Current and emerging strategies for patients with mTNBC

DR LOVE: Welcome to the Research To Practice “Virtual Case Library.” Today our focus: metastatic triple-negative breast cancer. This is medical oncologist Dr Neil Love.

For this program, Dr Rita Nanda from the University of Chicago and Dr Sara Tolaney from the Dana-Farber Cancer Institute discussed cases presented by Dr Julia Foldi, Dr Laura Huppert and Dr Saba Shaikh.

But to begin, I asked the faculty for their perspective on where we were 5 years ago in this arena and where we are now. Dr Nanda began.

DR NANDA: I have to say pre-2018 we had chemotherapy, and that was it. And it wasn’t that great. Patients didn’t do very well. Median progression-free survival in the front-line metastatic triple-negative breast cancer setting was on the order of a few months and we just didn’t have great options for patients. I think the PARP inhibitors for that small subset of patients who have BRAC1 and 2 associated triple-negative breast cancers have been a nice add. But immunotherapy has certainly added a fair bit to patients, and I even have a number of patients who are off of all their therapy with no evidence of disease. And so that’s really been game changing for a very small subset of patients I will say. And then, the antibody-drug conjugates have been great as well. Patients who don’t respond to taxanes, anthracyclines, recur very quickly after their neoadjuvant therapy. Sacituzumab govitecan, trastuzumab deruxtecan have certainly offered some patients an extension in their life. So, I think it’s really exciting to see where we’re at now, but there still is a lot of room for improvement.

DR LOVE: So that’s for sure. And we put a number of review articles, some of which were written by our group here today for you all to check out. But there are a couple of specific papers that I was really interested in. One, Sara, I had not heard about this. I know it’s in earlier stage disease, but I was just fascinated by this estimate triple-negative tool. It kind of reminds me of the adjuvant online program we had a million years ago that Peter Ravdin did. This kind of looks very similar, but I guess it’s localized triple-negative?

DR TOLANEY: Yeah, so this was developed by one of my colleagues, Pablo Leone, who works with the SEER database very often. And one of the questions we had is, could you put in individual patient level characteristics and be able to predict breast cancer specific survival? And so he’s done this both in the hormone receptor positive setting as well as the early triple-negative breast cancer setting. It is limited because with SEER you don’t get recurrence data, so you are specifically getting breast cancer-specific survival as the endpoint. But it’s very cool because, particularly in hormone receptor positive disease where patients can recur many, many years after their initial diagnosis, this tool can look at 20 years of data to be able to look at survival events. So really interesting to be able to do that.

DR LOVE: Well, the other thing, and again, I’m not sure whether people who are fairly new to oncology are aware of the adjuvant online tool. I feel like it came out even before the internet. I’m not even sure, but it was a long time ago. But one of the things I like about this, and I liked about adjuvant, was it incorporated non-cancer causes of mortality. So as you get older patients in their 80s and beyond, that gets to be an issue.

The other paper I wanted to ask you about, Sara, and this relates to one of the cases that we’re about to hear, which is of a patient who presented with metastatic disease, was your paper that you were on that was just from San Antonio looking, again, I guess at this SEER data, for people presenting with Stage IV disease over the last decade. Can you kind of summarize what you saw there? Also, there’s some pretty interesting numbers about, I guess, recurrence-free and mortality data that was pulled. Can you kind of talk about that, Sara?

DR TOLANEY: Yeah. So this came up because I think one of the things we’re all noticing is that we’re seeing more patients with specific subtypes of breast cancer presenting with de novo metastatic disease. So, for example, I think we are seeing more cases of de novo triple-negative breast cancer than we have in the past and more cases of de novo HER2 positive breast cancer than we have before. And so we were actually interested in looking at this over time and how presentation of de novo disease has evolved and how it differs by subtype. And so what you can see is that in hormone receptor positive disease, for example, presenting with de novo disease is not quite as common, it’s about 5% of cases. Whereas it is much higher in triple-negative and HER2 positive disease, and we are seeing that it is becoming more common as time has gone on. I think one can say that we also are carrying more patients in the early disease setting in HER2 positive disease, for example, where you’d imagine you’re not seeing as many recurrences. And so when you look at prevalence of patients who present with metastatic breast cancer, you’re going to see a larger proportion of patients with de novo metastatic disease as well. And I think this is coming out as we’re starting to do clinical trials because we are seeing different trials reach their caps for de novo metastatic disease much more quickly than we have in the past. So, it is actually actualizing in our real-time at work.

DR LOVE: Any hypotheses about why? Are these tumors more aggressive? Or what’s your thinking about what’s going on?

DR TOLANEY: Yeah, I do think that these are subtypes of disease that are more quickly growing cancers. And so they are unfortunately more likely to spread over a quick period of time than, for example, an ER positive disease. So, you know, if it’s not caught quickly, there is this risk. And so again, we are seeing it become a little more common.

Case: A woman in her early 60s with a history of well-controlled HIV is diagnosed with mTNBC — Dr Shaikh

DR LOVE: All right, let’s talk about some cases here.

And Saba, you have an interesting case of a 60-year-old woman, well-controlled HIV. What happened with her? And what questions do you have about this case?

DR SHAIKH: Sure. So this is a 60-year-old very lovely woman. She’s had HIV for decades, very well-controlled, never had opportunistic infections related to that. And she self-palpated a breast mass which led to her initial presentation. On mammogram, it measured about 2.5 cm. There was no associated axillary adenopathy. And it was biopsied ER/PR 0 and HER2 was actually 1+. And so she reported back pain at that time, and so I got a baseline PET scan. The PET didn’t identify anything that could have potentially caused back pain, but she was found to have a 1.4 cm FDG-avid pleural-based nodule, and the SUV was 20 on that. And we biopsied it, ER was 0%, PR was 20% but weakly staining, and HER2 was 1+, CPS was 20. So because she had a low volume of disease, I started her on pembrolizumab and I paired that with nab paclitaxel. And after the first, basically at the first set of restaging scans, the disease had, in the pleural- based disease was virtually gone and the breast mass had shrank significantly. So I presented her at our multidisciplinary tumor board to talk about actually if there would be any role for definitive local treatment for this patient who has very minimal metastatic disease that’s responded to systemic therapy. And the primary breast tumor as well is T2, clinically node negative. And so I’m really curious to get the rest of the panel’s thoughts on that. I think the data for definitive therapy in metastatic cancer is very mixed, but I think patients like mine are not really reflected in the trials very well. So, I wanted to know if you’ve ever done something like this or what the experience has been.

DR LOVE: So that’s a really great case. So let’s, actually, first, I want to go back to Rita. Any thoughts about the case, but also starting out with the HIV issue here. In what situations, if any, in managing breast cancer is that relevant? For example, patient getting immunotherapy. Any therapies that you would think twice about or think differently about in a patient with well-controlled HIV, Rita?

DR NANDA: No, I mean, HIV is not now what it used to be when it first presented, and I have many patients who are doing very well on their therapy. And so I think given how well-controlled this is, the only question I would have was the question of drug-drug interactions and whether any doses of chemotherapy needed to be modified. So I’d go to my PharmD and I would ask them their thoughts about that. But it sounds like this patient’s been doing very well, and so I don’t think that that would impact my decision to start her on therapy for her metastatic triple-negative breast cancer which is obviously the more urgent of the issues. And so, from that standpoint, I think I would forge ahead.

In terms of local management though for patients with metastatic triple-negative breast cancer, I guess I would say that she’s had a great response which is clear 3 months in. But I think what you don’t know at this point, is this an immunotherapy response or is this a chemotherapy response? And we have data, not with immunotherapy, but with just traditional chemotherapy, even HER2 directed therapy, in patients with metastatic de novo disease. We’ve got surgical data which suggests that operating on the primary doesn’t necessarily improve long-term outcomes. We’ve got data from radiating oligometastatic disease which also shows us that radiating oligometastatic disease doesn’t improve outcomes. One hundred percent understand this patient was not included in those trials. But I think from my perspective, if this is an immunotherapy response, you don’t need surgery and radiation to potentially cure someone of their metastatic disease. I’ve seen a number of patients who are off all therapy after having completed a period of time of immunotherapy with NED and are just getting periodic scans and are off all therapy.

So I guess from my standpoint, I would certainly give this more time. I do drop the chemotherapy after a period of time. And then that will really give you a sense, is something new going to pop up? You don’t want to put this person through a lot of surgery and radiation that also comes with some comorbidities, lymphedema, a lot of surgery, unless you know for certain that you’re going to have a beneficial impact on their long-term outcome. And so I would most certainly give this time on immunotherapy alone, and then she’ll declare herself one way or another. And if this is an immunotherapy response, I think she’s going to do very well on immunotherapy by itself. So I guess I would not be rushing to do surgery or radiation on this individual.

DR LOVE: So Julia and Laura, in a minute, I’m going to see if you have any questions that you want to put out or any comments. But I just want to go back to Sara to get her thoughts about particularly this issue that we have this question about. Any thoughts about the case, cell-free DNA, and do corticosteroids matter for IOs, Sara?

DR TOLANEY: That’s a lot of different good questions. So first, I very much agree with Rita’s comments here, that it’s hard because in these de novo patients, particularly someone who had such a small area of metastatic disease, when they have a complete response, it’s very tempting to try to go resect a metastatic site or resect the breast primary. And as Rita alluded to, there have now been several studies that have looked at trying to remove the breast primary and do consolidate radiation after people have had induction therapy, but unfortunately have not found a survival benefit. And in fact, in the more recent cooperative group study with the triple-negative subgroup, in fact had a worse quality of life from pursuing that. And so generally speaking, it’s not the road I’ve taken. But I very much agree we don’t have data in the setting of modern therapies with immunotherapy. And again, every case is an individual case, and this one had very minimal metastatic disease. And so, one truly doesn’t know the answer here, and it’s a good question. But again, just given our data, it’s not been the road I’ve taken.

With regards to the immunotherapy, again, I would also, as Rita alluded to, go on to continue chemotherapy until someone’s had maximal response and then go on to continue immunotherapy. When you think about is there an ideal chemo backbone, this was sort of looked at in KEYNOTE-355 where there were a choice of chemotherapy in that study, it was nab paclitaxel, or paclitaxel, or carboplatin/gemcitabine. The challenge was it wasn’t randomized to chemo choice, right? It was investigator choice. And so there’s a lot of bias in who chose what. There’s a lot more patients, for example, who had an early relapse where the physicians is going to choose carboplatin/gemcitabine and those patients have higher-risk disease, and so obviously they aren’t going to do as well. So you can’t really address the question, but I think your question’s a good one. We were also really worried in breast cancer about the steroid pre-medication use with immunotherapy. But when we saw the data, the subgroup data from KEYNOTE-355 that suggested that the relative benefits seem very much similar between nab paclitaxel and paclitaxel, it made me feel very comfortable thinking that that steroid pre-medication is probably not what’s driving any efficacy difference. And so I don’t, for example, necessarily pick nab paclitaxel over paclitaxel if I’m using combination immunotherapy. I feel comfortable with either.

So with cell-free DNA, I think in the metastatic setting, we are commonly using ctDNA to understand genomic alterations in the tumor. And so that’s been tremendous because you don’t have to biopsy someone, you can get very quick information about genomic alterations. In triple-negative disease, there are not a lot of actionable mutations we’re looking for, for example. It’s important to know if someone has a high tumor mutation burden. In case they’re PD-L1-negative, it could give them an opportunity to get checkpoint inhibition. MSI-high could also give you an opportunity to get checkpoint. But we don’t usually see MSI-high, we don’t usually NTRK fusion, so it’s not as useful potentially as in ER positive disease where we do need this information.

But I think there’s another utility to ctDNA where we’re, I think, not quite there yet which is trying to look at minimal residual disease. And in this particular case, that becomes really interesting, right? Because it makes you wonder, could we use the detection of minimal residual disease to understand if we’ve cured a patient? And so in this setting, as Rita talked about, there are some times we give immunotherapy in metastatic disease and we have many patients many years out who we think could be cured. But could we do a test to know that? And I think the assays aren’t super reliable right now. There are tumor informed assays to help you look at minimal residual disease, and these assays are becoming more and more sensitive. But in my mind, not quite actionable yet. And I think we have to wait until those assays are a little more sensitive.

DR LOVE: So I was just flashing on the fact that one of the most common reactions we get to our work is people like it when the investigators don’t know the answers of what to do. Because they feel like they’re not alone anymore. You all know all the answers. A case like this, who knows? Well let’s just, Laura, any thoughts or questions?

