daily with the same schedule, which is really all that's tolerated. So the objective of this trial was to see whether or not you could do better or the same if you received a platinum versus capecitabine with the idea that DNA damaging agents work very well in basal-like triple negative breast cancer. So the patients were enrolled in this trial. 415 patients were randomly assigned. And then the data safety monitoring group who were following the results at the interim analysis ended up closing the trial because they found that based on the statistics so far that it was unlikely that the platinum arm would either be better or worse than the capecitabine arm. And they saw more toxicity in the platinum arm. So the trial was closed. And that's the data that was presented. So there was a total of 160 patients who received capecitabine, [and] 148 [patients] who received platinum. Most of the patients had basal-like disease. The age, it was about 52. It's all what you would have expected to see in this patient population. So I don't think we have any concerns about the patient population. The 3-year invasive disease-free survival in patients with basal-like triple negative breast cancer, the primary endpoint of the trial, was identical between the two arms. But actually, discouragingly, it wasn't great. So IDFS for capecitabine was 49% and platinum 42%. So this was actually very disappointing data. And I think it just highlights how we really need to provide better treatment for our patients who don't achieve pathologic complete responses to the best neoadjuvant therapy. It is true that the ECOG-ACRIN trial didn't require that patients receive anthracyclines, but 85% did. So I think that we feel really comfortable that they got good chemotherapy. They looked in the non-basal-like sub-type. And in the non-basal-like sub-type, which are cancers that are more likely to be responsive to capecitabine in the metastatic setting, actually, the outcome, although small numbers, looked better with capecitabine than with getting the platinum-type therapy. And if you looked at non-basal versus basal, regardless of therapy, the patients who had non-basal-like disease did much better than the patients who had basal-like disease, something that we would have guessed, but hasn't been shown before. So I think it was really important, [and] really helps us to identify the patients who need the most intervention. But even the basal group, the IDFS, the non-basal group, it was 55.5%. So better than basal at 46%, but still you got 45% of patients with invasive disease-free survival event over a 3-year medium follow-up. Overall survival at 3 years, also, was disappointing at about 66% for capecitabine and 58% for platinum. So I think that, really, this trial just identified, I think, in a very confirming way how we need to make progress in the treatment of these patients who have residual disease after neoadjuvant chemotherapy. In terms of toxicity, the platinum-based therapy clearly was more toxic. Most of the toxicity that was seen was grade I and II, as you would expect, but there was more grade III toxicity even with the platinum-type therapy. Again, as you would expect. You get hand-foot syndrome with capecitabine and not with platinum. But there was more of the standard toxicities that you would expect with the platinum or bone marrow suppression, primarily some thrombocytopenia, et cetera. So when they looked overall at the trial population, I mentioned that most had basal sub-type by PAM50. It was 80%. So it is a group of patients where I think even going into neoadjuvant therapy about 80% have basal-like disease. So I think it makes us very interested in the results that we expect to see in the very near future from the KEYNOTE 522 trial, where we've seen an improvement in pathologic complete response, particularly in patients with node positive disease with the addition of pembrolizumab, to standard taxane platinum and anthracycline-based neoadjuvant chemotherapy (DOI: 10.1056/NEJMoa1910549).  But a very recent press release noted that they have reached their event-free survival endpoint. And that pembrolizumab improves event-free survival. And the importance of this data, which, of course, has not yet been shared, so we have to see what it looks like and what the differences are, is that they had shown earlier at the FDA's ODAC meeting in February of this year that possibly patients who don't achieve a PCR, who received pembrolizumab before and after surgery, had a better outcome than patients who did not receive pembrolizumab and received placebo. So how we incorporate capecitabine into the post-neoadjuvant treatment or other novel agents will very much be a subject of the next few years as we sort this out. But if the pembrolizumab data is indeed exciting--and we'll talk more about the durvalumab data in just a moment--then I think the question would be, what chemotherapy do you give? And based on this trial, there is absolutely no indication for platinum postoperatively in patients with residual disease after neoadjuvant therapy. Capecitabine should be given. But clearly, we need better options for therapy. And this is also being studied with some of the new antibody drug conjugates, like sacituzumab govitecan to see whether or not we can improve outcome in these patients. ASCO Daily News: Right. Well, let's look at Abstract 506. This is the phase II GeparNuevo study. The data presented by the German Breast Group showed that neoadjuvant durvalumab improves long-term outcomes for patients with triple negative breast cancer. What is your takeaway from this study? Dr. Hope Rugo: You know, this was really interesting, and I think unexpected results based on their original presentation. This was a phase II neoadjuvant trial in patients with triple negative breast cancer. And the data by the GBG and Sibylle Loibl, who runs the GBG, had already presented the data from the primary endpoint of this smaller neoadjuvant trial, which was pathologic complete response. And what they did in this trial was they treated patients with a nab-paclitaxel followed by epirubicin and cyclophosphamide. And the patients were randomly assigned to receive the checkpoint inhibitor durvalumab versus placebo. There were 174 patients stratified by a low, medium, or high TILs. And their main endpoint, as I mentioned, was PCR. So this is a secondary endpoint of invasive disease-free survival. A group of patients received 2 weeks of durvalumab as sort of a lead-in first. And they've looked at that group separately. But it's hard to know because it's such a small trial what that means. And nobody is using a lead-in right at the moment. So their primary endpoint, as I mentioned, has been published already in Annals of Oncology in 2019 (DOI: 10.1093/annonc/mdz158). Although numerically there was a higher PCR rate in the durvalumab treated arm, this was not statistically significant. The p-value is in no way significant. And they looked at, in a forest plot, they showed that the patients who had the window seemed to have a higher PCR, but it was hard to justify exactly why that was the case in this group of patients. Now, it's important to keep in mind that the data that we have from KEYNOTE 522, the