Future Directions for Treatment of TNBC

Joyce A. O’Shaughnessy, MD: Adam, say a few words for us about what therapeutic approaches you’re most excited about from an investigational standpoint that might take us into the future.

Adam M. Brufsky, MD, PhD: There are lots of things that people are doing now. They’re doing the usual of combining immune checkpoint inhibitors with PARP inhibitors. Someone on this call did review that—it may have been Kevin—about the CGAS pathway that’s activated by PARP inhibitors in immune cells and antigen-presenting cells, that may be involved in tumor immunity. You’re boosting them by relieving the suppression with a checkpoint inhibitor. It was a really nice theory behind it. A number of different checkpoint inhibitors are being used. Sacituzumab is used in earlier lines of therapy with or without checkpoint inhibitors.

Even trastuzumab deruxtecan is being used in the triple negative space. That’s not even thinking about all the other immune approaches that are in very early trials in the phase 1, phase 2 setting, bispecific antibodies trying to join various points of the immune system. People are trying to figure this out. The overall theme is that triple-negative breast cancer is an inflammatory disease. It’s the inflammatory or immune response that you really have to modulate or that is being modulated and being suppressed somehow as you get to later lines. How do we activate that? We call it making cold tumors, hot or whatever that is. That’s the other thing.

Of course, we haven’t even talk about all the AKT inhibitors. It turns out 10% to 15%, or more or less depending on whom you listen to, of triple-negative breast cancers have a mutation to the AKTp 10 and 4 pathway. Then there’s the whole PI3 kinase pathway. There’s this whole area there that could be exploited and is—capivasertib and ipatasertib are being used. A lot of things out there are exciting. The whole thing with sacituzumab and everything just jazzed everybody up about this field. At least it jazzed me up. When Suzette Delaloge or that group in France redoes this real-world analysis 4 or 5 years from now, we’re going to see some survival benefit in triple-negative breast cancer because of it.

Joyce A. O’Shaughnessy, MD: Beautiful. Thank you so much. I’m going to give everybody a chance to go around. Let’s go around the Zoom here—give just 1 final thought. Anything you’d like to highlight from our discussion from triple-negative breast cancer, early stage or metastatic, from ESMO [European Society for Medical Oncology]? Let me start with Kevin. Do you have any last words?

Kevin M. Kalinsky, MD: Yeah, as we’ve discussed, sacituzumab govitecan was really a huge story out of ESMO. As we’ve discussed, there is this story in terms of checkpoint inhibition in the metastatic, operable setting. That story evolves and continues. The other thing, in terms of future directions to think about, is what’s going to be the role of circulating markers in the operable setting like cell-free DNA. As prognostic and predictive, we think about some of these super-interesting agents in the metastatic setting, which may translate to the operable setting. Will that help us define risk and response better?

Joyce A. O’Shaughnessy, MD: Thank you. That will be a brave new world, I must say. Sara Tolaney, how about you?

Sara Tolaney, MD, MPH: First, I’ll echo Kevin’s comment that a lot of our discussion stemmed around at the beginning: Who needs preoperative immunotherapy? While we all hand wave and think about risk, I think we need a biomarker. I do hope we can learn to be able to tailor therapy for our patients better than we are. We need to improve outcomes, lessen the toxicity, make sure we’re not giving patients drugs that aren’t helping them.

I do hope we’ll learn more. I know there is a lot being invested to be able to discover potential predictors. Hopefully we’ll be able to get there. In terms of exciting combinations, there are just so many exciting things, which is very promising. Taking the sacituzumab story, a lot of us are really interested to better understand if ADCs [antibody-drug conjugates] work better with immunotherapy. Could it be a way for us to get those tumors that aren’t traditionally responding to immunotherapy to respond? For example, could you take a PD-L1–negative tumor and get it to respond to immunotherapy if it’s used to maybe a better backbone? An ADC could get us there. There is a lot of work being done to potentially allow immunotherapy to work in these colder tumors. We’ll see more to come.

Joyce A. O’Shaughnessy, MD: Thank you. Such great thoughts, you guys. It’s really super. Sara Hurvitz, how about you?

Sara A. Hurvitz, MD: At the risk of being redundant, I will echo what my colleagues have said: Biomarkers are the key because triple-negative breast cancer is classified by what it is not. It’s clearly very old school, and we need to define subsets. Biomarkers are going to be the key. Not only genomics but proteomics are going to be very helpful in defining targets we can go after.

The second thing I would like to say is that with the Delaloge data that we’ve all been referencing, the rates of de novometastatic breast cancer are very high for HER2-positive and hormone receptor–positive breast cancer. It’s underscoring how we are getting really good and sophisticated at how to treat in the curative setting. We need to get there for triple negative, so that the majority of the triple negative we’re seeing in the metastatic setting is de novo and not recurrent. That will move the survival forward.

Joyce A. O’Shaughnessy, MD: Thank you. None of us can retire until we get there. We have to see that one too. Adam, you have the last word, with something you’d like to note from the top of your mind.

Adam M. Brufsky, MD, PhD: I’ll echo everything you say. We have a lot of new directions. As I think about this disease, in particular triple-negative disease, 1 of the things I’m going to try to do—because we have some pretty strong, hard-core, basic immunologists at my institution—is try to get them interested in this as a model system. They are at some of our other institutions. For the hard-core basic immunologist, the answer may rest in the tumor. But because the immune response has so much to do with the host that maybe there are biomarkers in the host that will tell us which way to go. I’ve started to interact with them. They do these 15-dimensional flow-cell sorting of immune cell subsets of the peripheral blood and single-cell RNA sequencing of these subsets after they flow them.

Maybe there’s something in there. It’s incredibly complicated stuff. It’s way over me, but it seems as if that may be where some of these answers may lie. It will also be in the tumor, it will be in circulating DNA, but the markers are there. I agree with everybody. We need markers for who is going to benefit from this. Because when you benefit, you do really well, and I think that’s fine. I’ll leave it at that.

Joyce A. O’Shaughnessy, MD: Super. Thank you, guys. It’s so exciting talking to you. I am really struck by the energy people have to continue to push up that hill. It’s really apparent that you guys are asking the next questions. It’s really gratifying. Thank you for a wonderful conversation. Thank you to everyone who participated. I hope you found this really useful. Nice update on ESMO, with a lot of new data. We hope to be back after San Antonio Breast Cancer Symposium with another discussion. Thank you very much for participating.

Transcript Edited for Clarity

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