DR HUPPERT: Not too much to add. I think the one other thing in addition to Rita’s comment about the HIV is I usually do contact their primary care doctor or infectious disease doctor prescribing their HIV medications because sometimes, chemotherapy can drop their CD4 count. And so they’ll want to prophylax those patients for OIs related to that. And so I think just being in contact with them is the one other piece that I usually have on my list of to-dos for my patients with HIV.

DR LOVE: That’s a great point. Julia?

DR FOLDI: Yeah. So actually, I have a very similar case that I added as one of my extra cases that’s, I think, at the end of the slide deck. A patient who was diagnosed with de novo metastatic triple-negative breast cancer back in the era of atezolizumab. And so she was started on nab paclitaxel with atezolizumab. This was actually around 3 years ago. So I did not treat her initially. But she similarly had a complete response and eventually came off the nab paclitaxel because of neuropathy that she developed. And before I took over her care, it was actually decided to go for locoregional treatment of her breast mass. And interestingly, after she had a mastectomy and axillary lymph node dissection, she had a path CR in the breast and lymph nodes which was not, I think, was not unexpected given that she had a complete response elsewhere. But this patient has had a lot of morbidity due to her surgery and radiation, has a lot of lymphedema. And she actually continues on the atezolizumab. She’s now around 3 years from her original diagnosis. And I would love to hear your thoughts, Sara and Rita, on the safety of stopping the immunotherapy. And I think this discussion also gave me the idea of perhaps doing a cell-free DNA assay like Signatera to try to risk stratify. And if she is ctDNA negative, I would feel more comfortable stopping her immunotherapy and just following that. So if you have any thoughts on a case like that.

DR LOVE: Rita?

DR NANDA: Yeah, I’ve had a case like this. And I will say, and I was going to chime in, but I think we’d wrapped up that discussion. I had a patient who was on a clinical trial with atezo and tiragolumab, and had a complete response, imaging response. And most of the trials discontinued immunotherapy after 2 years, right? But I had the option to continue this patient on this therapy, but she developed 3 immune-related adverse events over time while I was trying to get her to discontinue. Because I think most of the trials only stopped after 2 years. We had the option, she was PD-L1 positive, to give her pembrolizumab should her disease sort of act up after stopping therapy. But I actually did order a ctDNA test, recognizing that they’re not perfect but really, to help reassure her and myself. Her ctDNA assay was negative. It was a tumor informed ctDNA assay that I used and was how I finally managed to get her off of treatment after her third immune-related adverse event. And so she’s doing great. This is about a year out off of all therapy. Her scans have been stable. So I think that when I do use a ctDNA assay in the metastatic setting, a lot of times, it’s for something like this, for patients who’ve had complete imaging responses, maybe they’re HER2 positive, maybe they’re triple-negative on immunotherapy as a way to add an extra piece of information to help me make the patient and me comfortable stopping their targeted therapy. And so I’ve successfully used it in a number of cases like this.

Case: A woman in her mid 40s with de novo mTNBC — Dr Huppert

DR LOVE: So I want to go on to this next case and have Laura present. A 45-year-old woman with de novo metastatic disease again. And one thing maybe we can add into your presentation, Laura, and I was going to ask Saba, we can go back to her too, in terms of a little bit about how patients who walk in and get diagnosed with metastatic disease deal with it and how you assist them to deal with that. Because it’s one thing to be diagnosed with breast cancer, it’s hard enough, but metastatic disease is another story. So maybe we can bring a little bit of that element here.

DR HUPPERT: Sure.

DR LOVE: But what happened with this 45-year-old lady?

DR HUPPERT: Yeah. So this is a 45-year-old patient who initially developed right breast pain and swelling, and got an MRI that showed locally advanced disease. And so biopsied her breast first which showed triple-negative disease with a HER2 IHC of 0. And then subsequently got a PET scan which unfortunately showed a 5 cm hypermetabolic liver mass concerning for metastatic disease which then we biopsied and confirmed triple-negative disease there. PD-L1 CPS of 10. And so started her on weekly nab paclitaxel 2 weeks on, 1 week off, and pembrolizumab q3 weeks per KEYNOTE-355.

And, I think, to your question about dealing with the new diagnosis of de novo disease, I think it’s challenging. Many of these patients are young patients and they have a whole life ahead of them. And to get a diagnosis of metastatic disease is challenging in general. And then I think in particular, triple-negative metastatic disease with the worse prognosis I think is particularly hard. I think with some of our newer therapies, we can have longer-term responders. And so I try to, as much as possible, support them, support their family, connect them with our social work, SMS, other resources to kind of help support the psychosocial piece and just acknowledge what a challenging diagnosis this can be but we kind of take things one step at a time. I think it’s also important to let patients know that unfortunately metastatic triple-negative disease is not considered curable, but it is treatable, just so they have a sense of that prognosis off the bat.

DR LOVE: What was her life situation in terms of family, work, et cetera?

DR HUPPERT: Yeah. So this patient was married, but did not have children. She had actually recently been married. And so I think it was quite a devastating diagnosis for her and her partner. I always bring up, with young patients, fertility concerns off the bat too. She was not interested in future fertility. I think often, it’s more challenging in our metastatic patients in general. But I think that regardless, it’s important to acknowledge that important aspect of their care and life wishes for all patients that are premenopausal.

DR LOVE: So before we go on in terms of her case, again, just to come back to you, Saba. What was the life situation of your patient? And kind of what were the issues that you were trying to help her with as she coped with the diagnosis initially?

DR SHAIKH: She was married as well. And she was — it’s always, I think, hard to have these discussions with the patients and to, you know, give them what may be some of the worst news that they’ve ever received. And so she was really tearful. It was hard for her initially. But her attitude towards it changed a lot because she noticed her breast mass shrinking so quickly once she started therapy. And so after that, she became a lot more optimistic because she was feeling the changes.

DR LOVE: So just, again, one more thing going back to you, Sara, in terms of thinking about your paper about people presenting with metastatic disease. I know you couldn’t figure this out from looking at SEER data, but I’m just kind of curious in terms of your clinical experience. How often do you see that the patient has delayed coming in even maybe really to the point of locally advanced? That’s sort of the other side of presenting with metastatic disease. How much of a problem is that? And do you think that’s changing?

DR TOLANEY: Yeah. I agree, it’s hard to know. Because I definitely see patients who were right on time with their annual screening mammogram and you find de novo metastatic disease and they just had a very rapidly growing breast cancer. We also see the flip side, someone who maybe hasn’t had screening in years and presents with a locally advanced tumor and can have metastatic disease at presentation. And so I don’t know what the proportion is for the people who are on time with screening versus not and the rates of de novo disease. But I definitely think this phenomenon is becoming a little bit more common where we are catching it, particularly in the HER2 and triple-negative patients, more than we had in the past. And so these cases unfortunately are occurring. And I very much agree with my colleagues here that this is a tough one. These young women who come in thinking they just have an abnormal mammogram and thought they had a localized breast cancer. And to completely change roads and tell them they have metastatic disease, it’s really hard.

DR LOVE: Yeah, we maybe will come back to this and even chat about it at the end because I’m also wondering what else can we do for patients besides directly treating their cancer. But let’s get back to this case. Kind of an interesting issue here in terms of what happened. So can you kind of bring us up to date?

DR HUPPERT: Yeah. So about a month after starting the pembrolizumab, I noticed that her LFTs were abnormal. Her Tbili was 0.7, her AST was 255, her ALT was 255, and her alk phos was 180. So I got a right upper quadrant ultrasound just to make sure that there was no obstruction first which was negative. Checked viral serologies and other autoimmune hepatitis serologies which were negative. So suspected IRAE hepatitis, so went ahead and held the pembrolizumab and started her on steroids. Continued the chemotherapy. She completed a steroid taper, and her LFTs did normalize. Her imaging around that time showed significant improvement in the size of her disease. And then her LFTs continued to remain normal after finishing the steroid taper. And so there was a discussion with her and hepatology at length about the risk of recurrent IRAE hepatitis and whether it was worth restarting. She really strongly wanted to retrial the pembrolizumab. So after counseling her about the risks, we ended up restarting it. And fortunately, her LFTs have remained normal since we did restart it.

So I guess my questions really to this case are, what is your general threshold for, in particular IRAEs? Which ones are you willing to restart it for and which ones are you not, particularly in the metastatic setting? I think LFT abnormalities are a challenging one because it can be quite problematic if it does recur. And I think similarly, I’m hopeful that she will be one of these excellent responders. When do you consider dropping the chemotherapy? And then when do you consider, if on immunotherapy she’s stable for a while, when would you consider dropping the immunotherapy?

DR LOVE: So Rita, any thoughts?

DR NANDA: Yeah. This is a great case. I think one that we certainly come up with and see a fair bit. Immune-related adverse events are quite common, and I’ve definitely seen my fair share of hepatitis. I actually have someone in the hospital right now with steroid refractory hepatitis getting ready for a biopsy.

DR LOVE: Wow.

DR NANDA: But there are some of these severe cases. This is probably, I’m trying to do the math in my head here, but Grade 2/Grade 3.

DR HUPPERT: Grade 2.

DR NANDA: Grade 2. Okay. In a young woman like this who has had a great response and has responded to steroids and has normalized her LFTs, it’s absolutely a conversation with the patient, but I think I would agree with you. She’s had a great response. It could very well be that she will have a great response with her immunotherapy-based treatment. So I would agree with restarting, particularly if the patient is on board with that. And even in a Grade 3, this is kind of right on that border depending on what your upper limit to normal is. But in a just barely Grade 3, I would also have that conversation in a young woman like this who is having a great response to therapy.

In terms of chemotherapy backbone, a lot of times with my young women, they really don’t want to lose their hair. And scalp cooling can be a heavy lift when you’re talking about weekly chemotherapy, 2 weeks on, 1 week off. I do occasionally give carbo/gem to these patients or I usually use more paclitaxel than nab paclitaxel. I don’t think the steroids matter, quite frankly. And I usually drop the steroids after a few weeks if patients don’t have infusion reactions with paclitaxel anyway. But I think for young women who want hair preservation, I will consider carbo/gem. I think Sara had mentioned perhaps the data from KEYNOTE-355 didn’t look as good for carbo/gem, but I think there was a lot of bias there in who got the carbo/gem, right? These were patients who’d relapsed early or after neoadjuvant therapy with a taxane. So I think certainly, choice of options. I would absolutely consider rechallenging this patient. Obviously, if the hepatitis comes back, then I would consider stopping permanently.

And so, again, in this young woman, I would absolutely rechallenge her. I usually drop the chemo after about 6 months. That’s usually, even if they’re continuing to respond, I probably would consider dropping it at that point. Especially with nab paclitaxel or paclitaxel, you’re going to run into neuropathy issues anyway. And then just keep the pembrolizumab monotherapy going, provided her LFTs remain under control, and just continue to scan and monitor and hope for the best.

DR LOVE: A really interesting, provocative case here. Any other questions, Laura?

DR HUPPERT: And then, Rita, how long would you, if she did have an excellent response and you went down to the pembrolizumab, when would you drop the pembro typically?

DR NANDA: Yeah. Provided you can continue, you know, she doesn’t develop some other immune-related adverse event or doesn’t have a recurrence of her hepatitis, I usually like to stop at 2 years because that is what the trials generally did. But I think it’s a discussion, right? And how the patient is doing and what their thoughts are and if you see any disease or not. In those patients who kind of have a waxing and waning status, maybe I’d want to continue on for that 2 years. Sometimes, if patients want to stop a little bit earlier, certainly could consider that. But I would continue to monitor them. And that’s where the question of, is there a role for ctDNA testing here, could come into play. Again, it’s not perfect but sometimes, I will consider that in these cases as I’m stopping and maybe even monitoring early on ctDNA in these patients.

DR LOVE: So before I come back to Julia to see if she has any questions, Sara, any thoughts about the age, seems like age-old but I guess it’s not that old, question of is there a correlation between autoimmune toxicity and treatment benefit? Would you say to this patient, you may be doing really well because you have this autoimmune problem?

DR TOLANEY: Yeah, there have certainly been studies that have tried to look to see if there’s a correlation between developing significant IO toxicity and having better response. And there have been some series that have suggested this. In fact, recently, one of my colleagues had looked through our immune-related toxicity data and did find that patients who had IO tox seemed to have longer benefit. Obviously, these analyses are quite complicated to do. But I don’t tell patients that. I do not think there’s definitive data to tell you that that’s the case. So it could be there’s better response, but that’s not clear in my mind.

DR LOVE: So Julia, any comments or questions?

DR FOLDI: Yes. I would love to hear what your thoughts are on starting immunotherapy in patients who have underlying autoimmune diseases. I just recently saw a patient on our consult service who got 1 dose of pembrolizumab, has had a history of myasthenia.

DR LOVE: Wow.

DR FOLDI: Developed a crisis. So I’m just curious what kind of discussion you have, multidisciplinary discussions with the patients who have underlying autoimmune diseases.