neoadjuvant trial with pembrolizumab, and IMpassion 31, the trial with the atezolizumab, showed the benefit, particularly in patients with node-positive disease. In this trial, about a third of the patients had stage zero or I breast cancer. So 61 out of the total of 174 patients did not have positive nodes. So we thought the PCR difference really wasn't seen because they had a low-risk population. But now, they're presenting their secondary endpoint of invasive disease-free survival in this group of patients. And what they saw, actually, at a median follow-up of about 44 months, they saw a 12 IDFS events in the durvalumab arm and 22 in the placebo arm. And actually, there were twice as many distant recurrences in the patients treated with placebo versus durvalumab. So 13 versus six events for distant recurrence. So I think that's actually a really important endpoint. And if you looked at the invasive disease-free survival at 3 years, it was 77% for placebo and almost 86%. So almost a 9% difference in favoring the patients who received durvalumab. Pretty dramatic, you know? A hazard ratio of 0.48. And they did have a p-value of 0.0398. So that was quite interesting. And they looked at distant disease-free survival. Numbers are small here, but I think it's a really important endpoint, and overall survival. Overall survival is early to see, but they could see--this is a long follow-up, but it's a small study rather than early--and they showed that overall survival difference was 83.5% in the placebo arm and 95.2% in the durvalumab arm. Again, secondary endpoints with a hazard ratio is 0.24 and, again, a p-value of 0.1. Distant disease-free survival, such an important endpoint, was a huge difference 78.4% versus 91.7%. Again, hazard ratio of 0.31. So pretty dramatic. And when you looked at subgroups of patients, and they looked at PD-L1 positive versus negative. Almost all of the patients had PD-L1 positive disease, so 138 versus 20 that were PD-L1 negative. So it's kind of hard to interpret any of that. And that trial was stratified by stromal TILs anyway. They did show that patients who had a PCR had a better outcome than patients who did not have a PCR. But among the patients who had a PCR, the patients who had durvalumab did better, again, with almost a 10% difference, favoring durvalumab versus placebo. Now, this is a phase II randomized trial, so it's small. And so this is really hypothesis generating. But given the fact that KEYNOTE 522 and IMpassion 31 (NCT03197935) gave the checkpoint inhibitor for a year, and in this situation patients received durvalumab only in the neoadjuvant setting, it suggests that they saw this impact in patients who had a PCR that was greater in patients receiving durvalumab placebo. So it suggests that even though the PCR improvement was not significant, that just the treatment with a checkpoint inhibitor changes long-term outcome. And we know that there's more toxicity by giving longer course checkpoint inhibitor therapy, so we expect that we might see approval of pembrolizumab based on the KEYNOTE 522 trial. And it will bring up the question of whether or not you need a whole year of treatment to improve outcome. And whether or not simply treatment preoperatively might be sufficient, particularly in the patient group who achieves a PCR. It will be, I think, very, very important to be able to evaluate this in order to reduce the toxicity, both the physical toxicity, as well as financial toxicity from use of checkpoint inhibitors in patients with triple negative breast cancer. Also, we know that a third of these patients had stage I disease. And I think we really need to look at the larger trials quite carefully to understand whether or not all patients need checkpoint inhibitors who have triple negative disease. Or whether or not we could more correctly focus on the patients who have higher risk disease, node-positive disease who've been shown to have less tumor infiltrating lymphocytes than patients who have less burdensome disease at diagnosis. ASCO Daily News: Right. So what about the subset analysis in Abstract 1011 that looked at outcomes in patients who are age 65 and older in the phase III ASCENT study of sacituzumab in metastatic triple negative breast cancer? Can you tell us about ASCENT and the toxicities associated with this antibody drug conjugate in this older patient population? Dr. Hope Rugo: Well, ASCENT, of course, is a practice-changing trial as well. It led to the final formal approval of sacituzumab govitecan for patients with metastatic triple negative breast cancer in the second line or greater earlier this year after accelerated approval was granted earlier in 2020. This antibody drug conjugate is given 2 weeks on, 1 week off. And the primary toxicity is neutropenia, and then to a lesser degree diarrhea. But overall, the drug is quite well-tolerated. In the overall parent ASCENT trial, as the listeners know, showed an improvement in progression-free and overall survival at the first analysis. Very impressive data with sacituzumab in these heavily pretreated triple negative breast cancer population, compared to treatment of physician choice with standard chemotherapy options, where about 50% of the patients received eribulin, which had already been shown to be better in terms of overall survival compared to other chemotherapy in the subset of patients treated in the past with eribulin who had triple negative disease. So at ASCO this year, Kevin Kalinsky presented on behalf of our authorship group a subset analysis looking at patients who were age 65 and older to better understand whether there was more toxicity and as much benefit in this group of patients. So important when we're looking at novel therapies. So overall, there were 44 patients treated with sacituzumab and 46 with treatment of physician choice who were age 65 or older. Most of the patients had received two to three lines of therapy. And about 40% had received greater than three lines of therapy. The median prior anticancer regimen was pretty similar to the overall group. Most of the patients had initially been diagnosed with triple negative disease, but really, interestingly, about a third of the patients had ER-positive or something else disease initially and were triple negative on biopsy in the metastatic setting. So an interesting subgroup of patients that were also looked at separately and appeared to benefit to the same degree as the triple negative patients. So we looked at progression-free survival in this group of patients looking at patients under age 65 and age 65 and older. A hazard ratio was even greater in the age 65 or older for--it's hard. These are subset comparisons, but the hazard ratio is 0.22 going from 2.4 months with standard therapy to 7.1 months with sacituzumab. The hazard ratio in the younger group was 0.46. But still a big difference in progression-free survival. And then in terms of overall survival in the age 65 and older group, it went from 8.2 to 15.3 months with a hazard ratio of 0.37. And so also really quite dramatic. And overall response was also significantly increased with, in fact, the only responses seen in the age 65 or older group seen in the sacituzumab group. There were no complete