Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Meet The Professor, as today we start a new series focusing on the management of ER-positive and triple-negative breast cancer. Our faculty person today is Dr Komal Jhaveri who is the Section Head of Endocrine Therapy Research Program and the Clinical Director of Early Drug Development Service and on the Breast Medical Service at Memorial Sloan Kettering Cancer Center in New York City.

We have a great faculty for this program. And later on, we'll show you the results of a survey we did of the faculty of their usual treatment practices that we just completed now in the last week. As always, if you have any questions or cases you'd like to run by us, just type them into the chat room and we’ll talk about as many of these as we have time.

As always, we put out a very brief 1-minute survey for you to take before and after this program. If you take it, we’ll learn a lot about you and you’ll get more out of this meeting.

We do webinars all the time. Tomorrow, we’ll continue our Year in Review series focusing on lymphomas with Drs Flowers and Sehn. And then on Thursday, we’re going to do a very interesting different webinar focusing on adverse events seen with BTK inhibitors, particularly in the management of CLL and mantle cell. We’re going to do another program on breast cancer on February 8^th, it should be really interesting and different, focusing on ovarian suppression. We’ll have Dr Kathy Miller and Dr Ann Partridge there for that. And then, we’ll be heading out to the GU Cancer Symposium. We’ll be doing 3 web — programs there. So if you’re in the San Francisco area, come on over. If you’re not, we’ll be putting these out online live. So Wednesday night, we’ll be talking about renal cell cancer. Thursday night, prostate cancer. Friday night, urothelial bladder cancer. And then the next day, we’re actually doing a day-long symposium with the North and South Carolina Oncology Association covering a whole bunch of tumors. We’ve got about 15 investigators coming. And, again, that’ll be posted — that’ll be live online as well.

If you’re into audio programs, check out our Oncology Today podcast series, including a recent program on HER2-positive metastatic breast cancer with Dr Curigliano.

But today, we’re here to talk about ER-positive and triple-negative breast cancer. And as always, we have some great cases to present to Dr Jhaveri. Most of these are general medical oncologists who take care of every cancer. Everybody admires these docs so much for being able to keep up-to-date in all the different parts of oncology. And we’re very grateful that they are willing to present their cases.

So we’re going to start out with a little bit of an introduction and overview. Then, we’ll get into the cases. Then, we’ll show you the survey. And then, we’ll talk about some of the papers that Dr Jhaveri has written.

But I just want to start out as sort of a preamble. It used to be, we had nothing to talk about with ER-positive breast cancer. It was all HER2-positive. This actually, Komal, is — this is from the video that launched our company, believe it or not, in 1985, Hormonal Therapy for the 1980’s. And we had kind of a Pac-Man approach to understand, this is about where we were then, about understanding how — what estrogen receptor was. This is a fantastic paper that you put out in Cancer Treatment Reviews. And here’s where we are today. So we could spend a lot of time talking about everything that we’ve learned. But first of all, I want to recommend this paper to the audience. And I’m going to show you another fantastic presentation related to this topic you did at San Antonio. But let’s just start out with one major important addition, ESR1. So let’s just pick that as one example of the new biology of endocrine treatment of breast cancer. Can you talk a little bit, remind us what it is and kind of what the implications are when you see it? And how do you pick it up? Can you get it in a liquid biopsy?

DR JHAVERI: Yeah. Thank you so much. First of all, thanks for having me today. And I completely agree with you. This Pac-Man figure that we have in this paper looks very different than the figure in the video you were referring to in the 1980’s which looked a lot more palatable and easier. But I think the idea still remains the same, right? So ER-positive cancer, you want to target the estrogen receptor. You want to target it with effective endocrine therapy, effective antiestrogen therapy. But what we learned was while these therapies are effective, there are ways that the cancer cell figures out a way to outgrow and progress despite those effective strategies. And one of the ways that this works is while it is estrogen independent, it’s still dependent on the ER pathway. And this is mutation in the estrogen gene itself. It’s in the ligand binding domain of the estrogen receptor. And these ESR1 mutations are usually seen under the selective pressure of aromatase inhibitors in the metastatic setting.

And so if we were to take a primary tumor and look for ESR1 mutations, they are very less frequently seen there, 1 to 2%. If we’ve got them at baseline in a newly diagnosed metastatic patient before they start new therapies, about 4% as reported in MONALEESA-2 trial. But if you look at in a pretreated metastatic setting patient, this is about 40% in the plasma. It kind of tells you that under the selective pressure, these subclonal mutations are really something that we deal with in our patients which is a mechanism of resistance and we want to think about novel endocrine agents that can actually act on these. And this figure is trying to tell us that many of these agents are currently in clinic, one that just got approved on Friday, elacestrant, a new oral SERD. So unlike fulvestrant, the only SERD we had in clinic, intramuscular injection, we now have an oral SERD, elacestrant, that got approved for a tumor that has ESR1 mutation.

And the question about where to test it. Because these are subclonal, plasma seems easier to do. And the companion diagnostic that got approved with elacestrant is the Guardant360 liquid biopsy assay.

DR LOVE: Great. And as I mentioned, you did this fantastic presentation at the San Antonio meeting. I love the title, Word Salad. We have all these new terms to consider. Again, phenomenal graphics, talking about how these agents work. You mentioned SERDs. And, of course, now we have one approved. I just want to get your, this is your takeaway, but maybe just sort of summarize what we know about SERDs, in what situations you think they should be used at this point and also, anything about toxicity? When we think about fulvestrant, mostly, it was the injection. You kind of didn’t hear too much more, but I don’t know. How about with these oral SERDs?

DR JHAVERI: Yeah. I think when we think about post-CDK4/6 inhibitor progression and treatment in the metastatic setting, single agent fulvestrant, we’ve learned from now the VERONICA trial that looked at venetoclax and fulvestrant and we’ve looked at EMERALD now, the trial that looked at the oral SERD, elacestrant, that the control arm had a median progression free survival of 2 months. Meaning your first scan on study, the tumor had already progressed. And so the question is can you do better than that? Can you overcome this issue? And so that was why these novel agents entered clinic. We learned that, yes, at least in the ESR1 mutant patient population, these oral SERDs are more potent. They can overcome the issue that fulvestrant necessarily cannot because of lack of increasing the dose, because of lack or oral bioavailability, lack of activity against many of these mutations including the Y537S mutation. And so that’s why we have the approval for this oral SERD, at least in this setting.

But the tumor is more complex than that. Not every tumor can just get away with single agent endocrine therapy. And we might need more than that because it’s not that that’s the only mechanism of resistance. There are other mechanisms of resistance including activation of the PI3K mTOR pathway, FGFR1 amplifications, we have ERBB2 mutations and we can go on and on and on with so many mechanisms that could play a role. But for the right patient who is probably endocrine-sensitive who probably has limited disease burden, a surrogate of endocrine sensitivity is ESR1 mutation, perhaps single agent oral SERD is appropriate. For the others, we need combinations. And such combinations are currently being evaluated in clinic today and we await those data with those oral SERD combination partners. And then, we obviously have other agents. They’re also being evaluated in combination with CDK4/6 in the first line setting.