DR LOVE: Before I go back to Rita, could you tell us a little bit more about what happened with your patient?

DR FOLDI: So this was a woman who was started on chemotherapy and pembrolizumab for actually not breast cancer. It was a lung cancer patient. But she had a history of myasthenia which her history was generally ocular symptoms. And there was a lot of discussion between her and her oncologist as to the safety of being on a checkpoint inhibitor. It’s also someone who is a bit older, in her 70’s. Ultimately, it was decided to try. And after just 1 dose of pembrolizumab, she was admitted to the hospital with new neurologic symptoms. And this actually just happened this week. And so she’s still undergoing workup with CNS imaging, but there’s a concern that she has this precipitated myasthenia crisis in her.

DR LOVE: Do you happen to know her PD1 level?

DR FOLDI: Thirty percent, yeah, CPS of 30%.

DR LOVE: So Rita, what an important question here. And the reason I asked the PD1, because PD1-high non-small cell lung cancer, some people out there 5 years and who knows, maybe even cured. And I was curious whether, you know, it’s so hard to pick this up because they have chemo on board and all. And you had referred earlier, Rita, to could this be an immunotherapy response. Do you think mixed in here are some people who are going out, maybe even cured? Hate to use that word. But any thoughts?

DR NANDA: Yeah. I definitely have patients, you know, prior to immunotherapy, I would never have used the word cure with metastatic triple-negative breast cancer. But absolutely, I have some patients who are off all of their therapy with no evidence of disease. So we definitely do see it. It is a minority of patients, so I don’t — I always love to tell my patients about those as we’re starting immunotherapy. But caution them that it is a very small proportion of patients. So absolutely, it turns into a risk/benefit discussion when you’re talking about someone who has got a history of an autoimmune disorder. And we all have these patients and we obviously want to offer them therapy. If they’ve got a combined positive score of 30, that’s great. And that patient could very well respond to immunotherapy.

But I have to say for me when I’ve been faced with these patients, when you look at the trials that we’ve done that have led to the approval of these agents, it excluded patients who were on active therapy for their autoimmune disease and had been on active therapy for their autoimmune disease, I believe, within a year or 2 of study entry. And so I look at whether or not they’re still on therapy for their autoimmune disease, what is their autoimmune disease, and how life-threatening is it. I have patients who have autoimmune hepatitis, and I have to say that really gives me a lot of pause wanting to give them immunotherapy because they could have fulminant hepatic failure. And so it's always a discussion with the subspecialist who is managing them to get a sense of what their thoughts are about trying immunotherapy for these patients. But it does boil down to risk/benefit ratio and then if we’re going to be able to control that sort of autoimmune enhancement that we might see with immunotherapy. I’ve had a handful of patients who’ve ended up in the hospital with steroid refractory hepatitis. And so I’m always very cautious in those patients because you can’t live without a liver. And so you really have to think about it very carefully in those patients.

But for, say, rheumatoid arthritis, I’ve treated patients. If they have a flare, unfortunately, we have to stop but we generally can get their disease under control. And so it’s really a discussion with their subspecialist, a discussion with the patient and then thinking about how long they’ve been off of therapy for their immune-related adverse event. And when you look at some of the lung cancer data, for example, of efficacy with immunotherapy in patients who’ve got COPD who are on steroids, the real-world evidence, they do not get as much bang for the buck with immunotherapy as those patients who are not on long-term chronic steroids for a disease. So there’s also that to think about.

DR LOVE: It’s interesting because we started talking about this a few years before IOs even came to breast cancer because it started out with lung in melanoma. And then I’m curious, Sara, what your thought is on this. Also, the setting of adjuvant versus metastatic, for example, where adjuvant, some of these people are already cured versus metastatic where maybe you’re looking at the possibility of a cure. I’ll just tell you, Sara, one of my favorite cases I’ve heard in the last couple years was a patient with metastatic lung cancer, very well-informed, she had multiple sclerosis, but it was only treated a little bit. Ran out of options, had a couple of opinions. Said okay, let’s do it. Had a complete response and was doing great, no problems with multiple sclerosis. And the punchline was the PD1 was 0. So you never know. So, Sara, any thoughts for practical purposes in the breast cancer setting? Again, earlier, localized, and metastatic, how do you think through relative contraindications? Not just autoimmune, but also prior transplant, prior kidney transplant, for example.

DR TOLANEY: Yeah, these are really difficult discussions. So one of my colleagues, Mark Awad, had actually looked at people who had underlying autoimmune diseases and what was the frequency at which people had exacerbation of their underlying autoimmune disease if exposed to immunotherapy. And as Rita said, a lot of this is complex because it depends on what autoimmune process it is, were they on active therapy for that autoimmune disease. And those are all factors that need to get considered. But it seemed that over 20% of people did have exacerbation of their autoimmune process if they were exposed to immunotherapy. So it isn’t infrequent that it happens. But I think your point is a good one.

I think that I always worry. I look at what the autoimmune process is and what would happen if it was exacerbated. MS is one that would scare me because I don’t want to exacerbate that as a potential autoimmune illness. Transplant, obviously also very concerning in my mind because you don’t want someone to lose an organ. So in a curative patient population, I’m not going to be giving them immunotherapy. I think my problem is in the early disease setting is we cure a lot of patients with chemotherapy and we don’t actually know who needs immunotherapy. We do not have a good biomarker predictor. And so those are patients, again, that have hopefully a long life ahead of them. And if the chemotherapy is going to cure them, I’m not going to put them at risk of losing a transplanted organ, for example.

The metastatic setting is obviously very different. Unfortunately, it’s a disease that we’re, at this point, for the most patients, we’re not able to cure. And so your judgements are a little bit different in this setting. And so I think we act accordingly.

DR LOVE: So Saba, any thoughts or questions? I’ll also say I’m not trying to say do this at home type thing. I’m giving somebody an IO with MS, that sounds pretty scary to me. But that’s what happened with that case. Saba, any questions that you want to put out or thoughts you have?

DR SHAIKH: I have one just practical question I’m curious about. So in KEYNOTE-355 when they dosed nab paclitaxel and paclitaxel, it was on a q28-day schedule which doesn’t line up well with the pembrolizumab at all. Is that what you’re doing in practice or do you use a q3-week schedule instead?

DR LOVE: Rita?

DR NANDA: I use a q3-week schedule. It’s all about quality-of-life for patients. I think for the trial, they probably had to follow the package insert, and that’s why they did that. But when I use paclitaxel or nab paclitaxel, I do 2 on, 1 off.

Case: A woman in her late 50s with mTNBC receives up-front pembrolizumab/chemotherapy — Dr Foldi  

DR LOVE: So Julia, let’s hear about your 59-year-old woman.

DR FOLDI: This is a slightly different case. I really want to focus on her CNS disease. So this was a woman who actually had an early-stage ER-positive breast cancer about 6 years before she presented with new headaches and dizziness and seizure-like activity. And you can see here, her MRI brain from August of 2023 that showed innumerable parenchymal brain metastases. I think they listed about at least 27 on her initial brain MRI. They were not amenable to local therapy, local targeted therapy so she underwent whole brain radiation.

And at the same time, she also was staged with a CT chest, abdomen, pelvis which you can see there which revealed a left upper lobe lung nodule, mediastinal adenopathy as well as an adrenal nodule. This was actually initially considered to be a case of a metastatic lung cancer based on just the distribution of metastatic disease.

However, after a biopsy of the adrenal nodule, the pathology was reviewed actually by multiple different pathologists, and they agreed that this was actually a metastatic triple-negative breast cancer based on the immunohistochemistry pattern, was ER/PR-negative, HER2 0. Her CPS was actually low. I believe it’s on the previous slide. I think it was a 5. However, she did have a next-generation sequencing done on the adrenal biopsy which showed a high tumor mutation burden at 19 mutations per megabase. And so it was based on that high tumor mutation burden that she received pembrolizumab in addition to chemotherapy with nab paclitaxel.

Her first restaging scans showed some response. This was after about 3 months of therapy. However, shortly after that, she re-presented with new CNS symptoms. And she was found to have a new brain metastasis, a left frontal lobe large lesion, and she underwent resection of that followed by postop stereotactic radiosurgery.

And so I actually met her after she was discharged from the hospital for her resection of this new brain met. And I had sent another tissue-based next-generation sequencing panel on that which also showed high tumor mutation burden. Very similar, I think it was 18 or 19 mutations per megabase. And so in terms of her systemic disease at the time of this CNS progression, it was actually fairly stable showing that lung metastasis, some mediastinal adenopathy, and similar appearance of the adrenal met.

So this is someone who is predominantly progressing in her CNS. And so my question is, what would be your choice of next-line treatment for someone like this who has high tumor mutation burden as well, but is having CNS progression?

DR LOVE: And Sara, I was just kind of flashing on the algorithm in HER2 positive disease when you get brain mets. If systemic therapy is stable, the approach is usually treat the brain mets locally and keep systemic therapy going. Is that sort of algorithm what you do in triple-negative disease? And what about this case specifically?

DR TOLANEY: Yeah. In triple-negative disease, oftentimes when the CNS is progressing, usually the systemic disease is also progressing. And so we get into, it’s a lot trickier in my mind to deal with because you sometimes don’t have time for local therapy because they could be in impending visceral crisis systemically. And so sometimes, we are trying to use systemic agents and forego the local therapy in those cases. This case is obviously very different because this is a patient who had already had whole brain radiation and now has a new brain met, but has pretty much stable systemic disease. And that brain met has now been resected. I don’t know if there’s anything to follow in the CNS. Is there, you know, was it completely resected, the area of progressive disease?

DR FOLDI: Yeah, it was completely resected at the time. Actually, even since I put together these slides, she has again progressed in the CNS, unfortunately. But at the time, I just had that resected mass and there wasn’t anything to follow.

DR TOLANEY: And can I ask, at the time of pathology review from the resected brain met, I assume they retested ER/PR/HER2?

DR FOLDI: Correct.

DR TOLANEY: And do you know what the, I assume ER-negative/PR-negative, but what was the HER2 IHC?

DR FOLDI: Zero.

DR TOLANEY: Zero.

DR FOLDI: Yeah.

DR TOLANEY: And it was 0 previously on her biopsy systemically as well?

DR FOLDI: Correct. Correct, yeah.

DR TOLANEY: So I think in this case, I might be tempted to try sacituzumab because I’m so worried about not having good local control in the CNS and more disease popping up as it sounds like it did. With sacituzumab, one could ask, well what’s the data for actually using this drug in someone with brain metastases? And unfortunately, the data is pretty limited. In ASCENT, the registration trial that looked at using sacituzumab in pretreated metastatic triple-negative disease, they had a very small number of patients that had treated brain metastases in the trial. But there was another series that was done by Andrew Brenner where he had actually done a really cool study where he had given patients exposure to sacituzumab before getting resection of their brain metastases and then did follow those patients thereafter and saw that the drug levels of the sacituzumab in the tumor and the CSF were consistent with systemic drug levels, meaning that it was, the drug is getting into the tumor. And he has seen some patients who had lesions outside the area of resection that did have shrinkage in the brain. And there’s an ongoing trial now running through the SWOG group actually looking at CNS response to sacituzumab in patients with new brain mets or progressive brain mets. So we’ll get more data, but the fact of the matter is we don’t have that much data here. But clearly, the drug gets in and it is active in triple-negative disease. And so that’s probably what I would do in this particular case.

DR LOVE: So Rita, just kind of getting back to the HER2 of 0. Do you actually have patients where you just cannot find anything? And do you ever use T-DXd or can you access it for HER2 0? And maybe update us a little bit on what we know about, Sara just talked about saci, but what about T-DXd in the brain, particularly in HER2-low?

DR NANDA: Yeah. As I was listening to Julia present the case, I was very hopeful that she was going to say it was HER2-low in this brain met because we definitely have some great data looking at small series, for sure, the TUXEDO trial and I think there was another trial looking at a small proportion of patients with brain mets. And I believe those were HER2 positive patients, but seeing really nice disease regression. Response rates, 50 to 75% intracranially with trastuzumab deruxtecan. So we’ve definitely got some good data there in small series looking at patients with brain metastases and HER2 positive disease.

The ASCENT trial did allow a subset of patients with treated brain metastases. And those patients seemed to do as well as the overall study population. So I would agree with Sara. This is not like HER2 positive disease where we’ve got multiple systemic therapies that can benefit patients. Intracranially, I think this patient has already shown you she’s going to develop more brain metastases and you’ve already told us that she’s gone on to develop even more now. I think changing the systemic therapy is the only way to go here. And sacituzumab govitecan is an effective therapy. It can penetrate the CNS based on some of the data that Sara has just shared. And so I think that is what I would advocate in this patient as well.