or partial responses in the treatment of physician choice group. Of course, really important to look at safety in our older patients because we know that generally there is more toxicity in that group of patients. But actually looking at grade III or greater toxicity, keeping in mind it was 49 [patients] in the older group versus 209 patients in the younger group, there was no difference in grade III or greater toxicities. There were more dose reductions. So 35% reduced their dose versus 19% older versus younger. But there was no difference in adverse events that led to discontinuation between the younger and older group. So that was really encouraging. We see this in almost all trials that older patients have more dose reductions and that was seen here as well. And we also looked at this very small subset of patients who are age 75 or older versus age 65 or older. And the rates of adverse events were similar, albeit smaller number of patients. There was, if you looked at specific treatment-related adverse events that led to dose reduction, it was a neutropenia, fatigue, diarrhea, febrile neutropenia in a small number, 6% versus zero in the treatment of physician choice and nausea. So it's helpful to know what those toxicities are when you're thinking about treating these patients in clinical practice. And in a patient who might be a little less strong, a little older, more comorbidities, so slightly more frail, I would consider starting potentially at a 3/4 of the dose and then going up if they tolerate it well, versus starting at the full dose and getting a lot of toxicity. But this was really encouraging data that showed that you can give the drug to patients who are older and even elderly at age 75 or greater. So that was good to see. And then Lisa Carey presented additional data looking at patients who were treated in the second line or greater because the formal approval by the FDA is in second or greater line. But most of the data looked at patients who were treated in the third or greater line. So you were supposed to have at least two chemotherapies for advanced disease, but you could have had one in the early stage setting if your progression occurred within 12 months. So there were 33 and 32 patients in the sacituzumab and treatment of physician arm, respectively, who had a recurrence within 12 months of neo or adjuvant chemotherapy. They got one line of chemotherapy in the metastatic setting. And then they were randomly assigned on the ASCENT trial. And as you would expect, tiny numbers, right? 33 and 32 patients. But you get a lot of events in this patient population. The PFS was much greater in patients getting sacituzumab than treatment of physician choice. Hazard ratio of 0.41. And also, if you looked at overall survival, it was double. The hazard ratio is 0.51, even in the second line setting. I think it's really interesting to look to see what the toxicity is relative to the lines of therapy. But because the numbers are so small, it's really hard to look at this now. We'll see more data on toxicity when we see data in the first line, as well as the post-neoadjuvant setting in ongoing trials. And I think that will help us a lot to understand what I think we see in the current clinical trials and in practice, which is that patients who are treated in this second line setting have less hematologic toxicity as well as GI toxicity and need less growth factor intervention, et cetera. And I expect that we'll see that in the post-neoadjuvant setting as well. These numbers are too small to really look at any differences in toxicity. But all of this data I think was incredibly encouraging for us in terms of the use of sacituzumab in patients with metastatic triple negative disease, as well as the expansion to the first line and to post-neoadjuvant setting. ASCO Daily News: Excellent. Investigators of the phase III MINDACT trial, that's Abstract 500, evaluated the survival of patients with an ultra low risk 70 gene signature. How will MINDACT inform clinical practice? And do you think this study might guide more appropriate choices of chemotherapy in women with node-negative or one to three node-positive disease? Dr. Hope Rugo: Well, how MINDACT will inform clinical practice is a very big question. And it already has informed clinical practice identifying patients who are better candidates for chemotherapy and endocrine therapy versus endocrine therapy alone who have stage I and II hormone receptor-positive early stage breast cancer based on their primary outcome results. This particular analysis was something different. So we think about using this 70 gene score and the recurrence score from the TAILORx trial (DOI: 10.1056/NEJMoa1804710) and RxPONDER to try and identify which patients need more therapy versus less therapy. Now, we also know that these scores have some prognostic impact. Clinically, we mainly have used them to decide who should get chemotherapy in addition to endocrine therapy. This trial looked at a different way to use a gene expression scoring system. It's really to identify which patients need less. Given the fact that your middle of the line therapy is endocrine therapy, which patients do we know who will do very, very well with any endocrine therapy and don't need extended duration endocrine therapy? That's really the question here. So they looked at the patients who were in the MINDACT trial and used data published by my colleague, Laura Esserman who looked at a cohort of patients retrospectively and found that patients who had an ultra low score in MINDACT. And that's a score greater than 0.355 where plus 1 is the lowest end of low risk, and minus 1 is the highest end of high-risk, so greater than 0.355. She identified a group of patients who did well, regardless of whether they received tamoxifen or not apparently in this retrospective long-term outcome where there was 15-year follow-up. So they use that data to go into the MINDACT population and to try and understand which patients benefit. And the MINDACT is a much higher risk group of patients. So if you looked at that original trial that Laura Esserman published, these patients had screen detected cancers. And in fact, the 70 gene signature low and ultra low-risk tumors are, as you would expect, over-represented in screen detected cancers. So you've got this excellent survival regardless of treatment. So how did they apply to MINDACT? So in MINDACT, patients were randomly assigned, of course, who had clinical low, genomic high, or clinical high genomic low to receive chemotherapy or not. In this situation, you're really looking at the patients who have genomic ultra low disease. So most of those patients would not be getting chemotherapy because they would already have ultra low disease. So what they found actually when they looked at the overall population of MINDACT, 6,700 or so patients, they found 15% of patients or 1,000 patients fell into this ultra low category. And if then you looked at the patients who were high-risk, it was 36%. And patients who fell into the big low-risk group, it was about 49%, so about half of the population of patients. So they looked at the different metastasis-free interval rates in patients who had genomic low and ultra low-risk disease, regardless of the treatment the patients receive. They all receive endocrine therapy, remember? So they actually found that in patients who were ultra low versus low-risk, that the hazard ratio is 0.65, showing that patients who had ultra low-risk--remember, this was 1,000 patients at 8 years--there was only 36 events. So they had a 97% 8-year distant metastasis-free interval, compared to 94.5% for low-risk and 89.2 in high-risk disease. They looked at breast cancer-specific survival rates as well. And for ultra low-risk in 1,000 patients, there were exactly eight events. 