A good example of this is SERENA-6. SERENA-6 is looking at camizestrant, an oral SERD by AstraZeneca. And what they’re trying to do is a novel approach. Patients start on AI and CDK4/6. We serially collect the ctDNA. If there is ESR1 mutation detected, but there is no radiological progression, patients get randomized to oral SERD + CDK4/6 versus continuing the same AI/CDK4/6. And in PALOMA-1, we saw that there was doubling of PFS with that approach. Our hope is with an oral SERD, we might have an even larger benefit. Yet to see if OS would be impacted with such an approach. But an interesting model to study that. So combinations with PI3K mTOR ongoing. Combination upfront of the CDK4/6 ongoing. Approval right now is monotherapy in ESR1 mutant. And they have now entered adjuvant trials. They are being evaluated in early-stage either as an upfront strategy or as a switch strategy.

Side effects, I think it’s predominantly GI which is most common for them. Some have more nausea. Maybe some have a little bit more diarrhea. Some hot flashes, some arthralgias potentially. Some unique side effects of bradycardia and visual disturbances or photopsia have been reported with a few of these novel endocrine agents. But thankfully, they have not been high-grade. We yet have to understand the pathophysiology of those. The good news is we can adjust the dose because they are very potent and the PK profile and the exposures allow us to do that. So even in the early-stage with toxicity, we can dose reduce, something we cannot do with AI or tamoxifen in the early-stage setting. So very exciting to see these agents. We yet have to see how fully can we tap into their potential.

DR LOVE: So I like to say we have the most interesting chat room anywhere in the world. And we’ve got an interesting question for you, a case actually. Dr McKenna in the chat room has a patient with EGFR mutated non-small cell lung cancer who on ctDNA has an ESR1 mutation. Never had a history of breast cancer. Any thoughts?

DR JHAVERI: Oh, wow. Okay, you got me with that one.

DR LOVE: Okay. We’ll ask the lung people maybe.

DR JHAVERI: Yeah, we need the lung people. Is this a woman?

DR LOVE: EGFR mutated.

DR JHAVERI: Is this a woman?

DR LOVE: Oh, I don’t know. We’ll see. I don’t know. I’ll ask. We’ll see. Maybe she has an occult breast cancer.

DR JHAVERI: Yeah.

DR LOVE: That’s a good question. We’ll see.

DR JHAVERI: Yeah, yeah.

DR LOVE: All right. To be continued. Yeah, let me see. We’ll see if it’s a woman. Oh, 72-year-old woman.

DR JHAVERI: Right. So it’s possible —

DR LOVE: What do you think? She has a — you can’t — maybe. Occult breast cancer. That’s interesting.

DR JHAVERI: Yeah, it’s potentially possible. She’s 72. She meets the criteria for age as a risk factor.

DR LOVE: We’ll see. As this series continues, we’ll follow-up with this case and see what Dr McKenna finds.

Case: A premenopausal woman in her early 40s with a 5.8-cm, ER/PR-positive, HER2-negative infiltrating lobular carcinoma and microscopic sentinel node involvement — Arielle Heeke, MD

DR LOVE: All right. Let’s get into some cases here. We’re going to start out with a patient of Dr Arielle Heeke. This is a 40-year-old premenopausal women — woman. She’s got a big tumor, 5.8 cm, but it’s an infiltrating lobular. She’s got microscopic, like 0.3 mm, involvement of one node. Here’s Dr Heeke’s question.

DR HEEKE: 40-year-old lady with a 5+ cm tumor. So when I met her postoperatively, we discussed genomics, whether or not to pursue them? Traditionally, once we get above 5 cm, you know, you can make the argument to not do genomics and just go straight to chemo, especially considering she had lymph node involvement as well. But, because it was lobular, gosh, you just don’t want to give them chemo.

So the question is, how do we apply genomic assays to our lobulars? We know that they’re a little less chemo-sensitive. And our lobular breast cancer patients don’t get any less toxicity from chemo. They get all the same toxicities. But is it benefitting them to the same degree as our invasive ductals?

DR LOVE: So your thoughts?

DR JHAVERI: Yeah. It’s such a fantastic question and something that we struggle with our patients. So that’s right. When we think about those genomic assays and those trials, we had T2 tumors, not necessarily T3 tumors, more than 5 cm tumors. So we don’t have the prospective data. It’s kind of a data-free zone, if you will. But then, that’s when we think about applying science, data, art and a patient/physician decision making process together and try and figure out what’s the best solution for this given patient in clinic. So I completely agree.

I think it’s not unreasonable to consider a genomic assay. I think we have to have a conversation with the patient that we do not have any prospective data for this tumor size, that maybe at best, this is prognostic information. But maybe that prognostic information gives us the reassurance about what treatment we decide to move forward with knowing that lobular cancer is less chemo-sensitive than, say, a traditional ductal cancer and that microscopic sentinel lymph node is considered as node-negative in many ways and behaves like a node-negative node. So we can take comfort in that. But I think that has to be a decision we have to make.

Fortunately, we also have ovarian suppression along with endocrine therapy that potentially can be more effective. And there’s one speculation in premenopausal women whether that is driving the benefit when chemo is given to premenopausal women, that whether we shutting down their ovarian function with chemotherapy is what is driving the outcome and not necessarily the delivery of chemotherapy in itself. So I think it’s a reasonable thing to do. I think it’s a discussion we should still have with patients given the lack of direct prospective data and then coming up with a great plan for this patient.

Case: A premenopausal woman in her early 40s with a 3.1-cm ER/PR-positive, HER2-negative localized invasive ductal carcinoma (IDC) and a Recurrence Score^® of 18 — Alan B Astrow, MD

DR LOVE: So here’s another case where the question of chemo or not comes up. Another premenopausal patient of Dr Astrow who is a neighbor of yours up there in Manhattan and sees all breast cancer. But he’s got a 40-year-old woman, 3.1 cm tumor, so a bigger tumor, but a recurrence score of 18. Here’s Dr Astrow.

DR ASTROW: She’s young, it’s a Grade 3 tumor. It’s pretty large. It’s a T2 tumor. In this instance, because of the size of the tumor, if you put it into the RSClin, you’d find that there is an advantage with an Oncotype of 18 to chemo. So we gave her TC.

So then, the question would be, well, what do you do afterward? Do you do leuprolide or goserelin? Do you do tamoxifen?

I did suggest leuprolide + tamoxifen. But the patient thought about it. She thought about quality-of-life issues and she decided she was not interested in leuprolide. So she’s just getting tamoxifen at this point.