It will be very disheartening if new brain metastases developed on saci though. I think then I’m not sure that we’ve got a whole lot, unfortunately, that we’ll be able to offer this patient. I have gotten compassionate use trastuzumab deruxtecan in patients who have HER2 0 disease hoping, based on the DAISY trial, that there might be a little bit of efficacy in these patients who maybe have more modest HER2 expression, less than +1. So I definitely think it’s worth giving a try. I just don’t know that you’ve got any other option for this patient.

ADCs in the management of mTNBC; sequencing of these agents and ongoing investigations

DR LOVE: So we’ve moved into the area, of course, of antibody-drug conjugates in second-line therapy of metastatic disease. I pulled a bunch of papers, a number of review articles for the audience to consider but also some papers that I’d like to ask you about specifically that I think are really interesting. Also, a Trials in Progress that I’m kind of curious about. I also would like to come back to our presenters before we start getting into cases and see any sort of generic questions about ADCs. And I just want to start out, Sara, with something, again, we’re hearing about ADCs all over oncology, solid tumor oncology. And one of the things we’re hearing about is the sequencing of ADCs, when you have more than 1 available. And now we’re talking about sacituzumab. HER2-low, you would have T-DXd. Maybe dato is coming along. Any thoughts about what we’re learning about this, Sara? And particularly, “mechanisms of resistance” to ADCs. Can you kind of maybe provide a little bit of an update of how you envision the way these drugs work and, again, very specifically in terms of the issues that are specific to ADCs?

DR TOLANEY: It’s an exciting time that we have so many new antibody-drug conjugates that continue to emerge. So as you mentioned, we have sacituzumab govitecan which is targeting TROP2 and delivering a TOPO1 payload which is SN38, so the active metabolite of irinotecan. And then on the flip side, we’ve got trastuzumab deruxtecan or T-DXd which is targeting HER2 and delivering a deruxtecan payload which is also a TOPO1 payload. So they have different targets, but their payloads are somewhat similar and have similar mechanisms of action. And so this question arises. If you give one ADC and you develop resistance, why did that resistance develop? If it was due to some resistance mechanism in target expression, for example, then one could imagine that giving another ADC that uses a similar payload, but has a different target could work. But if you think that the resistance is due to payload resistance and they’re both TOPO1 payloads, then you would think well sequencing is probably not going to work out too well.

And we’re actually lucky to have Laura here who has actually done a real lot of nice work looking at efficacy of giving ADCs one after another. And, Laura, I’d love for you to share your data. But overall, my impression is from all these series that have been done is that when we’ve generally given the second ADC, we’re seeing shorter duration on therapy. There are rare cases where someone has a really short benefit to ADC 1, but then has a really long benefit to ADC 2, but that tends not to be the average. That tends to be more of the exception than the average person. And so I think a lot more work needs to be done here. But, Laura, maybe you could tell us about your data because I thought that was really interesting.

DR HUPPERT: Yeah, thank you so much. So I had the opportunity to collaborate with 5 different academic centers to look at patients who were treated per standard of care and got either sacituzumab govitecan followed by T-DXd or vice versa for HER2-low metastatic breast cancer. And as you kind of summarized nicely, Sara, most patients had a longer response to their first ADC than their second, regardless if they got sacituzumab first or T-DXd first. And in general, tended to have a shorter duration of response to their second. But there were some patients that had longer responses to their second than their first. And so with this retrospective data, I definitely still do try to do ADC after ADC, hopeful that I will find one of those patients that will have a longer response to their second. I think there’s definitely prospective data that we need. And I think in particular, the prospective data can better analyze mechanisms of resistance. So we are looking through the TBCRC at doing a prospective registry. There’s another trial out of Dana-Farber, TRADE-DXd, looking at Dato-DXd and T-DXd and vice versa. And so I think some of these prospective studies can kind of even better get at the mechanisms of resistance.

DR LOVE: So speaking of studies, Rita, I’m curious about this ASCENT-03 trial that is a trial in progress right now. Phase III trial looking at first-line therapy in metastatic triple-negative disease, sacituzumab versus physician’s choice. What your thoughts are about that. And I’m curious what you think it’s going to show, Rita.

DR NANDA: I think sacituzumab govitecan has been shown to be much better than traditional chemotherapy in the second-line and beyond setting. And I have no doubt that it’s going to be better than chemotherapy in that front-line setting. I will say for patients who recur pretty quickly after neoadjuvant therapy, particularly if they’re getting KEYNOTE-522, I think most of us try to move to sacituzumab in that front-line setting anyway just because I think there’s not really another chemotherapy we think is going to be very effective for patients who’ve progressed or relapsed quickly after a taxane, platinum, and an anthracycline. But unfortunately, there can sometimes be insurance challenges for these patients. But I think that this trial will hopefully help us move up sacituzumab into that front-line setting although I will say we’re already doing neoadjuvant and adjuvant studies, so I have no doubt that saci is going to find a place earlier on in therapy. I think potentially the neoadjuvant space. And certainly, in the adjuvant setting in patients who don’t have a great response to the KEYNOTE-522 regimen. In fact, there is a trial ongoing right now that I think Sara is leading looking at saci plus pembro versus physician’s choice standard of care therapy in that post-neoadjuvant setting for patients who aren’t, haven’t had a great response to the KEYNOTE-522 setting therapy in the neoadjuvant setting.

DR LOVE: That was actually one of the things I was going to ask Sara about in terms of what you were just saying. But I’m curious, Sara, what do you think this, again, this trial might show? But what about people who present de novo? Does that mean this is going to be, you know, I guess IOs will have to be factored in depending on their PD1 level. But do you think sacituzumab would beat chemo?

DR TOLANEY: It’s a good question. So they’re actually kind of sister studies. This is ASCENT-03 which is for people who are PD-L1 negative and getting first-line therapy for metastatic triple-negative disease, and that’s sacituzumab versus chemo of choice. And then there’s ASCENT-04 which is for people who have first-line metastatic triple-negative disease that is PD-L1 positive. And that gives sacituzumab plus pembrolizumab compared to, in essence, the KEYNOTE-355 regimen, so dealer’s choice chemo plus pembro. And it’s interesting, these trials do cap the number of de novo patients in each of the trials, so it’s capped around the 30% mark which isn’t that far off of what the overall incidence of having de novo metastatic disease is in this setting. But it is a good question. Rita very nicely discussed how when we’ve compared sacituzumab to chemo in pretreated patients like in ASCENT, it was a landslide, right? The PFS was more than 3 times as long. We doubled survival. It was nowhere near as effective as standard chemotherapy. But when you ask, well what’s going to happen to a de novo patient who is totally chemo naïve? Is sacituzumab better? And the truth is we don’t really know. I think we think it is because of its mechanism, right? It’s really able to deliver high doses of chemotherapy into a cancer cell. And so my guess is it would be more effective irrespective of being de novo or recurrent. But I guess we’ll have to see what the subgroups show from these trials.

DR LOVE: But also, it’s going to be really interesting in terms of what you were saying about IO plus saci in terms of what that might show. And, Rita, this whole idea of IO plus ADC is kind of interesting. You would think it’d be like IO and chemo. But like in bladder cancer, the new first-line therapy that beat cis/platinum combination is IO and ADC, pembro and enfortumab. Much better than cis/platinum. And I think there’s a trial we’re going to hopefully look at later that was just reported at ESMO. I think it was dato and durva. Any thoughts about IOs plus ADCs, Rita?

DR NANDA: Yeah. I think that there are a lot of groups that are investigating ADCs with IO in patients who are PD-L1-positive, and even PD-L1-negative. Actually, Sara and one of her colleagues at Dana-Farber are running a trial of saci with or without pembro in patients with PD-L1-negative front-line triple-negative breast cancer. I think that in the pretreated patient population, we definitely know that these ADCs are better than sort of traditional chemotherapy. But I don’t know that we know that they’re going to be more synergistic with immunotherapy than traditional chemotherapy. So I think that still remains to be seen. I suspect that these metastatic trials will be doing ADCs over traditional chemotherapy. But I don’t know that it’s going to be because there’s any better synergy between the 2 agents. It could just be because the ADC is better than the chemotherapy backbone.

DR LOVE: So we’re going to move on to some cases. But before we do that, Sara, one other thing I was going to ask you about. I see that were a part of this paper in Expert Opinions of Biology. I’m not even familiar with this journal. But in any event, “Managing Adverse Events of Sacituzumab.” I’m curious how you put that paper together and kind of what you think the main messages are.

DR TOLANEY: Well, I think some of the main side effects that we see with sacituzumab, one of which is neutropenia. So about half of the patients who get sacituzumab end up with Grade 3/4 neutropenia which is tough because it means if you start someone off, they could come in neutropenic, you have to hold their dose. And then most of the time, we’re using growth factor, so about half of my patients are on growth factor with sacituzumab. So a practical question that comes up is, if you’re getting sacituzumab which is dosed days 1 and 8 of a 21-day cycle, how do you actually give the growth factor, right? Because when you get a dose a week later, you can’t give a long-acting growth factor. And so some of us have tried to use a long-acting growth factor on day 8, so we’ll use pegfilgrastim, like on-body pegfilgrastim, on day 8 so that they’re covered for the subsequent 2 weeks. But that doesn’t help a patient who may come in on day 8 neutropenic. And so then those patients need to get short-acting G-CSF after day 1. And usually, we do that on day 2, 3, 4, for example. So that manuscript really just gives some tips and tricks of how to manage using growth factor, how to deal with diarrhea. Using intermittent loperamide usually is quite helpful. What do you do if you need to delay someone? How long do you really need to wait before you give them your next dose? Do you really need a neutrophil count to 1,500 which is what the guidance says for day 1 dosing? I don’t think any of us really do that. I think we all use 1,000 as our cut-off. So I think it’s just more practical than what the IB, for example, would tell you if you looked up sacituzumab.

DR LOVE: Laura, anything you want to add to that or any questions?

DR HUPPERT: I’m curious in terms of diarrhea management. Besides loperamide, I had a colleague telling me that they use octreotide sometimes for very severe diarrhea. And so I’m just curious if you guys have any tips and tricks on the diarrhea management for sacituzumab.

DR LOVE: Sara?

DR TOLANEY: It’s so funny because yesterday, or 2 days ago, I was talking to Hope Rugo who told me about a case where she did use octreotide. And I’ve never done it before. And so I was like oh really? Did it work? And she said that it did. And so I’ve never done it, but we’ll have to ask Hope for her thoughts because I know she’s done it before. But I usually use the standard loperamide period. And I find it’s usually low-grade intermittent diarrhea. It’s not usually like horrible diarrhea with sacituzumab. It’s just every once in a while, you get someone who you may need to escalate. And then I alternate sometimes diphenoxylate and atropine with loperamide. And so I think those are standard. But yes, I’ve never done octreotide before. Sometimes I’ve tried colestipol, but that’s the most adventurous I’ve gone.

DR HUPPERT: And then do you check the pharmacogenomics also or not usually?

DR TOLANEY: Yeah, I usually — I’ll be honest that I don’t always check. I check in someone who has a lot of, if they’ve had unusual toxicity, so a lot of diarrhea or neutropenia. It’s not that we would manage them necessarily any differently because we kind of check blood counts and see them on day 8 anyway. And so the guidance says that you don’t have to. But it’s a good point because if you do have UGT1A1*2828, we have seen data, actually there’s a really nice subgroup analysis that was recently presented from TROPiCS-02 that had shown that these patients did have higher rates of neutropenia and diarrhea, and so that they are at risk for higher-grade toxicities.

Case: A woman in her early 50s with mTNBC receives first-line chemotherapy/immune checkpoint inhibitor followed by sacituzumab govitecan — Dr Shaikh

DR LOVE: So let’s move on to another case here. We have this 50-year-old patient with metastatic disease. What happened to this lady, Saba?

DR SHAIKH: So this is a 50-year-old woman, no significant past medical or family history, but she presented with a palpable breast mass that was growing rapidly. At the time of presentation, it measured 6.8 x 5.7 cm. Interestingly, there was no suspicious axillary adenopathy. She had a biopsy done which showed triple-negative breast cancer, ER/PR 0, HER2 0, and Ki-67 was 60%. We got a baseline PET scan on her which identified a 3.5 cm hepatic mass, SUV 15, which was biopsied, and triple-negative, HER2 0, PD-L1 CPS was 40. Germline genetic testing was negative and nothing really notable on her somatic testing either. So she started first-line treatment with paclitaxel and pembrolizumab which overall she tolerated well. And she was on that for about 9 months until she developed progressive disease in the liver and the breast as well, and then started sacituzumab govitecan. She’s been on this now for about 9 months. She’s had a clinical response. The liver mass has shrank down to about 6 mm. And she’s tolerating it really well. She hasn’t had issues with cytopenias, but she has had diarrhea which has been pretty well controlled with loperamide so far.

