Advances in Breast Cancer With Dr. Hope Rugo

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.