99.6% 8-year breast cancer-specific survival. So really, quite remarkable. So clinical high-risk tumors tend to have larger size, higher grade, be node-positive. We already know that. For the 1,000 genomic ultra low-risk patients, about almost 70% were greater than 50 years. 80% were node negative. 81% had tumors that were T1, so up to two centimeters. And most of them, except for 4%, were grade I and II. 97% were hormone receptor-positive HER2-negative. Only 14% of patients who had ultra low-risk disease received chemotherapy in MINDACT. And most of the rest received endocrine therapy. Some actually didn't receive endocrine therapy. 16% had no adjuvant systemic treatment at all. So if you looked at the genomic ultra low-risk patients and divided them into clinical low-risk and clinical high-risk, there was really no difference in the events overall, a little bit less 8-year distant metastases-free survival, but not much of a difference. So really, a quite remarkable outcome. Now, what you want to know, of course, then is, does it make a difference if you get endocrine therapy at all? And they looked at the patients who had chemotherapy versus no chemotherapy. And as you would expect, it made no difference. Again, it was a tiny number of patients. But if you looked at endocrine therapy versus no endocrine therapy, it was hard to tell. Because, again, no adjuvant systemic therapy was only 157 patients. There were four events. And for the patients, 685 patients who got endocrine therapy, there were 23 events. So the 8-year metastasis-free interval was identical, but there just aren't enough patients in that no adjuvant systemic therapy group to really understand. So what we know is ultra low-risk defines a group of patients who have excellent outcomes. Does it tell us that they don't need adjuvant systemic therapy? No. Eight years really isn't enough time, unfortunately, in is group because 50% of recurrences occur after five years and out to 20 plus years. We have to keep in mind the Early Breast Cancer Trials Group data showing how many recurrences occurred after five years of endocrine therapy. But in this group of patients who have ultra low-risk disease, they clearly do not benefit from chemotherapy. And I think that's regardless of their clinical risk. And it's likely that 5 years of adjuvant endocrine therapy is absolutely all those patients would ever need. If you have a small cancer that's ultra low-risk, could you get by with less than 5 years of endocrine therapy in a patient with a lot of toxicity? Potentially. And I think that's a really important bit of information to take back into clinical practice when you're talking to patients about the duration of endocrine therapy. But a stage I tumor or stage II with ultra low-risk disease, in general, I would treat for 5 years. I think it's important to keep in mind that premenopausal women, even with ultra low-risk stage II disease, have an ongoing risk of recurrence. And I still think that those patients should be treated with a varying function suppression and aromatase inhibitor if tolerated and tamoxifen otherwise because our very young patients tend to have higher risk of recurrence over time. And it's very hard to separate them out in these studies. Interestingly, there are a few young women who have ultra low-risk disease. So I think this really helps us understand yet another impact of genomic tests, which is who needs less therapy, not just who needs more. ASCO Daily News: Great. That's good to hear. Well, finally, the theme of the Annual Meeting was equity. And in Abstract 1092, you and your colleagues at University of California, San Francisco (UCSF) looked at decreased enrollment of patients with advanced lobular breast cancer compared to ductal breast cancer in interventional clinical trials. Can you tell us about this study? Dr. Hope Rugo: Yes, this was a really interesting evaluation. My colleague surgeon Rita Mukhtar at UCSF actually led this evaluation with a very good student who's working with us on some of our research trials. And the idea was that we had observed anecdotally, as have others, that patients with invasive lobular cancer tend to be less likely to meet criteria for clinical trials. So they don't have measurable disease as much. We tend to see sclerotic bone lesions, diffuse infiltration without measurable disease. And it can be much, much more difficult to meet the criteria for clinical trials. So actually, what my colleagues did in this trial is look at whether or not patients with lobular breast cancer are underrepresented in clinical trials. And so they looked at the proportion of interventional stage IV clinical trials that used RECIST in clinicaltrials.gov. And then actually looked at the patients who have RECIST measurable disease who have lobular cancer. And it's really interesting. I mean, we just have a lot less RECIST measurable disease. And in the UCSF cancer registry, patients who were enrolled in clinical trials, if you looked at invasive lobular cancer were markedly decreased if you compare it to patients with other sub-types of breast cancer. So we think that that's probably due to the requirement for measurable disease. And that what we should do in patients who have metastatic lobular cancer is develop trials that are specifically for lobular cancer that focus on the unique biology. And there's a lot of work going on now looking at that biology. And allow patients to enroll based on their disease control rates rather than response. So that we don't require RECIST measurable disease since that's hard to come by in invasive lobular cancer. So I think it's a really important area. It's about 15% of invasive breast cancers. We see a lot of lobular cancer in the metastatic setting. And I think it's unfortunate not to be able to enroll these patients in clinical trials. There is a lot of interest in the cooperative groups in the United States in Europe and in Asia, of course, in trying to do trials that are focused on addressing the needs of patients with lobular cancer, both in the early and late-stage setting. ASCO Daily News: Excellent. Thank you, Dr. Rugo. It's been great to have you on the podcast today. Thanks so much for sharing your valuable insight with us on the ASCO Daily News podcast. Dr. Hope Rugo: It was really a pleasure to participate and thank you for putting together these podcasts. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us, wherever you get your podcasts.     