So my question regarding this case is in terms of sequencing of sacituzumab govitecan, I think, you know, in the FDA approval, 2 prior lines but 1 of those could have been in the neoadjuvant/adjuvant setting. But for patients with de novo metastatic disease, they’re really just getting it after 1 prior line. And so I was interested to hear the experience with that, if that’s what clinically you’ve been doing as well, especially for patients who don’t have a BRCA mutation because the only other — and they’re HER2 0, there’s not really much else that I’d be able to offer that’s standard of care besides chemotherapy. So that’s why I preferred sacituzumab in this case.

DR LOVE: So Rita, any thoughts? And one thing I was going to mention or ask before when we were talking about chemo plus IO is the possibility, particularly maybe a patient who had a long response or high PD1 level, of double immunotherapy. For example, ipi/nivo. And also, again, Rita, any thoughts about this case?

DR NANDA: Yeah. So I think that I agree with the decision to use sacituzumab here. That is what I would do. We know that sacituzumab is better than other chemotherapy options and associated with a survival advantage. And sometimes with patients with metastatic triple-negative breast cancer, you don’t get another line of therapy. So I definitely don’t save my good therapies for later, so absolutely would have wanted to use sacituzumab here. I think that, I’ve had patients who actually participated in ASCENT who’ve been on therapy for 3+ years. And so it's just been life changing for patients to have this extension in their life. Sounds like she’s tolerating it really well. So absolutely, I think that that is great here.

In terms of immunotherapy after progression on a line of immunotherapy, I don’t think we have any data, really robust data in that space here. So I generally do discontinue unless I have a trial to offer patients. We’ve got a bunch of Phase I trials ongoing looking at immunotherapy after progression with some mixed responses. It’s all anecdotal data and you don’t really know how well someone is going to do. I will say that I have a lot of experience managing immune-related adverse events for patients who’ve gotten dual sort of checkpoint blockade therapy on my in-patient experience. I think that using ipi/nivo in patients, although there are some new dosing that’s been used, less ipi dosing with nivo, but it’s a pretty toxic regimen. And so it’s definitely something to think about. I know that Sara and her colleagues have presented some data on their experience looking at ipi/nivo in patients with advanced cancer. I have to say I don’t know that I’ve been remarkably overwhelmed with the efficacy data, but I certainly have to give some pause when I look at the toxicity data. Although I will say I’m very biased because I always see the sort of patients who end up admitted with a lot of immune-related toxicities. So Sara, I don’t know what your thoughts are and if you wanted to chime in here.

DR TOLANEY: We had looked at low-dose ipi with nivo in patients who had metastatic breast cancer that had a high TMB, so it was a very specific population. And what we saw was that there was, and actually our updated data has a little over a 20% response rate, but the people who responded tended to have pretty high TMBs. There were TMB over 14, in fact. And these are people who, much to the cases you were sharing, Rita, a lot of these people are now off all immunotherapy and, again, have been off treatment now for a couple of years and potentially could be cured. But as you point out, there can be significant toxicities. Actually, the first patient who went onto the trial had a TMB over 100 and developed myocarditis after the first infusion. She ended up being fine. Obviously, never got exposed to immunotherapy again, but never got any further treatment. And in fact, now it’s over almost 5 years with no further treatment, and had a wonderful response to that 1 dose of ipi/nivo. So I think we need more information. We also don’t have data about how to use it in someone who has had progression on prior checkpoint inhibition where there really isn’t data. So I think more to learn.

DR LOVE: So just to mention, Rita was mentioning other approaches to anti-CTLA4 PD1. In HCC, they have a regimen of tremelimumab and durvalumab in the incidence of the need to use steroids. And with ipi/nivo, it’s 50%. With this regimen, it was 20% which is not that much higher than IO alone. So if it works, there may be a way to give it with less toxicity but I guess we’ll see.

Again, getting back to this case, Saba. Another younger woman presenting with metastatic disease. Interesting. The mass is pretty big, but Ki-67 is 60%. Any thoughts about whether she delayed or not or came in? And also, what was her life situation that now this disease is coming into?

DR SHAIKH: Absolutely. I think there may have been some delay in diagnosis. Well it’s hard to say for sure because she wasn’t getting screening mammograms. So it’s hard to say if this would have been apparent on a screening mammogram a year prior. But potentially, anytime I see a breast mass this large, I do get worried about delay in diagnosis. Although to be fair also, breast masses, it’s depending on the location, depending on the size of the breast. Sometimes, it’s not really easily palpable until it is a little bit larger. And lately, I’ve actually been unfortunately seeing a lot of very young women with advanced disease, both metastatic and locally advanced. Some of the patients, especially the ones that are younger than 40 and don’t necessarily have a family history, they’re not eligible for screening. So they’re picking these masses up sometimes when they’re 4 or 5 cm. This patient in particular, I think, again initially when presented, we know about the primary breast mass. There wasn’t necessarily any axillary adenopathy. We talked about getting staging scans to rule out metastatic disease given that it was a T3 lesion. But the initial conversation is always about neoadjuvant therapy at that time. And so then when they follow-up after the staging scans result, it’s unfortunately metastatic, and so the conversation changes. And like we talked about earlier, it’s always a hard pivot.

DR LOVE: What’s this woman’s life situation in terms of her family, her work, et cetera?

DR SHAIKH: She’s working. She’s married. She has adult children. And so she has a lot of support around her and her family is able to come in with her for her visits and her infusion as well.

DR LOVE: Interesting.

Case: A woman in her late 30s with mTNBC receives sacituzumab govitecan — Dr Huppert

DR LOVE: All right. Let’s go to another case. And we have this patient, another younger patient, 37-year-old woman. What happened with her, Laura?

DR HUPPERT: Sure. So this is a 37-year-old who has a history of right breast cancer that was diagnosed back in 2021. At that time, she underwent up-front surgery which showed a 3 cm Grade 3 ER-0positive 71 to 80%, PR-positive, HER2-negative. She had 1 out of 4 lymph nodes. She was under the care of a different oncologist at that time. She was treated with adjuvant TC x 4, radiation. She was started on OFS/AI but didn’t tolerate it, unfortunately. Was switched to tamoxifen, and stopped that after 18 — almost 2 years. I was going to say 18 months, but it was a little bit longer than that. And so had stopped her adjuvant endocrine therapy. And then unfortunately, presented with abdominal pain and was found to have an elevated Tbili. Imaging showed that she had liver metastases as well as bone lesions, extensive lymphadenopathy, large-volume ascites. She had a dry weight of 125 pounds and was up to 160 pounds with the extra fluid, so quite ill at that point. A biopsy showed metastatic carcinoma that was now triple-negative, ER negative, PR negative, HER2 negative with an IHC of 0 and a PD-L1 with a CPS of 3. We performed a paracentesis to remove some of the fluid which was diagnosed with a malignant effusion, also IHC 0. And started her, based on the lack of PD-L1 positivity and the lack of germline testing, started her on single agent chemotherapy initially with weekly paclitaxel that was dose reduced given her elevated LFTs. Fortunately actually started chemo, she did quite well and her LFTs improved. She felt better. We started diuresing her. And so she did well on first-line chemotherapy for about 4 months until she had progression in liver. So actually just last week, started her on sacituzumab govitecan. And so that’s kind of where we are with her case.

But I think a few things worth discussing here. I think, you know, she was IHC 0. I think if she had been IHC 1, would you have still done saci first-line or would you have considered T-DXd in her? And then I think fortunately, her liver numbers had improved and so I was able to start her on full dose sacituzumab govitecan, but how you might manage if her LFTs had been still elevated at that point. Because there’s limited data with ADC dose reductions for elevated LFTs. So maybe starting with those questions.

DR LOVE: So Rita, would you like to tackle those questions?

DR NANDA: Yeah. I think this is a great case. I’m glad she responded to paclitaxel. I think I might have been tempted to try to get her sacituzumab govitecan in that front-line setting because this really is that patient you’ve got 1 line of therapy. And if you don’t get a response, then you’re probably not going to have a lot of opportunities there. I think that it’s interesting that, you know, I might have considered platinum-based therapy since she’s triple-negative and never had a platinum. You don’t really have to worry as much about the LFTs with platinum therapies in that front-line setting. But I’m glad that you gave her paclitaxel and she’s had a nice response. But I may have chosen a different route. But, again, I think platinum early on is an option. And with sacituzumab govitecan, I actually have given it in patients who’ve had elevated LFTs. I usually have a frank discussion with my PharmD in clinic just to get their thoughts about how to dose it in that setting. But I’m glad that her LFTs have improved and you’re actually able to give her full dose.

I think for my triple-negative patients who are HER2-low, I generally do favor sacituzumab over T-DXd, really just because of the robustness of the ASCENT data. When we think about DESTINY-Breast04, only 10% of those patients, so 58, had hormone receptor negative disease. So I generally do favor saci over T-DXd for patients who are triple-negative and eligible for both. But then flip that order in patients who have hormone receptor positive disease. Again, just based on the, not to do cross-trial comparisons, but based on the line of therapy that DESTINY-Breast04 looked at, you know, 1 to 2 prior lines whereas TROPiCs-02 was more 2 to 4 prior lines of therapy. So I would be in agreement with SG here. I might have even tried to use it a little bit earlier if I could have gotten the approval for it. But I’m glad that she’s gotten to that point where she can get it and hopefully benefit from it.

DR LOVE: So before I ask Sara to comment, I just want to go back. You said you would actually do, outside of trial, you would, you have, you’re able to access saci and use it first-line in a situation like this?

DR NANDA: I have. It’s a challenge. It’s an uphill battle with insurance companies. Some have not necessarily had issues with it and I’ve been able to give it in that front-line setting, especially in someone like this where she is in visceral crisis. You have 1 shot at a response to therapy here. I’ve certainly advocated for patients and been able to get it. And in other cases, I haven’t. So I’ve gone on to give another chemotherapy but then monitor them very closely with a chance to try to pivot quickly.

DR LOVE: So Sara, I think we’ve accumulated about 30 questions about this case. I hope you can remember them all. But I’m going to add 1 on which is, can you talk a little bit about how you think through people where receptors change?

DR TOLANEY: Yeah.

DR LOVE: Particularly, this ER negative to ER positive. Also, HER2 negative to HER2 positive. We hear different things outside of breast cancer like with HER2, and people just follow whatever it is. In term of ER, I guess that’s what we’re doing. But any thoughts about changing markers or ER and HER2, Sara? And also, all the other questions that come up with this case.

DR TOLANEY: So in terms, I’ll start with the last question which is this change in receptor status. And we are seeing this a lot. So in this particular case, this was someone who started off hormone receptor positive, but then at time of recurrence was triple-negative. And we do see that about 10 to 15% of patients are losing the estrogen receptor at time of recurrence. And I’m going to wonder if this is actually going to turn out to be a higher rate as people use more CDK4/6 inhibition in the adjuvant setting. Because our group actually just did a recent analysis where we looked at people who recurred after their adjuvant abema, and actually saw that 50% of them had lost ER expression at time of recurrence. And so this prevalence may change as we change our drug therapy. But right now, it’s probably around 10 or 15%, so not uncommon. It is a little less common to go the other direction though. So we don’t usually see gain of ER expression at time of recurrence. We also don’t usually see gain of HER2 expression at time of recurrence. The most common change we see is this particular scenario that was presented here which is a loss of ER, but does go to show how important it is to biopsy patients, not just to document and prove that it’s metastatic disease, but it totally changes your therapy to understand what the biology of the cancer is, and so very important.

I think another reason we’re rebiopsying a lot is this issue about HER2-low. And so we always are trying to find at least 1 biopsy where their pathology shows that they have some level of HER2 expression so that we could make them a candidate for potential T-DXd. And so I am finding myself doing more and more biopsies. Particularly if someone has always been HER2 0 in every single biopsy, I do try to re-biopsy in case they come back HER2-low. And in fact, there is this really interesting series done by Mass General in the triple-negative setting where they showed by the time someone had their 5^th biopsy, everyone had at least 1 HER2-low reading. So it is a tricky biomarker where I think the reproducibility and also the dynamic nature of it is such that it does change over time, so important to do these biopsies.