When do they use MammaPrint, if ever, in preference to Oncotype? And do they find there’s any use to asking for the blueprint with the MammaPrint? Which patients with the low intermediate Oncotypes would the panel recommend chemotherapy to? And if they’re not going to recommend chemo, which ones would they say tamoxifen alone in the pre-menopausal? And which ones do they need ovarian ablation + tamoxifen? What is the panel’s experience doing that, starting a young woman on ovarian ablation + an AI? How do they weigh in the quality-of-life concerns? And how do they discuss these issues with the woman herself?

DR LOVE: This is actually a memory test to see if you can remember all of these questions that people are asking you. I thought it was interesting that this woman, I don’t know how it was presented to her, but she was okay with TC, but she wasn’t okay with ovarian suppression. Well maybe — I thought that was interesting. Anyhow. A whole bunch of questions there. Any thoughts?

DR JHAVERI: Yeah, absolutely. But it’s such a good scenario and a really frequent scenario that comes up in clinic. And I’m very glad to hear that RSClin was utilized. So RSClin is looking at not only the recurrence score, the genomic characteristic that we get from the Oncotype assay, but also the clinical pathological features that we look at. And these clinical pathological features along with the RS score can potentially give a better idea. And as he said, it displayed that it was probably higher than what they thought it was going to be which is why TC was thought to be an appropriate approach.

So when I am thinking about a tumor where I’m concerned, where I’m thinking it’s high-risk enough and that I’m thinking about chemotherapy, in that patient, I am thinking about ovarian suppression. If I have a patient where I’m not really worried about it being too high-risk, where I’m not thinking that this tumor requires, so your low recurrence scores, less than 11, less than 10 where I’m thinking about endocrine therapy alone, I’m thinking about tamoxifen alone in premenopausal women. In a patient where chemotherapy is something that they could potentially benefit from, it’s a gray zone, so those intermediate scores, but the patient is not very keen on doing, again, there, I’m thinking about ovarian suppression with an aromatase inhibitor to begin with. If toxicity becomes an issue, I peel it down to ovarian suppression with tamoxifen. If that remains also a big issue and the patient is just not able to tolerate this therapy, that’s when I resort to tamoxifen. But I do think about our high-risk patients where I would offer ovarian suppression in those cases.

I think there are multiple genomic assays, MammaPrint and BluPrint and Oncotype. I think it’s the first kid on the block that we had, that was Oncotype. We have a large dataset with it. The utility of that is something that we have used over and over for many years. That’s been my practice. So I have been using Oncotype predominantly for these patients. I do have patients who come in with MammaPrint and I would not repeat an assay. There’s no reason to compare one assay to the other. I don’t use them as a dealbreaker, if you will. But I think I have been utilizing Oncotype in my practice. And otherwise, I would use sometimes Breast Cancer Index when I’m trying to figure out extended endocrine therapy.

DR LOVE: So we did a program a couple weeks ago with Peter Schmid and Joyce O’Shaughnessy. And Peter showed this really cool slide. I’m not going to even ask you to talk about it. I’m just putting it up there for the audience to check out the program. He goes through in detail like how he approaches it and really gets into a lot of the nitty gritty. And, of course, brings up the JCO, the ASCO guideline.

Case: A woman in her late 50s with ER/PR-positive, HER2-negative, microsatellite stable, BRCA1/2 wild-type, metastatic IDC with PALB2 mutation who receives palbociclib/letrozole and zoledronic acid — Shaachi Gupta, MD, MPH

DR LOVE: But I want to get into another case. This is a patient of Dr Shaachi Gupta, a 59-year-old woman who interestingly has a PALB2 germline mutation, but also has ER-positive and HER2-negative breast cancer. Here are her questions.

DR GUPTA: 59-year-old woman. Healthcare worker. We started her on palbociclib and letrozole and zoledronic acid for her bone metastases, and she’s had a good response. But interestingly, she did have PALB2 alteration at a very high frequency. So that led to testing her genetics and that showed pathogenic PALB2 mutation. So, so far, she’s doing well on palbociclib and letrozole.

A question that I have, can these patients with PALB2 mutation be considered for PARP inhibitors? One question that always comes to my mind, certainly for BRCA mutants, is how important is it to use carboplatin as part of the chemotherapy regimen?

DR LOVE: Any questions about choice of CDK inhibitor?

DR GUPTA: I always wonder about that, what investigators feel about the choice of CDK4/6 inhibitor? I feel that palbociclib is really easy, other than neutropenia, which is more or less asymptomatic. But there is data from ribociclib as far as overall survival, and abemaciclib is, in general, considered a more potent drug.

DR LOVE: So I’m not, you know, I hear that a lot. But anyhow. A lot to go through there too, Komal. Any thoughts?

DR JHAVERI: Yeah. So let’s talk about the case first and then, we’ll go into the CDK4 next. So we have, obviously, approval for olaparib and talazoparib for these BRCA mutations, so germline BRCA mutant tumors. And we can absolutely offer them PARP inhibitors for that given the benefit we’ve seen in the OlympiA trial in the adjuvant setting and then we also have data in the metastatic setting for our metastatic patients. In hormone receptor-positive patients, it’s about 3 to 5%. But certainly, something we use before I think about chemotherapy. What we also learned from a very interesting clinical trial in the TBCRC 048, it’s a Translational Breast Cancer Research Consortium study and Nadine Tung was running that study, where they evaluated a cohort of germline PALB2 mutations and they also evaluated a cohort of somatic BRCA2 mutations. And certainly, beyond the germline where we already have approval, these 2 cohorts had phenomenal response rates. Germline PALB2, 80% response rates that were reported out. Somatic BRCA2, 50% response rate. And so that trial was further expanded to see if we can confirm this efficacy. And I’m hoping that once that gets confirmed, we might be able to offer this to our germline PALB2 and somatic outside of a clinical trial as standard of care as well. Would I do that for a given patient in clinic as compassionate use right now? I would consider that given that that data has been compelling so far. So that’s the question on that.

CDK4/6, I guess, you know, we have 3 agents that got approved. The first kid on the block that we had was palbociclib. Certainly, with the easiest toxicity profile in terms of management and what we need to monitor. And so certainly, our comfort level with palbociclib was the highest in many ways. But now, we have multiple mature datasets where we’ve seen overall survival that have been reported out across all programs with ribociclib and also in MONARCH 2 with fulvestrant and abemaciclib and in the interim analysis too from MONARCH 3 in the first line. We’re seeing a numerical trend and final OS is pending. So I think because of that, despite that not being the primary endpoint, it’s hard for me to tell a patient who is sitting in front of me why would I not offer an agent which has consistently delivered overall survival benefit. And so my practice has shifted a little bit and I have now been offering ribociclib as new start for a patient. I haven’t switched out my older patients on palbociclib who are doing well. But a new start, I am discussing ribociclib.   