Disclosures: Dr. Hope Rugo Honoraria: Puma Biotechnology, Mylan and Samsung Research Funding (Institution): Pfizer, Merck, Novartis, Lilly, Roche, Odonate, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, Astra Zeneca and Immunomedics. Travel, Accommodations, Expenses: Pfizer, Novartis, Mylan, AstraZeneca, Merck 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Featuring an interview with Dr Kevin Kalinsky, including the following topics: Genomic assays in early-stage breast cancer (0:00) Case: A woman in her early 30s with a family history of breast cancer is diagnosed with hormone receptor (HR)-positive disease and receives a 21-gene assay Recurrence Score® (RS) of 16 (35:08) Case: A woman in her early 60s with ER/PR-positive, HER2-negative breast cancer and a 21-gene RS of 11 receives a recommendation of radiation therapy and an aromatase inhibitor (38:45) Case: A woman in her mid-20s with ER-positive, PR-negative, HER2-negative breast cancer and axillary involvement receives a MammaPrint® high score (40:42) Design and key findings of the Phase III RxPONDER trial evaluating the role of chemotherapy for patients with ER-positive, HER2-negative early breast cancer with 1 to 3 positive lymph nodes and a 21-gene RS of 25 or lower (43:42) Benefit of chemotherapy for premenopausal versus postmenopausal patients enrolled in the RxPONDER trial (47:15) Predictors of late recurrence; use of ctDNA (circulating tumor DNA) as a biomarker of recurrence (51:40) Utility of the RSClin educational tool integrating the 21-gene RS and clinical-pathological features to individualize prognosis and prediction of chemotherapy benefit for patients with HR-positive, HER2-negative, node-negative breast cancer (56:59) Impact of the COVID-19 vaccine on screening for breast cancer (1:00:30) Perspective on the use of genomic assays in the neoadjuvant setting (1:02:41) Age-associated benefit from chemotherapy for women with luminal breast cancer in the MINDACT trial (1:06:53) CME information and select publications

In deze podcast bespreken prof. dr. ir. Koos van der Hoeven, internist-oncoloog, en prof. dr. Laura van ’t Veer, moleculair bioloog bij de Universiteit van Californië, Verenigde Staten, de laatste resultaten van de MINDACT-studie.

Nesse Podcast, discutimos dados de sobrevida livre de metástase à distância de pacientes classificadas com alto risco clínico e baixo risco genômico, randomizadas para receber quimioterapia combinada à terapia endócrina versus terapia endócrina isolada. Além disso, discutimos as implicações dos achados para pacientes com mais ou menos de 50 anos de idade. Confira o episódio, com participação da Dra. Debora Gagliato, oncologista clínica da BP – A Beneficência Portuguesa de São Paulo.

Breast Cancer Update for Surgeons, Issue 1, 2019 — Part #2: Our interview with Dr King highlights the following topics as well as cases from her practice: Recent developments in the surgical care of patients with breast cancer (00:0s Predictive versus prognostic role of the 21-gene assay RS in ER-positive, HER2-negative, node-positive breast cancer (01:45) Clinical implications of the TAILORx trial results (05:11) Reliability of the 21-gene assay RS in guiding neoadjuvant therapy decision-making (07:19) Impact of genomic assay testing and clinical features on the use of chemotherapy after the implementation of standardized reflex testing criteria  (10:39) Clinical utility of the 21-gene assay RS in the selection of therapy  (15:34) Application and utility of the MINDACT trial results; use of the 70-gene signature assay in breast cancer  (17:48) Criteria for surgeon-initiated reflex gene-expression profile testing for patients with early-stage breast cancer to reduce delays in the initiation of chemotherapy  (19:26) Surgeon variability and factors predicting the need for reoperation after breast-conserving surgery (24:22) Recent trends in reoperation after initial lumpectomy for patients with breast cancer (26:45) Multidisciplinary management of the axilla for patients with breast cancer undergoing primary mastectomy (28:25) Optimal locoregional management of sentinel node-negative and node-positive breast cancer (31:54) Key issues regarding gross and microscopic evaluation of breast and lymph node specimens after neoadjuvant systemic therapy (36:36) Importance of accurate specimen evaluation in assessing treatment response (39:15) Factors predicting the use of preoperative therapy for young women with breast cancer; impact on breast-conserving surgery (41:55) Updated AJCC Staging Manual: Incorporation of tumor biology into breast cancer staging to tailor treatment and refine prognosis (43:46) Case: A woman in her mid-40s with ER/PR-negative, HER2-positive IDC receives neoadjuvant paclitaxel/trastuzumab/pertuzumab on the Phase I DAPHNe trial (47:22) Perspective on the results of the KATHERINE trial (52:52) Threshold for neoadjuvant therapy in triple-negative versus HER2-positive breast cancer; side-effect profile of paclitaxel in combination with trastuzumab and pertuzumab (54:51) Case: A woman in her mid-30s with triple-negative breast cancer has residual invasive disease in the breast and axillary lymph nodes after receiving neoadjuvant dose-dense AC followed by paclitaxel (56:49) Perspective on the importance of genomic testing in guiding treatment decision-making for patients with newly diagnosed disease (1:01:7s Surgical treatment options for patients with triple-negative breast cancer and germline BRCA mutations (1:03:20) Case: A woman in her mid-40s with ER/PR-positive, HER2-negative IDC receives a RS of 18 (1:05:37) Effects of age, menopausal status and RS on the prediction of benefit from chemotherapy (1:08:14) CME information and select publications  

An interview with Dr. Lynn Henry from University of Utah Huntsman Cancer Institute on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." This guideline update includes data from the MINDACT and TAILORx trials to clarify the recommendations for patients with hormone receptor-positive, HER2 not overexpressed, axillary node-negative early breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines  TRANSCRIPT 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin. And today, I'm interviewing Dr. Lynn Henry from the University of Utah Huntsman Cancer Institute, lead author on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." Thank you for being here today, Dr. Henry. Thank you very much for the invitation. So this guideline was updated to incorporate new data from the TAILORx and the MINDACT trials. So can you give us an overview of these trials and their results? Sure. So patients with hormone receptor-positive, HER2 negative breast cancer, are generally treated with anti-estrogen treatment and are sometimes also recommended to have chemotherapy. Since these tumors don't always respond well to chemotherapy, tests have been developed that provide more information about how much benefit, in terms of reduction of the likelihood of cancer coming back, an individual patient is likely to get from treatment with chemotherapy. It is important that the benefit of a treatment outweighs the risk of toxicity from the treatment. Two of those tests are called Oncotype DX and MammaPrint. And they have recently been tested in large clinical trials. So TAILORx is a large prospective trial that tested the Oncotype DX assay. In the Oncotype DX assay, a tumor is tested to get