But in terms of the other questions, I actually very much agree with Rita in terms of sequencing between sacituzumab and T-DXd. In someone who is HER2-low, I generally prefer sacituzumab over T-DXd as the first choice, again, simply due to robustness of data because ASCENT was a large Phase III study but as Rita pointed out, there’s only a small exploratory subgroup in DESTINY-Breast04 that was in fact triple-negative. And so it’d be nicer to have a bit larger dataset. And there actually are larger trials that are planned that will not just give us more data in the triple-negative setting for HER2-low, but in fact, there are also studies planned that will have larger numbers of HER2 0 patients with metastatic disease to help us understand efficacy in the triple-negative setting. So I think we’ll have to see what that shows.

DR LOVE: Could I just go back to you, Sara, in terms of HER2-low, again, in terms of sequencing of saci and T-DXd, and ask you how you might think through a patient maybe in their 70s, a little of COPD from a long history of smoking who has soft-tissue metastatic disease and not very symptomatic? Would you still go with T-DXd first?

DR TOLANEY: Sorry, I do usually prefer sacituzumab first and T-DXd second in the triple-negative setting.

DR LOVE: I’m talking about ER positive though.

DR TOLANEY: Oh, ER positive. I see.

DR LOVE: ER-positive, HER2 — so you said for, I think Rita said, everybody said ER positive, HER2-low, you usually use T-DXd before sacituzumab. And so my question is, what about a case like I described, not very threatening disease, maybe smoker, non-smoker, whatever, are you still going to go with T-DXd first?

DR TOLANEY: It depends on the exact situation with the lungs. In general, the data has suggested that if you have underlying COPD or you’re a smoker, that was not a risk factor for developing higher rates of interstitial lung disease with T-DXd exposure. The risk factors seemed to be people who had very high dose exposure to T-DXd. The original study had suggested being of Asian ancestry was also a risk factor. And obviously, it’s a complete contraindication if you’ve ever had any drug-induced interstitial lung disease before. But I think, to your point, we all get a little nervous if someone doesn’t have good pulmonary function up-front because we all worry that if they did develop interstitial lung disease, their reserve is not there. It’s going to be a much more serious complication in that particular patient. And it is 10 to 15% of patients who are going to get ILD with T-DXd. It’s not that it’s super uncommon. It is something we are seeing, unfortunately. So I think it would depend on sort of the degree of the COPD, how bad it is, if she’s symptomatic from that. And so I think we put all those pieces together. But technically, COPD in itself is not a contraindication.

DR LOVE: So we can take out the COPD and just focus, you know, again, what’s the big rush? I’m just trying to push you. I don’t know what the right answer is. But Rita, any more thoughts about that?

DR NANDA: Yeah. I think this is an interesting case. In somebody who is completely asymptomatic for the most part with well-controlled COPD and it’s just something you see on imaging, it doesn’t really give me pause and I don’t think there are, as Sara had said, any higher risk for developing interstitial lung disease. If somebody is already on O2, they’re symptomatic, then it gets harder to monitor, right? For my patients, for example, who are on T-DXd, at the first sign of hypoxia or shortness of breath or cough, I’m going to want to look to make sure that they’re not developing some interstitial lung disease early to consider holding therapy. And in someone like this, it may be a little bit harder to monitor. So I think depending on how symptomatic someone is and how bad that COPD is, then I may want to start with sacituzumab in someone like this. But I think if it’s well-controlled, they never really get admitted with exacerbations, they’re not on any real therapy other than some inhalers, then I think I would feel comfortable moving forward with T-DXd.

DR LOVE: So Sara, I think I’ve told you before that your colleague, Hal Burstein, is always accusing me of coming up with these weird situations that you never see and asking people about it. But anyhow. We’ve already heard of a whole bunch of stuff from your cases that I’ve never heard about before. So that’s life in the real world.

Case: A woman in her early 40s with mTNBC (IHC 1+) with sacituzumab govitecan-intolerant disease experiences an excellent response to trastuzumab deruxtecan (T-DXd) — Dr Foldi

DR LOVE: All right. So Julia, let’s hear about your 40-year-old woman. All these patients are young. I think obviously, you all tend to see younger people but also, they’re such challenging cases. What happened with this lady?

DR FOLDI: So this is a woman who was treated for her early-stage disease initially at one of our community sites. So her life situation at the time of diagnosis was she actually has school-aged children, 3 children, and she’s divorced, and she’s a single mom, so it was extremely challenging. She has some family support, but very difficult social situation. So she was 40 when she was diagnosed with what appeared to be a clinical T2N0 triple-negative breast cancer. She was treated with the KEYNOTE-522 regimen. This was complicated by immune-related hypopituitarism, secondary adrenal insufficiency, so she is on life-long replacement steroids and levothyroxine. She did undergo a segmental mastectomy after finishing the KEYNOTE regimen. She did have residual disease with 1 out of 6 lymph nodes that had a micro metastasis. So she completed adjuvant radiation as well as 6 cycles of capecitabine, given residual disease. Unfortunately, very soon after completing her adjuvant treatment, she began to experience breast changes with development of skin nodules, discoloration. And she did have a punch biopsy that confirmed recurrent triple-negative breast cancer. Unfortunately, her oncologist who was treating her at that time, before pursuing any systemic imaging, they had sent her for a completion mastectomy. And so she did have this big surgery. And then she was referred to me shortly after because her skin lesions, as you can see on this picture, really blew up after her surgery. And at that point, we did order some systemic staging scans which did show some adenopathy, as you can see indicated with that arrow, she does have this large left axillary lymph node which is on the other side from her cancer, and this really bulky chest wall disease. So because she was so close to completing her adjuvant treatment, and like it was mentioned before, she really received all of the different chemotherapy classes of agents as part of KEYNOTE. We did start her on sacituzumab govitecan. Unfortunately, she was one of the cases where neutropenia was a significant issue even after her day 1 treatment. So she came in neutropenic on day 8, so she had to be delayed immediately. And whether it was due to delays or just no efficacy of the sacituzumab, she did progress during just those initial few weeks with increasing chest wall disease.

So my question here was, what is next? But I actually, she did have HER2-low disease, and so the next step was really, we did switch her to T-DXd. And she’s had a really remarkable response. She was 1+ on IHC, so I didn’t have really high hopes for the T-DXd. But her chest wall disease has remarkably improved. I don’t have a picture of it but fortunately, she continues to respond to the T-DXd.

DR LOVE: Wow, a lot of things there to talk about. Before we kind of get into some of those things, I’ll note, interesting that I noted that she had hypopit with her initial chemo/IO for localized disease. Pretty interesting. A terrible photo of what she had before the T-DXd, of course is interesting. Very interested by the fact that she’s a single mom of 3 young children. Also, that’s something we have talked a lot about. Oncology Nursing Society meetings. We always get into that there with the nurses and nurse practitioners. So it’s hard to say exactly. Let me ask you. Do you think there’s a partial response in this recurrence, more than 50% at this point?

DR FOLDI: You mean with the T-DXd?

DR LOVE: Yeah, with the T-DXd.

DR FOLDI: Yes, yes.

DR LOVE: That’s great. That’s really amazing. We actually, Sara, I’m not sure if either one of you were at this meeting, but not the last San Antonio, San Antonio before, we always do 3 meetings there but we had 3 cases, no 2 cases of women with localized, bad local recurrence who had great responses to T-DXd, but one was 89 and the other was 90. And they had great — so first of all, I’m kind of curious, Sara, do you see better responses to T-DXd in the skin? Just based on the 3 cases. And how do you approach elderly patients? This doc actually preemptively dose reduced them before he treated them. They responded to a subclinical dose.

DR TOLANEY: I’m not aware of any data to understand if we have better, have seen better responses with T-DXd in skin versus other sites. Obviously, we’ve seen it works across all sites, even in the CNS, quite well. So I’m not sure that it’s a predilection to response that’s better in the skin, so I don’t know.

But in terms of the older patients, we actually have seen some data that’s been presented from the DESTINY trials that has shown that in older patients, the rates of ILD are higher than in the younger patients. And so it is something we do take into account. And so I will say if I think someone is older or frail for other reasons or has other comorbidities where I’m a little nervous about potential toxicities, I have started off with a dose reduction in those patients. And you always have the opportunity to dose escalate if someone is flying through therapy. But I have generally done that. So for that 89 or 90-year-old, they were very bold but I too would have had dose reduced that person too.

DR LOVE: So a couple other issues I wanted to get into. And, again, here are some papers we pulled for the audience to check out. I love the How I Treat HER2-low Disease. We were just talking about that. I really refer you to check it out. But, Rita, I was curious about a couple other things. It’s really interesting now that we’re talking to the lung cancer people, the GI people, the colon people, the biliary, GU, bladder, HER2 is everywhere, Gyn. And they are like, the investigators do not know as much as the general oncologists in practice about what’s going on. So one of the issues we’ve been trying to get through to them, Rita, and I see this paper here that we pulled for the audience, Management of Nausea and Vomiting, you know, chemotherapy-like side effects. Because, again, outside of breast, people are not exactly as tuned in. How do you approach that? And, again, the other common question they all want to ask is about screening for ILD in terms of imaging. So maybe you can just repeat that. We actually, at the GU meeting this year, we actually showed a breast cancer investigator explaining what you all do rather than a GU person because they didn’t know. Anyhow. Rita, any thoughts?

DR NANDA: Yeah. I have to say I think that with sacituzumab govitecan, there was a lot of reluctance from non-breast cancer docs concerned about the diarrhea and the cytopenias because of that SN38 toxic payload, right? They’re expecting to see with sacituzumab govitecan what is seen with irinotecan. And I have to say it is nowhere near as bad as irinotecan in terms of toxicities. And so I have to say I find the diarrhea and the cytopenias with sacituzumab govitecan generally very tolerable.

In terms of nausea and vomiting, with T-DXd, I have had some challenges with delayed nausea and vomiting. And so, again, pulling Hope Rugo into the conversation. What I used to do was bring patients back about a week after. Some patients do just fine with the sort of traditional antiemetics that we use, and both of these I think are classified a highly emetogenic, using sort of long-acting fosaprepitant and ondansetron with prochlorperazine as needed for patients. But with T-DXd, I have a handful of patients who really do struggle with nausea and vomiting that really kicks in about a week after their infusions. And so I was bringing them back for IV fluids and some more IV antiemetics. But Hope has taught me that giving, low dose olanzapine, like 2.5 mg kind of continuously can really help these patients. And so I’ve been doing that with my patients on T-DXd with good management of kind of that delayed component of nausea and vomiting.

DR LOVE: So in a second, I’m going to ask Laura if she has any questions. But just to come back to you, Sara, what about screening for ILD? Particularly, in people who don’t need chest imaging. Are you doing it just for that purpose? And how often and for how long?

DR TOLANEY: Yeah, this is a tough one where, again, no right answer here. But in the DESTINY trials, they had done repeat restaging every 6 weeks. And so they were getting chest imaging that frequently. In the real world, insurance won’t always pay for you to get restaging scans that often. And so some of us try to, but can’t always do that. And so sometimes, we are extending and doing it every 9 weeks. And then I know some of my colleagues even do their restaging every 12 weeks. And that restaging adds in that high res chest CT as part of that that you could look for ILD. But I think the question really is, does it matter if you’re screening more often? Are you more likely to pick up a low-grade ILD if it occurs? And maybe that allows the patient to hold and get re-exposed to T-DXd versus if you picked up a Grade 2 ILD, you can’t re-expose that patient again. And so are you able to prevent higher-grade ILDs from developing? And are you able to keep patients on drug more by screening them more often? And the truth is we don’t really have the answer to that question because it’s not that we’ve done a trial looking at different intervals of screening.

But I will say, I’m very cautious about interstitial lung disease. Obviously, there have been deaths on the DESTINY trials. It’s a little under 1% death from ILD, but it does mean we have to be cautious. And so I do usually restage my patients every 6 or 9 weeks if they’re getting T-DXd.

DR LOVE: So Laura, any questions or comments?

DR HUPPERT: Yeah, I think one thing that also comes up with all of these agents in our patients is alopecia risk with the ADCs. And I know that there’s an ongoing trial at Dana-Farber about this. But just wanted to pick your brains about your practice pattern with using cold capping. Does that work for your patients?

DR LOVE: And do you do cold extremities to prevent neuropathy? Sara?

DR TOLANEY: Yeah. So I think it’s a good question. So, for example, with sacituzumab, everyone will lose their hair with that drug. And so that’s obviously a problem. We have done a study where we enrolled patients to get scalp cooling with sacituzumab or just be in a control group where they have not been cooled. And we haven’t reported that data yet. But I will say anecdotally, I have not had success with scalp cooling with sacituzumab to date. None of my patients have kept their hair.