DR LOVE: Any thoughts about the abema data at ESMO? It looked like maybe there’s a survival benefit emerging there too.

DR JHAVERI: Yes, I think it looked very compelling. In fact, numerically, it seemed like the longest overall survival to date, about 67 months. And this is interim analysis too. And the way the curves were actually going apart, I think I’m hopeful and would predict that that survival benefit hopefully will be maintained at the final OS analysis. And MONARCH 2 already has shown statistically significant overall survival in the second line metastatic setting. We have abema approved in the early-stage setting as well.

I do think, however, given that the toxicity profiles are slightly different and given that there are trials that are looking at CDK4/6 beyond progression. So we have the Phase III postMONARCH trial. We have EMBER-3 which is an oral SERD and has a cohort of oral SERD + abema post-CDK4/6, my strategy would be use ribociclib and then maybe if these trials also provide that confirmation, think about utilizing abema as a second line approach.

DR LOVE: Getting so many questions in the chat room. It’s like buzzing by. We’ll never get through all of these. We’ll have to deal with these in the other ones as well. But I was just flashing. I don’t know if you know Dr Johann de Bono from the UK. He’s a PARP investigator in prostate. He calls PALB2 BRCA3.

DR JHAVERI: Oh, nice.

DR LOVE: It’s kind of a joke.

DR JHAVERI: Okay. Yeah, I like it. I like it.

DR LOVE: Yeah. Anyhow. So Fadee in the chat room wants to know, he’s got a patient with, let me see if I can find it here, okay, triple-negative breast cancer, gets neoadjuvant therapy. Doesn’t say whether they got pembro also. But has a path CR, but I guess has a BRCA germline mutation. So would you give olaparib, he wants to know, in that situation with a path CR as adjuvant therapy? And also, I’m curious in general what your experience has been with adjuvant and a post-neoadjuvant PARP.

DR JHAVERI: Yeah. So I think this is a very interesting question. I think, I offer PARP inhibitor to patients who would have qualified for the OlympiA trial. So when we are thinking about tripe-negative or HR-positive patients, anybody who would have qualified that high-risk criteria that was set out, so 2 cm or higher or node-positive, triple-negative breast cancer or 4 or more positive ER-positive nodes or a CPS+EG score of 3 or higher in the residual HR-positive setting post-neoadjuvant therapy. That’s complicated, my God. How did I say that in one breath, right? But when we’re looking about — when we’re thinking about these tumors, these are your highest-risk tumors and that’s where they utilize the PARP inhibitor. And that was partly because they were worried about the MDS and the AML risk from PARP inhibitors. So they wanted to justify that only in those patients where you know that they have the highest risk and they probably need the most benefit from this. And fortunately, we’ve not seen that to be a signal. But we do not have datasets for this lower-risk patient population or everybody to get it. So I think if they follow the OlympiA trial eligibility, that’s where I’m practicing kind of the using a PARP inhibitor in clinic.

DR LOVE: So you hear the same kind of thing about adjuvant abema. But then, when you think about I guess classically, how we look at adjuvant trials in breast cancer, when you think of the old meta-analysis and tamoxifen and chemo, the idea is you get a hazard rate and then you just apply it all the way down. You may not want to do — it may not have been a good risk/benefit rate, but you could theoretically calculate what the benefit would be even in people who were lower-risk that went on the trial.

DR JHAVERI: Right.

DR LOVE: But yet, I don’t see people doing that with abema or olaparib. They’re just like this is what the trial did. We don’t know about the other stuff. Whereas before, like tamoxifen, I don’t know how much data we have on 0.5 cm node-negative tumor and tamoxifen, but maybe offer it to patients. Anyhow.

DR JHAVERI: Yeah.

DR LOVE: Any thoughts about that? There was also an editorial in the JCO about the issue of number of nodes and the fact that a lot of people don’t get axillary dissection, so you just have a couple sentinel nodes, so maybe they have a lot more in the axilla. Anyhow.

DR JHAVERI: Yeah.

DR LOVE: I hope that question is understandable. But that’s just kind of something I’ve been thinking about.

DR JHAVERI: I think that that’s a very excellent question, Neil, and totally understand exactly. I think the one way I think about why such a discrepancy in what we do with tamoxifen, say, or what we would do with PARP inhibitor and abema. Why do we try and be purists when it comes to abema and PARP inhibitor, but not so with other therapies? It partly has to do with all these targeted therapies, it’s great we have them, it’s great we’ve made an impact, but they also come in with a lot of toxicity. They are not benign medications. They’re expensive. And they come in with a lot of toxicities that we have to deal with, extra blood draws, extra visits. Patients are so exhausted when they are done with chemotherapy. And then, we’re telling them you have 5 years of endocrine therapy, in some cases, 10 years of endocrine therapy. But you also have to have 2 years of abemaciclib and you’ll have diarrhea that you’re going to be dealing with. So it’s a whole lot already. And so I think that’s why the whole risk/benefit kind of narrows down to the right patient until we can see that this can be justified to masses alike. And I think that’s where potentially this ease of utilizing tamoxifen in a 4 and 5 cm tumor versus not utilizing a PARP inhibitor for a 1 cm tumor comes from.

Case: A postmenopausal woman in her early 60s with de novo ER/PR-positive, HER2-low (IHC 1+) metastatic IDC after disease progression on abemaciclib/letrozole and alpelisib/fulvestrant — Zanetta S Lamar, MD

DR LOVE: All right. Another case. This is from Dr Zanetta Lamar, one of the Florida Cancer Specialists here with us in Florida. 60-year-old woman with metastatic disease, ER-positive, but HER2-low, IHC 1+. Here’s the case.

DR LAMAR: 60-year-old post-menopausal woman who was diagnosed with de novo metastatic ER/PR-positive and HER2-negative breast cancer. I started her on abemaciclib and letrozole. And unfortunately, she progressed. Later, I treated her with alpelisib and fulvestrant. She had scans earlier this week which actually showed evidence of progression. Around the same time, I realized that the FDA had approved fam-trastuzumab. So I went back to her original biopsy report and it showed that by immunohistochemistry, she was found to be HER2 1+. So our pathologists do not routinely check immunohistochemistry for HER2 and will often just use FISH. So I’ve requested that they begin checking immunohistochemistry to try to find these HER2-low patients.

How are you sequencing fam-trastuzumab in ER-positive, HER2-low metastatic patients? In a patient like this, would you consider chemotherapy such as weekly paclitaxel or would you consider fam-trastuzumab?

DR LOVE: Any thoughts about that?