more information about how likely a cancer is to return and how much benefit the patient is likely to get from chemotherapy. Scores on this assay can range from 0 to 100. Previously, a study showed that patients whose tumors had scores of 10 or less, and who received five years of anti-estrogen treatment, were very unlikely to have their tumors return. So chemotherapy is not recommended for them. For patients with higher scores, above 30, we also already knew that chemotherapy is likely to decrease the chance of cancers in those patients, and, so, therefore, we generally recommend chemotherapy for women with higher scores. In the TAILORx trial, the recently reported trial, more than 6,700 women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer had their tumors tested and were found to have Oncotype DX recurrent scores between 11 and 25, which is in that intermediate range or at the higher end of the low range. Before this trial was conducted, many people with tumors like these, in the intermediate range, were treated with both chemotherapy and endocrine therapy because we weren't sure how much benefit they would obtain from chemotherapy, and we didn't want to leave out a potentially helpful treatment. In this trial, patients were randomized, or randomly assigned by a computer, to treatment with chemotherapy followed by endocrine therapy or to treatment with endocrine therapy alone. The trial was mainly looking at whether leaving out chemotherapy would increase the likelihood of invasive cancer returning. And, luckily, overall, the trial showed that the likelihood of cancer returning in those patients who got endocrine therapy alone, without chemotherapy, wasn't significantly different compared to those who were treated with chemotherapy followed by endocrine therapy. They also looked, specifically, at the group of women who were 50 years of age or younger. So mostly premenopausal women. Now, this was an exploratory question, meaning it provides information that may be correct, but it hasn't been as fully tested as the main question about what do we do for all women? In these younger women, there appeared to be some benefit from chemotherapy in those whose tumors had scores from 21 to 25, and, also possibly, in those whose tumors had scores from 16 to 20. Therefore, we still consider giving chemotherapy to younger women with Oncotype DX scores in the middle range, from 16 to 25, but not to women over age 50. So that was the TAILORx trial. The MINDACT trial was a bit different. It was testing the MammaPrint assay and the trial also included primarily women with hormone receptor-positive, HER2 negative breast cancer. But in this case, most women's sorry lymph nodes were negative, although a few women had up to three lymph nodes involved. In that trial, patient's risk of disease recurrence was assessed in two ways. First, it was assessed based on clinical factors. So the size of the tumor, how many lymph nodes were involved, and the estrogen receptor, progesterone receptor, and HER2 receptors. Second, it was assessed based on genomic factors-- that was using the MammaPrint test. So if patients were low for both clinical factors and genomic factors, they only were treated with anti-estrogen therapy. If they were high for both clinical factors and genomic factors, then they were treated with chemotherapy followed by anti-estrogen therapy. However, if they were high for one and low for the other, then they were randomized to either endocrine therapy alone or chemotherapy followed by endocrine therapy. So it was a little bit of a confusing trial. In the MINDACT trial, those patients who were thought to be high risk based on their clinical risk, so the size of the tumor, the number of lymph nodes, but then found to be low risk on the MammaPrint assay. They found that there was no benefit to treatment with chemotherapy in terms of how likely a woman was to develop distant metastatic disease. And if they were low risk, based on the clinical assessment, then there didn't appear to be a benefit of actually doing the test, the assay, because chemotherapy wouldn't be recommended for the patient, regardless of the results. So that was the MINDACT trial. So what are the new and updated recommendations for the guideline? Yes, so in this guideline, we, based on the TAILORx trial, we made new recommendations for use of the Oncotype DX results. All of these results apply to women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer. So for women older than age 50, if they have an Oncotype score of 25 or lower, then clinicians may offer endocrine therapy and no chemotherapy. However, for women age 50 or under, if they have an Oncotype score of 15 or lower, 15, then, clinicians may offer endocrine therapy and no chemotherapy. But if the score is 16 to 25, then chemotherapy can be considered in addition to endocrine therapy. So it made a difference in that gray area in the middle. For all women with score 26 to 30, chemotherapy may be considered. And for scores above 30, chemotherapy should definitely be considered. The data from the MammaPrint trial actually aren't that new. Results from that trial were originally published in 2016. However, that was after the original guideline was published, so we wanted to add these results to these updated guidelines for completeness. For a patient with hormone receptor-positive, HER2 negative, node-negative breast cancer, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then treatment with chemotherapy can be avoided. If a patient is thought to be at low clinical risk, the MammaPrint should not be used as chemotherapy can be avoided regardless. And for a patient with hormone receptor-positive, HER2 negative breast cancer, but who has one to three positive lymph nodes, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then it is possible that chemotherapy could be avoided, especially if only one lymph node is involved. So I think the bottom line for this part is that both of these tests-- there are now women who previously would have been recommended to have chemotherapy that maybe now we can avoid chemotherapy based on using these assays on their tumors. So why are these changes so important and how will they affect practice? Yes, that's a good question. Before the publication of the TAILORx trial, we had good information about how to treat patients who had either very low or very high Oncotype scores. But we really weren't sure how best to treat those patients who scores fell in the middle. Now, we have important information to guide decisions about chemotherapy for patients with intermediate scores. For many patients with scores in this range, these new results mean they will be able to avoid chemotherapy and just get endocrine therapy. While these results don't give us answers for every patient, they do provide more information that oncologists can use when having discussions with patients about the benefits and risks of chemotherapy. And what does this mean for patients with early-stage invasive breast cancer? And what should they talk to their doctors about? So as a result of both of these trials, we now have additional tools that can help oncologists provide more individualized treatment recommendations for