With T-DXd, the trick is that alopecia is much less frequent with T-DXd. So if you were to think, well how many people actually go bald if they get T-DXd? It’s probably only about 20% that actually have true Grade 2 alopecia. And so it’s hard to know when you do scalp cooling, did you actually help prevent that hair loss or were they just not going to lose it anyway? And so we, again, have a trial ongoing and, again, have not reported that data yet. We just need to enroll a couple more patients. I don’t have clean data to share with you. But I find that harder to interpret because I’m just not sure if my patients who’ve had scalp cooling have kept their hair because they weren’t the ones who were going to lose their hair anyway. Because, again, the majority of people aren’t losing their hair. So I do offer it though to patients with T-DXd because if it’s going to help, a lot of people do want to try it. With sacituzumab, I am a little bit less gung-ho about it when I describe it to patients just because I’ve never had success. And unfortunately, most patients are paying out-of-pocket to do scalp cooling. And for them to spend all that money with very low probability of success I think is hard.

DR LOVE: What about cooling of the extremities?

DR TOLANEY: Yeah. So that’s really interesting. We actually are just about to start a trial with the scalp cooling. But they have this really cool system where you’re hooked up into these big gloves and bootie things into the cooling machine which is a great idea to help prevent, for example, taxane-induced neurotoxicity. There have been other studies that have been done that suggest that this could be efficacious. I will say I’ve had a lot of my patients just buy off Amazon little gloves and booties for the time being and a lot of them like to try it. But I think it can be efficacious. We just don’t have very large trial data at this point though to tell you what that rate is of success.

DR LOVE: I’ve heard about frozen peas. But anyhow. Bags of peas.

Case: A woman in her mid 50s with HER2-low metastatic breast cancer receives T-DXd — Dr Shaikh

DR LOVE: All right. Let’s go to the next case. And then after this, we’re going to move on to PARP. But just to finish out here on T-DXd and HER2-low, we have this 55-year-old lady that Saba has.

DR SHAIKH: This is a 55-year-old woman. She has a germline BRCA1 mutation. And she had most of her care done out of state and then she moved. And that’s when I met her. So I’ll summarize her treatment course. But she was initially diagnosed in 2017. She had a 3.3 cm breast cancer that was triple-negative at that time. She underwent bilateral mastectomy and she got adjuvant ACT. She had a recurrence 2 years later in the lung and she had very extensive cutaneous metastases. Biopsy at that time was triple-negative, HER2 0, CPS was 0. And so I’ll summarize the treatments that she received out of state which included capecitabine, olaparib, vinorelbine, sacituzumab, she was on a Phase I novel immune checkpoint inhibitor trial which she was only on for 2 cycles, and then eribulin which she was on eribulin when I met her. None of the — all of these treatments that she was on, she was on for a few months. The longest was probably a duration of response of around 9 months or so for her. So the part of her disease that really was very bothersome to her were the cutaneous mets. They were very extensive throughout the chest wall. They were friable. They’d ooze a lot. And so it was difficult for her to manage and just move about her life with those. So a few of those had been previously radiated as well. When I met her, we biopsied 1 of the cutaneous mets. And this time, it came back HER2 1+, so still ER/PR 0, HER2 1+. So we started treatment with trastuzumab deruxtecan. And she had a clinical response. The oozing dried up and the cutaneous mets started shrinking. She’s been tolerating trastuzumab deruxtecan very well. She has some nausea which she is able to manage with prn antinausea medications. She has some fatigue. And one thing that was a little bit bothersome to her was some of the hair loss. She had lost a lot of hair already from her prior therapies. But it had started to grow back a little bit and then it thinned out again on trastuzumab deruxtecan.

So I have a few questions here. One was, we talked a little bit about biopsying more frequently now especially that we have trastuzumab deruxtecan for HER2-low patients. How often do you biopsy? Are you re-biopsying at every time that the patient progresses? Additionally, I’m interested to hear more about you talked about your experience with cold capping and ADCs. Personally, I’ve only used cold caps more in the neoadjuvant/adjuvant setting. So how does it work when it’s more of an indefinite treatment and they’re cold capping with each of their infusions? And then the last question is, we also talked about the frequency for monitoring for ILD. How often do you continue that frequent monitoring? Is it a year and a half, 2 years, or is it even beyond that if patients are still on treatment at that point?

DR LOVE: So Rita, would you like to tackle this case and these questions?

DR NANDA: Yeah. I think this is a good, excellent questions. In terms of re-biopsying, I have to say I do not continually re-biopsy patients. I am aware that we’ve got data out there that suggests if you biopsy someone 5 times, you’re probably going to end up with a HER2-low at least 1 of those times. And so what my general strategy would be would be to try to get compassionate T-DXd even in the setting of a HER2 0 based on the DAISY trial. And I’ve been successful in negotiating with insurance companies based on that data. I think hopefully, DESTINY-Breast06 will give us some good data that will then make that not something we have to do all the time. But I don’t re-biopsy someone 5 times to try to get to a HER2 1+ generally.

I think with this patient, you’ve got that luxury of having easily biopsiable disease, right? You can just do a quick punch biopsy and get at it. So I think it makes it a little bit easier in this setting. But in somebody who has got liver mets and definitely lung mets, you’re not going to want to re-biopsy multiple times. Initially, you’ll biopsy because you know your receptors can change about 20% of the time or so, but you’re not going to continually re-biopsy somebody with lung disease. So in that sense, I have a tendency to re-biopsy at the time of initial presentation of recurrent disease. And then I do it in a situation where their disease isn’t behaving necessarily the way that I think it should behave or if I’m seeing a mixed response that really doesn’t make a lot of sense or they’ve had some sort of mixed disease, they were maybe hormone receptor positive and recurred as triple-negative, and I’m trying to figure out do I want to throw some endocrine therapy into the mix or something. Those are the cases where I will consider re-biopsying again. But generally, not every time somebody progresses. I think that’s a lot to ask patients and it’s a lot to put them through, especially when you can sometimes negotiate with insurance companies or get compassionate use for a therapy like T-DXd for a patient.

In terms of scalp cooling, I think it’s challenging. And I have to say a lot of patients with metastatic disease, even if they start out scalp cooling, eventually stop because it just becomes so burdensome and it adds so much time to their visit, right? Half an hour before, an hour after. And when you’re talking about 2 weeks on, 1 week off therapy, that’s really challenging, and especially if that therapy, say, sacituzumab govitecan, they’re going to lose their hair anyway which my experience has been quite similar to what Sara has done there. I’ve had a number of patients who wanted to try scalp cooling and we’ve never really been very successful. So I guess to hear that others are having that same experience, I think that is information to definitely share with patients.

In terms of interstitial lung disease monitoring, I have to say I’m probably a little bit more lax than most. I do not do restaging scans every 6 weeks or even every 9 weeks. I usually do my every 3-month sort of restaging. But I have a very low threshold for someone with any pulmonary issue, a cough, you know, they cough the wrong way or they’re developing some increasing shortness of breath even if they’re not hypoxic. I have a low threshold for then doing sort of non-infused high res CT, right? But in general, I do not do imaging. I have colleagues, we’re different at the University of Chicago, I have colleagues who do restaging every 3 months and do a non-infused high res CT at 6 weeks if their insurance will allow it. So I think there are different ways to approach it. I think that a lot of people want to catch that ILD when it’s asymptomatic so they can potentially rechallenge. But even when I’ve rechallenged patients with just imaging detected ILD, they’ve gone on to develop some issues. And so I think we need some data that it actually makes a difference for patients before I’m going to start doing all of this additional imaging which can be burdensome to patients.

DR LOVE: Yeah. That last comment, very, very interesting.

Efficacy and tolerability of olaparib in patients with a germline BRCA mutation and HER2-negative breast cancer

DR LOVE: So I think the fact that this patient was BRCA1 is a good introduction to our last topic, which is the use of PARP inhibitors. I don’t know that any groundbreaking data came out this past year. But, Sara, can you kind of summarize right now what you think some of the key questions that are coming up and issues about using PARP inhibitors in metastatic disease including now, I guess, a new generation of patients who would have had adjuvant treatment?

DR TOLANEY: Yeah. So it’s nice that we have the availability of olaparib in the high-risk adjuvant setting. I think in that setting, there are questions about how we should be using olaparib. Right now, we generally use it in patients, for example, with triple-negative disease who had residual disease, that becomes a nice option. Often, I’ll give it in combination with the pembrolizumab if they got preop KEYNOTE-522, but we don’t really have data for doing that. I think we just continue the pembro and add on the PARP. And if someone has ER positive disease though, in the adjuvant setting in the OlympiA study, if you had 4 or more positive nodes was the eligibility. And to me, that’s really, really high risk.

And I think the question is, should we be using it in people with a little bit lower-risk? And I think a lot of people, again, in practice aren’t necessarily sticking to that hard and fast criteria. And so I think, again, this is complicated. But you’re right that we could see patients who relapse after adjuvant PARP. And we certainly have no data about whether or not you would re-expose them to PARP. Does it depend on disease-free interval? Again, we don’t know. I’ve actually never had someone yet have that situation just given the time that we’ve had PARP inhibitors available in the early disease setting.

But in the metastatic setting, I think a common question is, which PARP inhibitor do you use? You’ve got 2. You’ve got olaparib, you’ve got talazoparib. So which one do you use and when do you use it? How many prior lines of treatment do you need before you’d think about it? So I think for choice of them, I don’t think there’s a wrong or a right here. Both of the, the data from both the Phase III trials looking at olaparib and talazoparib in the metastatic setting look almost identical, about a 3-month delta between the arms of PARP versus chemo. And so I think, again, you could choose either. To me, there’s a little bit less neutropenia with olaparib and a little bit less alopecia with olaparib. And so I’ve tended to use that. And in terms of when, for a PD-L1 negative patient who is germline BRCA mutant in the first-line setting, I’ll often think about a PARP inhibitor in that setting. And then if someone is PD-L1 positive and they progressed on checkpoint inhibition and chemo, then I’ll often think about PARP post-immunotherapy in that setting. So I think it’s nice because it’s an oral agent, it’s nice to try to give it when they can.

DR LOVE: And Rita, maybe you can add onto that in terms of how you approach utilization. But also, the kinds of tolerability issues that come up, particularly in the metastatic setting, cytopenias, anemia. Do you dose reduce or transfuse? Any comments about when you use PARP, which PARP, and how you manage side effects?

DR NANDA: Yeah. I have to say I would agree with everything that Sara said. In the metastatic setting, I’m primarily using olaparib just because I find it a little bit more tolerable. I have to say I haven’t run into a whole lot of problems with anemia. I was very worried about that early on because it was just so talked about. But that really hasn’t been a challenge for me. It’s nausea that really can be a challenge, particularly in these really young women. And that can certainly be a challenge. I’ll use antiemetics, sometimes consider dose reducing for that, and it can be beneficial.

And I do just want to share my n of 1. But while we have no data on using a PARP inhibitor in the metastatic setting for patients who got it adjuvantly, I did have 1 patient on OlympiA and we unblinded her. She was getting olaparib. And I did use a PARP inhibitor in the metastatic setting and did get some milage out of it. So I think, again, it had been about a year since she’d recurred. So again, anecdotal data but I do think it’s something worth considering while we’re waiting for hopefully some data to come out in this space.

Case: A woman in her mid 30s with mTNBC receives olaparib — Dr Foldi

DR LOVE: So we have actually 3 cases. So let’s start out with Julia’s 35-year-old woman.

DR FOLDI: So this is a patient who was treated a number of years ago for her early-stage disease by a different oncologist, so she was 35 years old at the time. Had a locally advanced breast cancer that was ER-low positive at 3%, PR negative, and HER2 0. And so her oncologist did send a MammaPrint just to confirm that this was a basal-like cancer. She did have genetic testing which was negative for germline variants. She did get neoadjuvant dose dense ACT. This was pre-KEYNOTE-522 era. She did have a path CR and then completed adjuvant radiation to the chest wall. She was trialed on tamoxifen given the low ER, but could not tolerate it. She did unfortunately suffer a recurrence 2 years after her initial diagnosis when she presented with a new cough and she did have mediastinal lymph nodes on imaging. And a biopsy confirmed metastatic breast cancer that was again ER-low positive. We use H scores here which was an H score of 1, PR negative, and HER2 1+. It was PD-L1 negative with a CPS of 5. So she was started on capecitabine. She did have some radiation to mediastinal lymph nodes. Unfortunately, she had only short response to this first-line therapy. And then a FoundationOne liquid biopsy assay was sent which revealed a somatic BRCA1 pathogenic mutation.

And so my question here is, we did start her on olaparib and she’s having a really great response after 1 year. I know that that’s not how olaparib is approved currently, but I know there’s some Phase II evidence. If you could maybe address what evidence we have for somatic BRCA mutations. And do you use PARP inhibitors in this setting?

DR LOVE: Let me just ask you. Has she had germline testing?

DR FOLDI: She did, and it was negative.