DR JHAVERI: Absolutely, absolutely. And she brings up such a great point, Dr Lamar brings up such a great point. Because we started off with HER2 testing and the reason HER2 IHC was really developed was to identify the HER2 3+, the overexpresser, so we can offer them anti-HER2 therapy. It was not really designed to look for HER2 1+'s or 2+'s. In fact, we learned that for a 2+, we have to get the reflex FISH and that there is a small proportion of patients who are either HER2 0 or 1+ who could still be FISH amplified which is why many of these laboratories shifted their practices from IHC to FISH. And now, we've come a 360 again and now, we have these novel antibody drug conjugates with bystander effect which kill not only the HER2 targeting cells but also the neighboring HER2 cells that might have some expression of HER2 which is why this expression with IHC has become important again. But is this the right way of identifying them? We don't know that yet, but that's what we have to date in clinic and that's where the approval for fam-trastuzumab occurred with the data of the DESTINY-04 trial that enrolled patients with HER2 IHC 1+ or 2+ that is not amplified, had at least 1 line of chemotherapy in the metastatic setting, endocrine therapy certainly and then received either fam-trastuzumab deruxtecan versus chemotherapy, with doubling of PFS and really a good overall survival benefit as well.

So I would say, yes, I utilize fam-trastuzumab deruxtecan very much so for my HER2-low patients as long as they have any single tissue, primary or metastatic at any point in their disease where there is HER2 1+ or 2+ that is not amplified. I would offer them fam-trastuzumab as long as they don't have baseline ILD or a concern that they would develop pneumonitis. And I would technically think about utilizing them after my endocrine manipulations, I've given 1 line of chemotherapy the way the label is and give fam-trastuzumab. It sounds like your patient is primary endocrine resistant. They really did not derive a good benefit. I did not hear whether the durability of benefit was less than 6 months, more than 6 months. It seems like they progressed immediately on the alpelisib/fulvestrant kind of suggesting that this is really not behaving like your traditional endocrine-sensitive tumor, that this is rather more refractory. So I would absolutely think about chemotherapy. DESTINY-06 is currently enrolling first line chemo with fam-trastuzumab, so post-endocrine therapy first line chemo. I'm hoping that that will also turn out to be a positive study and maybe we can think about certain patients there more appropriately. But yes, I would offer this patient fam-trastuzumab. You could consider a taxane first per the label, 1 line of chemo and then move to fam-tras immediately after if you want to stick with the label and that would be very appropriate for this patient.

DR LOVE: So I'm waiting for somebody in the chat room to say suppose she had an ESR1 mutation but I'll say it.

DR JHAVERI: Yeah. So, yes, I — well one, I think it's not an endocrine-sensitive tumor and ESR1 mutation to me is like a surrogate of endocrine sensitivity. Even if there was, I don't think given the way this patient is responding to their endocrine therapies including a CDK4/6 and a PI3K inhibitor that I would believe that this patient is appropriate for single agent endocrine therapy. So I would absolutely not go that route. I would absolutely think about chemotherapy or ADC in this patient.

Case: A premenopausal woman in her mid 30s with ER/PR-positive, HER2-negative IDC receiving neoadjuvant chemotherapy and goserelin, now with sexual dysfunction — Laila Agrawal, MD

DR LOVE: All right. Let's go to another case. This is a premenopausal patient of Dr Agrawal, a 35-year-old woman. ER-positive, HER2-negative disease getting, a big tumor, getting neoadjuvant therapy and goserelin. Here's the case.

DR AGRAWAL: She was offered fertility preservation prior to starting chemotherapy and declined the procedure for oocyte retrieval. She did elect to take ovarian suppression with goserelin during chemotherapy to attempt to preserve ovarian function.

How do you counsel patients who are interested in future fertility who have ER-positive breast cancer? At what point would you recommend or offer patients to be evaluated by a fertility specialist prior to neoadjuvant chemotherapy? What timeline do you consider acceptable since some of these procedures take a few weeks to complete? How do you counsel your patients in terms of whether it’s safe to proceed with that or not? Do you utilize ovarian suppression during chemotherapy to attempt to preserve ovarian function in patients who desire to get pregnant in the future?

DR LOVE: Any thoughts?

DR JHAVERI: So I think this is such an important issue. And we see so many young women in our practice and this is something that we certainly absolutely discuss. So I think certainly, we discuss the diagnosis. And it's such an overwhelming visit for this woman and the family because we talk about the diagnosis, the implications of that diagnosis, management strategies. We have more and more things to offer in the adjuvant setting for these patients but very importantly, we need to cover 3 things. Fertility preservation, especially given that they are childbearing age. So we need to know what's happening with their family planning decisions. Genetic testing because we have PARP inhibitors to offer and we definitely don't want to forget about that. And then scalp cooling. So these are 3 things that I touch upon once I'm done discussing the medical aspect of what needs to happen next whether imaging needs to happen, surgery needs to happen, chemo needs to happen, endocrine therapy needs to happen. So yes, I absolutely do that. I fortunately have a team of fertility specialists that I can refer them to who can talk them into it. Depending on how they present and how much delay they've had from their time to diagnosis, we can request this appointment to be rather urgent or emergent than wait for a week, if you will, to see the GYN specialist because then it has to be timed around their menstrual period and then the cycle has to match for egg retrieval and they have to wait for a few weeks as pointed out. So I do prioritize that. I understand that that generates some anxiety about not initiating therapy in a timely way, but this is the only opportunity to be able to do it. And I think we really need to work very closely with our fertility specialists to be able to offer that to our women.

With respect to ovarian suppression, I think the data is not as robust, if you will, in terms of absolutely doing that for all women. Has that absolutely helped with live birth rate? At the end of the day, that's the endpoint we're looking for. The data is not that clear and it's a little more complex. It's not generated for all disease types alike. I think the meta-analyses did not have all disease types alike. I have offered that to my high-risk patients, especially those patients who really have expressed that they really want childbearing. So I try and offer both of these to them and I have offered low-dose leuprolide during chemotherapy for such cases.

DR LOVE: So another issue, we've mentioned this program we're doing with Dr Partridge and Miller, and when I was working with Dr Partridge, she brought up another thing I hadn't thought about. Well first of all, I want to ask you, do you consider ovarian suppression during chemo with both ER-positive and ER-negative disease? And the other thing that she brought out that I hadn't thought about is just preserving ovarian function in women who don't want to become prematurely premeno — menopausal. Maybe they don't want to have future children, but they'd rather not get menopausal at the age of 35. Any thoughts about that? And, again, any difference in how you think it through whether the primary tumor is ER-positive or negative?