patients and really assess whether or not chemotherapy, in addition to endocrine therapy, is likely to provide benefits. Knowing which patients' tumors will respond to chemotherapy can help some patients avoid unwanted side effects from a treatment that's not likely to actually give them much benefit. Now, these tests aren't appropriate for everyone and don't provide all the answers, but they are an important step in the right direction for providing more personalized treatment for women newly-diagnosed with certain types of breast cancer. Patients should talk with their doctors about whether these tests are right for them when they're making important decisions about whether or not they should receive treatment with chemotherapy. Great. Thank you, Dr. Henry, for this informative overview of the guideline. Keeping these clinical practice guidelines updated is really crucial and it takes a lot of careful thought to ensure these recommendations represent the evidence. So thank you for coming on the podcast to discuss the "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." Thank you very much for the opportunity to talk with you today. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

An interview with Dr. Lynn Henry from University of Utah Huntsman Cancer Institute on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." This guideline update includes data from the MINDACT and TAILORx trials to clarify the recommendations for patients with hormone receptor-positive, HER2 not overexpressed, axillary node-negative early breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines  TRANSCRIPT 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin. And today, I'm interviewing Dr. Lynn Henry from the University of Utah Huntsman Cancer Institute, lead author on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." Thank you for being here today, Dr. Henry. Thank you very much for the invitation. So this guideline was updated to incorporate new data from the TAILORx and the MINDACT trials. So can you give us an overview of these trials and their results? Sure. So patients with hormone receptor-positive, HER2 negative breast cancer, are generally treated with anti-estrogen treatment and are sometimes also recommended to have chemotherapy. Since these tumors don't always respond well to chemotherapy, tests have been developed that provide more information about how much benefit, in terms of reduction of the likelihood of cancer coming back, an individual patient is likely to get from treatment with chemotherapy. It is important that the benefit of a treatment outweighs the risk of toxicity from the treatment. Two of those tests are called Oncotype DX and MammaPrint. And they have recently been tested in large clinical trials. So TAILORx is a large prospective trial that tested the Oncotype DX assay. In the Oncotype DX assay, a tumor is tested to get more information about how likely a cancer is to return and how much benefit the patient is likely to get from chemotherapy. Scores on this assay can range from 0 to 100. Previously, a study showed that patients whose tumors had scores of 10 or less, and who received five years of anti-estrogen treatment, were very unlikely to have their tumors return. So chemotherapy is not recommended for them. For patients with higher scores, above 30, we also already knew that chemotherapy is likely to decrease the chance of cancers in those patients, and, so, therefore, we generally recommend chemotherapy for women with higher scores. In the TAILORx trial, the recently reported trial, more than 6,700 women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer had their tumors tested and were found to have Oncotype DX recurrent scores between 11 and 25, which is in that intermediate range or at the higher end of the low range. Before this trial was conducted, many people with tumors like these, in the intermediate range, were treated with both chemotherapy and endocrine therapy because we weren't sure how much benefit they would obtain from chemotherapy, and we didn't want to leave out a potentially helpful treatment. In this trial, patients were randomized, or randomly assigned by a computer, to treatment with chemotherapy followed by endocrine therapy or to treatment with endocrine therapy alone. The trial was mainly looking at whether leaving out chemotherapy would increase the likelihood of invasive cancer returning. And, luckily, overall, the trial showed that the likelihood of cancer returning in those patients who got endocrine therapy alone, without chemotherapy, wasn't significantly different compared to those who were treated with chemotherapy followed by endocrine therapy. They also looked, specifically, at the group of women who were 50 years of age or younger. So mostly premenopausal women. Now, this was an exploratory question, meaning it provides information that may be correct, but it hasn't been as fully tested as the main question about what do we do for all women? In these younger women, there appeared to be some benefit from chemotherapy in those whose tumors had scores from 21 to 25, and, also possibly, in those whose tumors had scores from 16 to 20. Therefore, we still consider giving chemotherapy to younger women with Oncotype DX scores in the middle range, from 16 to 25, but not to women over age 50. So that was the TAILORx trial. The MINDACT trial was a bit different. It was testing the MammaPrint assay and the trial also included primarily women with hormone receptor-positive, HER2 negative breast cancer. But in this case, most women's sorry lymph nodes were negative, although a few women had up to three lymph nodes involved. In that trial, patient's risk of disease recurrence was assessed in two ways. First, it was assessed based on clinical factors. So the size of the tumor, how many lymph nodes were involved, and the estrogen receptor, progesterone receptor, and HER2 receptors. Second, it was assessed based on genomic factors-- that was using the MammaPrint test. So if patients were low for both clinical factors and genomic factors, they only were treated with anti-estrogen therapy. If they were high for both clinical factors and genomic factors, then they were treated with chemotherapy followed by anti-estrogen therapy. However, if they were high for one and low for the other, then they were randomized to either endocrine therapy alone or chemotherapy followed by endocrine therapy. So it was a little bit of a confusing trial. In the MINDACT trial, those patients who were thought to be high risk based on their clinical risk, so the size of the tumor, the number of lymph nodes, but then found to be low risk on the MammaPrint assay. They found that there was no benefit to treatment with chemotherapy in terms of how likely a woman was to develop distant metastatic disease. And if they were low risk, based on the clinical assessment, then there didn't appear to be a benefit of actually doing the test, the assay, because chemotherapy wouldn't be recommended for the patient, regardless of the results. So that was the MINDACT trial. So what are the new and updated recommendations for the guideline? Yes, so in this guideline, we, based on the TAILORx trial, we made new recommendations for use