DR LOVE: Interesting. Okay. And Sara, I’d be curious too in terms of, you know, we have this whole debate in ovarian cancer, I’m not sure you quite get to that level, about who should get a PARP inhibitor, LOH, and PALB2, and all the other mutations. So any comment about somatic versus germline, and all the other variations of HR deficiency that we see?

DR TOLANEY: Yeah. So this is a really good question because now, we are getting sequencing data off of tumors. And so we do find these somatic alterations in some of these genes. And so there is a study done by one of our colleagues, Nadine Tung and Judy Garber had run this trial, Olaparib Expanded, where they tried to address this. How well do PARP inhibitors work outside of germline BRCA mutations? And so they did have a cohort of patients who had somatic BRCA mutations and, in fact, found a little over a 50% response rate. So very much in line with about the 60% response that we’ve seen in the OlympiAD study. So it looked very similar, in terms of efficacy, to what we see in germline BRCA patients. There was another cohort that had looked at germline PALB2 and found about an 80% response rate in that cohort. They’ve actually, they were very small cohorts and they’ve actually added additional patients in. We’ll be presenting the data in a larger number of patients soon. But I think really does suggest that these particular cohorts, germline, PALB2, and somatic BRCA, are additional patients we could consider PARP inhibition for outside of the traditional germline BRCA alterations. They, however, did not see benefit in things like ATM. And so it’s not all DNA damaged pathway genes where we should just be throwing PARP inhibition at. I think we need a little more information.

DR LOVE: So I’m just kind of curious with this woman. Did her hoarseness ever go away?

DR FOLDI: Yes.

DR LOVE: Really?

DR FOLDI: So she had a lot of lymph node burden. And so I think, we thought that was what it was related to. And she did have some radiation to that.

DR LOVE: But it went away clinically, the hoarseness?

DR FOLDI: Uh-huh.

DR LOVE: Interesting.

Case: A woman in her mid 60s with mTNBC and a BRCA mutation receives olaparib — Dr Huppert  

DR LOVE: So let’s go on to another case. Finally, somebody over the age of 50: 66. I was hoping you’d give me like 85 or 90 but okay, I’ll take it. So, Laura, what happened with this lady?

DR HUPPERT: This is an interesting case. This was a patient who actually initially got her care in Russia and then moved to the US in the context of the conflict there. And so her initial care was in Russia where she got up-front lumpectomy and sentinel lymph node biopsy which ended up being a 3.1 cm triple-negative disease with 1 out of 3 lymph nodes. Of course, we would have rather have treated her neoadjuvantly, but that was what was done there. They didn’t get germline genetic testing done at that time. She was treated with adjuvant ACT as well as radiation. And then moved to the US about 6 months after completing her radiation. And then presented to the ED at UCSF with mid-back pain where she was found to have new osseous lesions including a T4 compression fracture without cord signal abnormality. So the remainder of her CTs chest, abdomen and pelvis staging scans just showed the bone lesions. After I met her, I reviewed her case and realized she hadn’t had the germline genetic testing despite her family history of breast cancer. And so ordered that which showed, interestingly, a pathogenic BRCA1 mutation. We got a bone biopsy which confirmed triple-negative metastatic disease with a PD-L1 score of 0. So she got radiation to help her pain and then I started her on olaparib 300 mg BID as standard dose. Her baseline hemoglobin was 10.7. This is one of the only patients I’ve actually had, to your comment Rita, where I did run into trouble with anemia. A month after starting, her hemoglobin was 7 so I held her olaparib and gave her a unit of blood. And then repeated and her hemoglobin had improved with the blood and the brief hold. And so did restart her at the 250 mg dose. She’s since actually moved back to Russia, but I’ve communicated with her and she did well on it for about 11 months. And her oncologist in Russia had been considering options at that point, seeing if they could get access to SG or gem/carbo or other standard chemotherapies as next lines.

So I wanted to kind of bring up the points. Some of these we’ve talked about already. Which PARP inhibitor do you typically use first? How do you manage anemia? And then, of course, this case was treated, you know, hopefully we may have prevented her metastatic disease if we had known about her mutation and potentially given her the PARP in the adjuvant setting up-front. Unfortunate for her that it ended up this way. But, again, PARP to PARP, I guess we sort of touched on that as well.

DR LOVE: So Sara, any comments about this? And I was just maybe sort of flashing on it. I don’t know if there’s any data on whether or not — what fraction of patients actually end up getting tested, you know, having NGS or germline testing. I wouldn’t be surprised if, you know, we see all kinds of things in the real world. Have you seen any data on that? And any comments on this case and the questions about it, Sara?

DR TOLANEY: I think we’re not doing NGS in the real world probably as much as we should. In the metastatic ER positive setting, this is where I think germline — or actually, genomic testing like NGS really matters, right? Because then, they need to be able to test for mutational status. And I think in the ER-positive setting as well, people tend to forget about germline testing as well. They tend not to associate BRCA mutations as commonly, I think, and they forget about it. In triple-negative disease, we know that about 10% of people in the metastatic setting may end up having a BRCA mutation. And so it’s really important to make sure we do germline testing. I usually try to do it all at the beginning because I forget otherwise. So like when I meet a new metastatic patient, I make sure I send off germline testing if it hasn’t been done. I also send off NGS testing just, again, to check the boxes, make sure I’ve checked PD-L1. So I think there’s just systematic things that we do when we meet a new metastatic triple-negative breast cancer patient so that we have all the biomarkers at hand to make a systemic treatment decision. But I actually don’t know how often, for example, germline testing is being done in the real world in the metastatic setting where I would guess people probably do forget, unfortunately, a lot.

Case: A woman in her mid 40s with a BRCA1 germline mutation and mTNBC receives olaparib — Dr Shaikh

DR LOVE: All right. Let’s see if we can do this last case, Saba, your 45-year-old woman. What happened with her?

DR SHAIKH: So a 45-year-old woman. She initially was diagnosed with a 2.5 cm right breast mass with abnormal axillary lymphadenopathy, triple-negative, ER, PR, and HER2 were all 0, Ki-67 was 30%, and the lymph node was biopsying positive as well. She was found to have a BRCA1 germline mutation, and so she was clinical T2N1 and received the neoadjuvant KEYNOTE regimen. She had a pathologic complete response to that. She underwent mastectomy, targeted axillary dissection, and she finished her adjuvant pembrolizumab. She received adjuvant radiation as well. And then, unfortunately, 6 months after completing adjuvant pembrolizumab, she presented to the ER with a severe headache and was found to have a solitary brain metastasis that was 2.5 centimeters. No other systemic metastases. So she underwent a resection and then received radiation to the tumor bed. The pathology from the brain met is ER 0, PR 0, HER2 0, CPS 5. So she started olaparib 300 BID. She’s been tolerating it well so far with nausea that’s managed with ondansetron.

And so my questions are, number 1, so she’s NED but she has triple-negative breast cancer that recurred very soon after completing adjuvant therapy, so I felt very nervous to have her not on any systemic therapy at all. So I’m curious to hear what your thoughts are about systemic therapy in patients like this who are NED. How long would you continue it? And then also, I came across — I mean, her CNS disease was treated with surgery and then radiation. So she doesn’t have any active CNS disease, but I did come across some reports that olaparib, especially when there’s a disrupted blood-brain barrier, may enter the CNS space and there’s been some case reports that people have seen responses. So interested to hear the group’s experience with that.

DR LOVE: So Sara, any thoughts about this case and about that question?

DR TOLANEY: Well, number 1, it’s always so upsetting to see these cases where someone has a PCR and you think this is someone who is going to have outstanding outcomes. We know that these patients have lower risks of recurrence. And then, you see this brain metastasis. And it’s interesting that we are seeing this phenomenon that people who had a PCR, there does seem to be these cases where people get isolated CNS recurrence. It’s like it was a reservoir for those cells even though they had very good systemic benefit to treatment. And so unfortunately, this is one of those cases. My colleague, Nancy Lin, actually has put together a series of patients who have BRCA mutations and have had CNS disease, and has looked at benefit to these agents and has had several patients who’ve had very prolonged benefit to PARP inhibition with CNS metastases in breast cancer. So it does seem like a really, I agree, this was a really nice choice.

This is complicated though in terms of how long do you treat. She doesn’t really have any measurable active disease, right? So we don’t really know truly what we’re treating. We’re treating in case there are microscopic cells that were not effectively treated with radiation and hoping it prevents further CNS events. And I have no idea what the right answer is to duration. I think I’d keep in mind tolerability, but I would do it for a long time. I think I’d be very nervous to stop unless I saw toxicity issues or unless it had been like, I don’t know, 18 to 24 months without any further events. And so I’d want to wait it out and see how things go.

DR LOVE: So final comment from Rita. Any comments about this case, about what we said about PARP inhibitors? But also, one comment that I hear from general medical oncologists is, why don’t we, why aren’t we doing the same kind of thing we do in ovarian where you do PARP and then you do — you do platinum induction and then PARP maintenance? I don’t know if that’s even been looked at in breast cancer. Rita, any thoughts about that and anything else you want to say about PARP inhibitors?

DR NANDA: Yeah. I think those are all really good questions. I think my only comment specifically about this case would be what Sara raised here, that this — you think of brain metastases and you see it in these kind of usually Stage III hormone receptor negative patients whether they’re HER2 positive or triple-negative, that the brain is a sanctuary site and that systemic therapy just didn’t get up there to treat these patients. But I think olaparib, it’s a small molecule. The potential that it will penetrate the CNS is there. And I think that it’s reasonable. But again, duration, a year, 2 years, it’s hard to know. And you may end up having to discontinue based on tolerability issues. She’ll also declare herself one way or another. So after a year or so, maybe you can back off a little bit on therapy if she continues to have life-altering nausea and think about that.

I think about the question of induction, say, chemotherapy and then maintenance PARP therapy is a good one. And definitely, the way we’ve developed PARP inhibitors for breast cancer has been different than they’ve been developed for ovarian cancer. But I think what we know from the OlympiAD and EMBRACA trials is that PARP inhibitors are associated with a better quality-of-life than chemotherapy. When we survey quality-of-life in these patients, PARP inhibitors are associated with better quality-of-life. And granted, neither of these PARP inhibitors were compared head-to-head to platinum-based therapy in either one of those trials. The PARP inhibitor had twice as high of a response rate, in the 60% range versus 30% range with chemo. A significant improvement in median PFS, 3 to 4 months. And while there wasn’t a survival advantage, the quality-of-life was dramatically better. So the way we’ve developed these agents in breast cancer has been a little bit different. Would, say, induction chemotherapy followed by maintenance PARP inhibitor in a mutation carrier population be a better strategy or not? The KEYLYNK trial, KEYLYNK-009 looked at induction chemotherapy and then maintenance PARP versus continuing chemotherapy. And essentially, there was no difference between those arms, but this was not limited to a mutation carrier population. So I think we don’t have the answer to that question in breast cancer. But from my standpoint, I like to give patients a therapy that’s associated with better quality-of-life. And so I think that starting out with a PARP inhibitor is a very reasonable approach and is associated with a very high response rate and a great PFS. So I think I’m comfortable with the strategy that we use in breast cancer.

DR LOVE: So I was going — I’ve got one more, now you made me ask one more question. I’ll make it quick. Just kind of curious. I don’t know why, I think you mentioned neoadjuvant. It flashed in my mind, Sara, the trial that was reported a couple years ago. It was a small number of patients. Neoadjuvant, I think, talazoparib, that had a pretty high path CR. Has that been followed up?

DR TOLANEY: Yeah. So there have now been a few trials that have looked at preoperative PARP alone, and have seen in germline BRCA carriers about a 50% PCR rate.

DR LOVE: Wow.

DR TOLANEY: That’s not that different than what we get with KEYNOTE-522, right? And with KEYNOTE-522, the PCR is a little over 60% in an all-comer population. And so it does make you wonder, could we achieve, you know, can we get rid of chemo for BRCA mutation carriers? And I think it’s a hard study, a hard path because I think — actually, we have a trial ongoing right now at our institution combining PARP/checkpoint preop for BRCA mutation carriers. But the challenge is if you hit a 50% PCR rate, it still means that half the people didn’t get a PCR. And then those people, we’re giving them a bunch more chemo in the adjuvant setting and we’re also worried that we’re giving the chemo without checkpoint because the checkpoint seems to work much better if you give it preop. And so there are some risks when you kind of try to de-escalate in a higher-risk population. And so this is where we’re truthfully struggling about how to move this forward to become a standard because you really do need a biomarker to help you figure out who are those 50% of people who can get away with just a PARP inhibitor. It’s obviously not just all germline BRCA patients. So I hope we’ll figure that out because it’s amazing to think you could just give an oral agent and cure patients. So hopefully we’ll get there.