DR JHAVERI: Yeah, you know, when we think about ER-positive tumors, we've at least gotten an indication that amenorrhea translates into a better outcome. And, in fact, when we're thinking about these women who get chemotherapy and become amenorrheic, we think that these women are the ones who probably are going to do better. In fact, I use that opportunity in those women to start the ovarian function right away so that they're not resuming their menses between the chemo and between like, you know, the radiation and all of that that begins. Because it's very hard to go from being completely premenopausal at a young age, kind of becoming perimenopausal/menopausal because of chemo, resuming your menses and then taking ovarian suppression. It's like two hits and I think that's not okay. That's actually really bad for this patient. So I absolutely think that for those patients where I know that that's the treatment goal, I actually want to utilize them a lot easier, a lot faster. And maybe thinking about utilizing them up early on helps them get into that phase and helps them get — tolerate that regimen better. The data, however, I think is more so in ER-negative than ER-positive. And so if we had to stay purist and think about what data we have and how can we justify that, it's not necessarily with ER-positive patients for suppression.

DR LOVE: So I really like the, your 3-pronged approach to these patients who are trying to consume so much information with their families.

DR JHAVERI: Yeah.

DR LOVE: But here's another issue that came up with this patient. Here's Dr Agrawal again.

DR AGRAWAL: With the initiation of chemotherapy and the initiation of the ovarian suppression, she developed sexual dysfunction. She initially, prior to the cancer diagnosis, had had no concerns about sexual function. However, now she describes pain with sex. She explains that there’s extreme dryness and due to the pain, is no longer able to participate in sexual activities. She’s also having stressors related to her cancer diagnosis, treatments and toxicities as well as financial concerns. She states that it is physically impossible to try to have sex. She describes that she still experiences desire and arousal, however, more foreplay is needed. She is still able to have an orgasm. She has dyspareunia to the point where she does not wish to attempt to have vaginal penetrative sexual activity. In terms of psychosocial issues, she reports distress about losing her hair. Her mood is somewhat depressed and anxious. She reports feeling moodier and generally weaker.

How would you counsel this patient regarding the sexual dysfunction? Her vaginal dryness persisted after use of nonhormonal moisturizers. How would you discuss the role of topical hormones such as vaginal estrogens? What do you recommend to patients who have low libido? In my practice, all these different biological factors, psychological factors and social and interpersonal factors all come together and they can just be totally impacted through cancer and cancer diagnosis.

DR LOVE: So I was telling Dr Partridge how much I liked it when she was presenting the POSITIVE trial that we'll talk about at this thing next week when she started out by saying we want our patients not just to survive, but to thrive. Anyhow.

DR JHAVERI: Yeah.

DR LOVE: Any thoughts about this issue?

DR JHAVERI: Yeah. I think we had a case where we spoke about how TC was something that the patient was okay with, but the patient did not want to do ovarian suppression. And I think this kind of ties in into that. Sometimes, it's a lot easier to finish the chemotherapy which, if you will, is the hardest part of treatment. But really, is it the hardest part of treatment? I think it's the antiestrogen therapy for these young women that we're seeing 10 years and 10 is better than 5 and leuprolide + AI is better than tamoxifen where we really face the challenge which is why the nonadherence and the compliance rate is 49% over 5 years. Only 49% of the women complete 5 years of planned adjuvant therapy based on population-based datasets. And one of the big important reasons there is sexual dysfunction. Mood disturbances, lack of libido, dyspareunia, and not really being able to do anything is so hard on these very, very young women who are forced into menopause.

So I think supportive management really is very, very key. Social work support, having them join support groups, providing them with obviously a tier of recommendations that potentially can help them starting with the lubricants as Dr Agrawal pointed out. So we have vaginal moisturizers. I always tell my patient, you want to look pretty, you have to take care of your face regimen. You want your vagina to work well, it has to be cared for equally well. It cannot be used when you need to have sex. It has to be used on a daily basis. You have to think about utilizing these lubricants every single day so that you are not suffering the day you want to use it. So we have vaginal moisturizers, we have hyaluronic acid there. We then resort to when all of this failed and this has been done very, very proactively with the patient it's hard sometimes to do it but if we do it and it still does not work, I absolutely am okay and comfortable with the data that we now had with vulvovaginal low-dose estrogen either topical or we have tablets in strengths, there's low-dose strengths that we use. Fortunately, at Memorial Sloan Kettering Cancer Center, we have a sexual health therapist, if you will, who runs a sexual health clinic. And so these are our patients who we are really struggling. We have done everything at our end with nursing and all the list of things that we can offer. They have not been able to do it. We send them to those clinics. They use those vaginal low-dose estrogen preparations. The data has been okay that it's not necessarily getting systemically absorbed and will not lead to recurrence. And we're comfortable that that will help them with their quality-of-life and not cause recurrence. And then sometimes, we have also used vaginal dilators for our patients. And we sometimes have to get our gynecologists involved, if you will, in very, very difficult cases with these patients.

This is where if a patient is on leuprolide + letrozole sometimes, I've gone to leuprolide and tamoxifen. And sometimes if it's so severe that it's just impossible to handle for a patient, we have to go to tamoxifen which is slightly better when it comes to vaginal health compared to AI. So I think it depends on what this patient is able to do, what you're able to accomplish. But, yes, needless to say, for them to thrive, there's a lot more support that they need just over a prescription. I think it's not just that. I think there's a lot more that goes into it.

DR LOVE: I'll just add I think it's important to get the information to ask about it one way or the other. I don't know if like these apps that collect patient's symptoms ask for sexual dysfunction or not, but I'm not sure that with all the other things going on with these patients whether they're being asked about these issues.

DR JHAVERI: Yeah. We do that. We do that for every follow-up. Every follow-up.

DR LOVE: That's great.

Case: A woman in her mid 60s with ER/PR-positive, HER2-low bone-only metastatic IDC on endocrine therapy alone since 2001, now experiencing asymptomatic disease progression (ESR1 variant, AKT1 mutation on liquid biopsy) — Philip L Brooks, MD

DR LOVE: All right one more case. We've got a couple others, but I don't think we're going to get to it. But I do want to hear what you have to say about this patient of Dr Phil Brooks. A 65-year-old woman, HER2-low also. I want to talk a little bit more about how you're approaching that not just with the hormone receptor-positive, but also triple-negative, although this woman was also hormone receptor-positive. She’s actually had metastatic disease, believe it or not, well you would believe it, it's in 2001. She was on, I think, tamoxifen for like 12 years and then finally, she's now coming up on third line therapy. He had a — he got a liquid biopsy and she does have an ESR1, but also an AKT mutation on liquid biopsy. Here's Dr Brooks.

DR BROOKS: 65-year-old woman who had metastatic breast cancer in 2001. She was said to have had progressive disease while on letrozole in 2013 and then was placed on tamoxifen. And I’ve been following her ever since on tamoxifen. She had previously had an atypical fracture and osteonecrosis of the jaw while on zoledronic acid, and has been off of that. Her only disease ever has been bony disease. She’s now asymptomatic, but she clearly has progressive disease. She had variants including ESR1 that were highly consistent with recurrent breast cancer. We’ve put her on fulvestrant with a CDK inhibitor at this time. Comments were made though at the Molecular Tumor Board about her original HER2-low that we had information about, and that would be a potential future treatment for her. She also has an ATK1 mutation, and they mentioned a drug, capivasertib. And they also mentioned everolimus may be an active drug with this mutation.