of the Oncotype DX results. All of these results apply to women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer. So for women older than age 50, if they have an Oncotype score of 25 or lower, then clinicians may offer endocrine therapy and no chemotherapy. However, for women age 50 or under, if they have an Oncotype score of 15 or lower, 15, then, clinicians may offer endocrine therapy and no chemotherapy. But if the score is 16 to 25, then chemotherapy can be considered in addition to endocrine therapy. So it made a difference in that gray area in the middle. For all women with score 26 to 30, chemotherapy may be considered. And for scores above 30, chemotherapy should definitely be considered. The data from the MammaPrint trial actually aren't that new. Results from that trial were originally published in 2016. However, that was after the original guideline was published, so we wanted to add these results to these updated guidelines for completeness. For a patient with hormone receptor-positive, HER2 negative, node-negative breast cancer, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then treatment with chemotherapy can be avoided. If a patient is thought to be at low clinical risk, the MammaPrint should not be used as chemotherapy can be avoided regardless. And for a patient with hormone receptor-positive, HER2 negative breast cancer, but who has one to three positive lymph nodes, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then it is possible that chemotherapy could be avoided, especially if only one lymph node is involved. So I think the bottom line for this part is that both of these tests-- there are now women who previously would have been recommended to have chemotherapy that maybe now we can avoid chemotherapy based on using these assays on their tumors. So why are these changes so important and how will they affect practice? Yes, that's a good question. Before the publication of the TAILORx trial, we had good information about how to treat patients who had either very low or very high Oncotype scores. But we really weren't sure how best to treat those patients who scores fell in the middle. Now, we have important information to guide decisions about chemotherapy for patients with intermediate scores. For many patients with scores in this range, these new results mean they will be able to avoid chemotherapy and just get endocrine therapy. While these results don't give us answers for every patient, they do provide more information that oncologists can use when having discussions with patients about the benefits and risks of chemotherapy. And what does this mean for patients with early-stage invasive breast cancer? And what should they talk to their doctors about? So as a result of both of these trials, we now have additional tools that can help oncologists provide more individualized treatment recommendations for patients and really assess whether or not chemotherapy, in addition to endocrine therapy, is likely to provide benefits. Knowing which patients' tumors will respond to chemotherapy can help some patients avoid unwanted side effects from a treatment that's not likely to actually give them much benefit. Now, these tests aren't appropriate for everyone and don't provide all the answers, but they are an important step in the right direction for providing more personalized treatment for women newly-diagnosed with certain types of breast cancer. Patients should talk with their doctors about whether these tests are right for them when they're making important decisions about whether or not they should receive treatment with chemotherapy. Great. Thank you, Dr. Henry, for this informative overview of the guideline. Keeping these clinical practice guidelines updated is really crucial and it takes a lot of careful thought to ensure these recommendations represent the evidence. So thank you for coming on the podcast to discuss the "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." Thank you very much for the opportunity to talk with you today. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

BARCELONA—Not only was breast conserving therapy safer than mastectomy for most low-risk patients in the large randomized EORTC 10041/BIG 03-04 MINDACT trial reported at the 2018 European Breast Cancer Conference but also many patients could be advised to avoid chemotherapy …Emiel Rutgers AJO PRODUCTION MASTER

Dr Martine Piccart speaks with ecancertv at AACR 2016 about the results of the MINDACT trial. Using a new diagnostic assay, Mammaprint, to scan for a 70 gene signature, Dr Piccart reports significant predictive potential for determining breast cancer relapse risk. With breast cancer being knowingly over-treated, the results from this trial enable the reduction of unnecessary treatments, even in patients classified as high risk via Adjuvant!Online, and lead to strategic de-escalation of chemotherapy.

Dr Martine Piccart presents at AACR 2016 about the results of the MINDACT trial. Using a new diagnostic assay, Mammaprint, to scan for a 70 gene signature, Dr Piccart reports significant predictive potential for determining breast cancer relapse risk.

Elżbieta Senkus, Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdańsk, Poland, (elsenkus@gumed.edu.pl) presents an overview of new therapies on the horizon for breast cancer in terms of data presented at the ESMO Congress, ASCO, and the San Antonio Breast Cancer Symposium. In the adjuvant setting, results from the MINDACT trial, which evaluated genomic versus clinical assessment for risk stratification, are described. Data on the role of anthracyclines in adjuvant chemotherapy is also discussed. In HER2-positive patients, dual HER2-targeted therapy was investigated in the KRISTINE study, and studies on the duration of adjuvant endocrine therapy in advanced breast cancer are also considered. Other ongoing studies in this population and the luminal population are also briefly mentioned. In the metastatic setting, the PALOMA-2 and MONALEESA-2 studies assessed the addition of CDK4/6 inhibitors to standard treatments. Results of the MONARCH 1 trial, evaluating a CDK4/6 inhibitor as a single agent, are also described, along with data on endocrine therapy in the luminal setting. Recent data on drugs interacting with the mTOR/PI3K/AKT pathway are considered. Studies in advanced HER-2 positive patients, considering HER-2 duel blockade plus either chemotherapy or endocrine therapy, are discussed. The situation in triple-negative breast cancer and advances and future directions in precision medicine and immunotherapy in breast cancer are briefly discussed. Read the abstract on the ESMO Open website: http://esmoopen.bmj.com/content/2/2/e000204.

Dr Delaloge meets with ecancertv at WIN 2016 to discuss results from the MINDACT trial. The results, which were first announced by Dr Piccart at AACR, indicate that patient subpopulations who are ranked as 'high risk' by Adjuvant!Online clinical assessment but exhibit low presence of predictive genomic markers could be spared chemotherapy. Dr Delaloge notes the differing survival rates of other subpopulations, and introduces other trial arms of MINDACT whose results will be presented at this year's San Antonio Breast Cancer Symposium.