So there are multiple options. But for the moment, we’re just starting her on fulvestrant and a CDK inhibitor. But I’d be interested in hearing opinions about how others might have looked at this.

DR LOVE: Any thoughts?

DR JHAVERI: Yeah, absolutely. So I think the very first thing that we notice from this case is that this is a super endocrine-sensitive tumor who stayed on 13 years with single agent letrozole with mild progression in the bone and then for the past 8 years or 9 years on single agent tamoxifen in the metastatic setting. So for 21 years, this woman has been on endocrine therapy alone. So a very endocrine-sensitive tumor. I think it's very appropriate to think about a CDK4/6 given the overall survival data that we've seen with CDK4/6 inhibitors. And so I think it's very, very appropriate to consider the fulvestrant which at least acts on some of the ESR1 mutations if not all. And certainly, with the addition of CDK4/6 inhibitors, hopefully that we will be able to overcome this issue.

Say if this patient had already received a CDK4/6 inhibitor and had such a durable benefit with bone only disease and now has an ESR1 mutation, I think this would be an ideal patient for elacestrant given its approval now and if it was available, especially if they've already seen the CDK4/6 inhibitor have a great durable response, bone only disease and an ESR1 mutation even though they have the AKT alteration. I think if they progress then on the elacestrant because of this endocrine sensitivity tumor, great quality-of-life you can get with elacestrant, I would then think about capivasertib because I'm hoping by then this patient, the capivasertib potentially is going to be approved and they can certainly justify it for this patient.

The HER2-low is certainly something we have to keep an eye out as we discussed, but I am not thinking about that for this patient right now. I think this patient can certainly justify a couple more endocrine therapy manipulations before we can think about capecitabine potentially as the first single agent chemotherapy and maybe with more aggressive disease think about trastuzumab/deruxtecan for HER2-low.

DR LOVE: So I want to ask you about capi. But first, here's the approval that just came out as you mentioned, for the first oral SERD. I imagine there may be more coming along. This is based on a Phase III trial comparing it to standard of care. Pretty good looking hazard rate there for PFS, 0.5, 0.4 in different populations. You mentioned camizestrant, another SERD involved. You mentioned this trial, the SERENA-2 trial. Very encouraging data. There's tons of trials. It seems like there's tons of agents. So I guess we'll just have to deal with it as they come out and the data comes out and they get approved. But you also mentioned capi or capivasertib which we saw a Phase III trial at the San Antonio meeting in December. And as you mentioned, a lot of people are saying based on these data, they'd like to have it in their practice. Basically, fulvestrant +/- capi. And the data looks pretty good. Any comment on efficacy, but also tolerability? Can you kind of put — this is, you know, in a class of agents where we've seen tolerability issues. I'm curious also the overlap between alpelisib and capi, the tumor testing for both, and the difference in benefit with AKT. There's like a lot of questions, but what's the bottom line and how are you thinking you might want to use this agent?

DR JHAVERI: Yeah. I think it's such a great question and it's like we have a waterfall of these agents that now have become available or will become very soon available for our patients. And how do we think about which one should be used first and how do we best sequence them is the challenge we face in clinic now. So I think when we're thinking about alpelisib, we're thinking about those 40% of PIK3CA mutant tumors that would benefit from alpelisib + fulvestrant. And when we look at the BYLieve cohort, the Phase II trial that was designed to study alpelisib + fulvestrant or alpelisib + endocrine therapy post-CDK4/6 inhibitor, we saw that the median progression free survival for patients who had AI/CDK4/6 and then for a mutation then received alpelisib and fulvestrant, the median PFS is about 7 months. Same is the benefit we've now seen in this Phase III CAPItello-291 study where we saw that patients, all-comers including the altered. So the primary endpoints were 2, you look at the benefit of capivasertib + fulvestrant in the entire patient population and the core primary endpoint was to look at the altered patient population. And what did we see? We saw that the benefit was about 7 months which was in the capivasertib and the fulvestrant arm. The hazard ratio was 0.6 for all-comers. It was 0.5 in the altered patient population. This study was not really designed to answer, will this be super active in the nonaltered patients? That's not what this study is able to address. We're still waiting for some ctDNA data because there were 16% of unknowns that were in this altered patient group that we don't have the data for and we don't know how that would play out in terms of the hazard ratios for this nonaltered patient population. But it will be interesting to see what the label looks like.

In terms of toxicity, hyperglycemia and rash. So 36% Grade 3 hyperglycemia in SOLAR-1, 10% Grade 3 rash in SOLAR-1 is what we deal with with olaparib in addition to some diarrhea and fatigue. When it comes to capivasertib, the hyperglycemia rates are rather low. What we see is a lot more diarrhea and we also see the rash.

So I think this a discussion we'll have to have. If it gets an all-comer approval, I think it's a reasonable drug to consider for any patient that might come in. And maybe we can offer this therapy to these patients with fulvestrant. We're expecting similar efficacy and then we have to really have a good handle on managing the diarrhea and the rash. So that's how we'll think about it.

The good news is we are going to be doing NGS. We are going to be looking for ESR1 mutations. We are going to be looking for PIK3CA mutations because we have therapies. So we know that we'll be able to at least identify and justify some of these so-called slightly toxic targeted therapies to the right patient for sure. The question is, how do we deal with the others that do not have these alterations and can we use either everolimus or capivasertib for them?

DR LOVE: So we had a couple of triple-negative cases, but I think I'm going to save them for the next program. But I did want to ask you about the issue of T-DXd in the HER2-low hormone receptor-negative situation.

DR JHAVERI: Yeah.

DR LOVE: I'm curious, when do you start thinking about T-DXd in those patients?

DR JHAVERI: Yeah, I think it's such an important point to discuss. So in triple-negative breast cancer, certainly we have approval for sacituzumab govitecan. So that's our Trop2-directed antibody drug conjugate. And that's for patients who've had, you know, it can be used in the second line and beyond metastatic setting essentially. And that comes in from the randomized Phase III ASCENT trial that showed not only a progression free survival, but an overall survival benefit with that agent and certainly has become our current standard of practice.

What also came by from the DESTINY-04 trial and led to its approval was for patients with HR-negative HER2-low, we saw that in those 58 patients, this was an exploratory analysis for this small group of patients that were HR-negative and HER2-low, we saw a very robust improvement in progression free survival and overall survival benefit. I think one can certainly say, yes this drug has delivered time and again, DESTINY-01, DESTINY-03, we have DESTINY-04 now. So certainly, this is an active drug. We know that. But I'm not able to forego the level I evidence from sacituzumab from the ASCENT trial and say now I'm going to just replace sacituzumab with trastuzumab deruxtecan based on that 58-patient data set.

Additionally, datopotamab deruxtecan is an antibody drug conjugate. It's a similar payload, another Trop2 ADC. A cohort was presented in triple-negative. We saw that the response rates were 52% if patients had not received prior deruxtecan or sacituzumab. If they had received those agents, it was still 32%. And so I think deruxtecan is a potent payload. Currently in my practice, until I have more data for dato or more robust data for trastuzumab deruxtecan, I use saci first and then I justify trastuzumab deruxtecan after if they're HER2-low.

DR LOVE: Yeah, we have a bunch of slides on data in the slide deck for people to check out and it sounds like it could very well become second line therapy in lung cancer, incidentally.

DR JHAVERI: Yeah.

DR LOVE: Of course, all these agents with the last name of DXd, one issue you have to think a little bit about or a lot about is ILD obviously. I'm curious, you know, I asked this, we did a big symposium, we did a couple of them at San Antonio. We were asking people how they screen for it in patients on T-DXd. Is it just asking for symptoms? Particularly, the issue of imaging. And I'm starting to hear more investigators saying they want to, if they could, they want to do imaging on these patients for a long time and regularly. Is that your take?

DR JHAVERI: Yeah. So these trials, they obviously imaged patients every 6 weeks on study. In practice, we do every 12 weeks. We definitely don't do every 6 weeks. So the question is, are we missing the opportunity of identifying the Grade 1 ILD which is asymptomatic? Your patient's not going to walk into your clinic and say, I'm having cough. So how do you not notice that? Unless you do a scan, you're not going to be able to identify those. So in my practice, I've justified 9 weeks as a compromise. 6 week was on trial, insurance is not going to approve every 6 weeks. 12 weeks might be too late. So I kind of do a 9-week timepoint. If there is something suspicious seen and I'm, say, following a patient on a PET scan, I will add in a separate HRCT or I will do every 8-week scans to make sure that I stay on stop of it or a 4-week scan for a patient where there is some suspicious lesion. And then obviously, involve my pulmonologist if I had to, give them steroids in some cases and just hold their therapy until I'm more comfortable in repeating the CT chest. Something we have to be very vigilant about and communicate with our patients to report as well.

DR LOVE: So we have a very granular way of doing consensuses. We ask 25 people what they do and if they all do the same thing, we say it's a consensus. And I'm hearing more and more people say what you just said, just to put it out there.

Faculty Survey

DR LOVE: Let's try to get through a couple of these faculty surveys. I really would hope people might want to check them out after the conference. But this is how we do it. These are our faculty for this program and how they manage these situations just to kind of get you used to that. You're there in the middle.

So we were talking before about genomic assays and Oncotype in the premenopausal patients. We presented a 30-year-old woman with a node-negative tumor and these 2 recurrence scores, either 8 or 20, so low or intermediate, and asked people what they would do. And interestingly, for the 8, everybody says they wouldn't give chemotherapy although some people would offer ovarian suppression. It's a little bit different when you get up to 20 where most people would give chemo, but also would offer ovarian suppression as an alternative. Although a couple, actually only Dr Burstein would not use chemo. So any thoughts about, again, node-negative, young, premenopausal patient, chemo or not?

DR JHAVERI: Yeah. I think if you think about the data, it's not very, very clear whether we can definitely answer this question one way or another. And that's why I think you're seeing not such concordance amongst all these investigators or all these doctors that you have here on the survey. But I think part of the reason is, is the benefit from chemotherapy related to the amenorrhea that chemotherapy would get and would be the same benefit potentially if one was to use ovarian suppression? None of these trials have really tried to address that question directly. However, there is an NRG study that has now begun its journey where this will be addressed more prospectively for premenopausal women to try and address the question, is chemotherapy appropriate for this intermediate-risk group or is it ovarian function suppression with endocrine therapy that might be enough? And I think that's why we have this discrepancy. I think we consider chemotherapy, we use RSClin for our node-negative patients. We try and look at the whole picture. We look at other parameters, how quickly this tumor developed, how big it is, what is the grade of this tumor, what is the tumor biology, how is the patient perceiving this information, and what is it that they are looking to get out of this therapy? And all of those factors really go into this decision making process.

DR LOVE: So one more question that we asked the faculty. Thank God we have 2 more of these programs because it's going to take us two more hours just to get through everything one time. But anyhow. This is a question, I know it doesn't happen very often but it's kind of interesting to think about. And we actually have a case we're going to present next time of a patient with triple-negative breast cancer and a germline BRCA mutation. This is a scenario where we're saying the CPS is 1 although everybody says they don't care what the CPS is. We just want to know what people would do in this scenario in a patient who has residual disease. And you see a little bit of a spectrum there. Some people say olaparib, probably because there's a survival benefit, but other people say both, including you. So what's your thought?

DR JHAVERI: So maybe I did not read this question appropriately.

DR LOVE: Oh, sorry.

DR JHAVERI: Did the patient get pembrolizumab in the neoadjuvant? I assume so. Maybe I —

DR LOVE: Oh yeah, that's a good question. We didn’t put that in there. But yeah, if you assume that, yeah.

DR JHAVERI: So my answer is, assuming that his patient did get pembrolizumab in the neoadjuvant with chemo and then they also have a BRCA mutation.

DR LOVE: Right.

DR JHAVERI: And yes, the KEYNOTE-522 did not address this directly and the OlympiA trial did not address olaparib with pembrolizumab, but we have many safety datasets in the metastatic setting for combining IO with PARP inhibitor. And we know that residual disease after such a kitchen sink approach in a metastatic, in a triple-negative residual disease patient is such a bad prognostic sign. So I would extrapolate that safety data and give both olaparib and pembrolizumab to this particular patient. And in the early-stage setting, PD-L1 expression has no bearing on this decision.

DR LOVE: So, Komal, thank you so much for working with us today. We all learned so much from you. A special thanks to the docs who present cases.

DR JHAVERI: Yeah.

DR LOVE: We're so grateful that they're willing to do that and put their treatment patterns out there for all of us to take a look at. Come on back tomorrow night if you want to hear about BTK first line in mantle cell lymphoma, the big plenary presentation at ASH and there was a big paper at ASCO also in older patients. We're going to talk about a lot more. A lot going on, bispecifics, diffuse large B-cell, et cetera, et cetera, follicular bispecifics. So much going on in lymphoma. Komal, thank you so much. Audience, thank you for attending. Be safe, stay well and have a great night. Thanks so much, Komal.

DR JHAVERI: Thank you so much for having me. Good night.

DR LOVE: Good night.