Expert Perspectives in the Management of Triple-Negative Breast Cancer: a Webinar Preview With Sara Tolaney, MD, MPH

Oncology Data Advisor: Hi, and welcome to Oncology Data Advisor. I'm Keira Smith, and today I have the pleasure of being joined by Dr. Sara Tolaney. Dr. Tolaney is hosting a live webinar for i3 Health next Wednesday, July 12th at 1:00 PM Eastern, focused on triple-negative breast cancer. Today, she'll be discussing a preview of some of the topics that will be covered in the webinar. Dr. Tolaney, thanks so much for coming on today.

Sara Tolaney, MD, MPH: Oh, thank you very much for having me.

Oncology Data Advisor: To start off, would you like to introduce yourself and what you focus on in your work with breast cancer?

Dr. Tolaney: Sure, my name is Sara Tolaney. I'm a Breast Medical Oncologist at Dana-Farber Cancer Institute and Chief of the Division of Breast Oncology here. My research interests have really focused on developing novel therapies for patients who have breast cancer and trying to move promising early drugs into the clinic for patients, so they get early access. The goal is trying to improve outcomes for patients, but at the same time, trying to be very mindful of the side effects that these drugs cause and tailoring drugs to the individual patient.

Oncology Data Advisor: Great. So, in the webinar next week, you'll be discussing the many important considerations in the management of TNBC. By way of background, what are some of the factors that make TNBC such a challenging disease to treat?

Dr. Tolaney: I think one of the challenges is that we've sort of defined triple-negative breast cancer by what it isn't—we've defined it as a cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). But in truth, triple-negative disease does have some receptors on it. We've made it sound like it doesn't have any targets, but that's certainly not true.

I think the other challenge is that triple-negative breast cancer is very heterogeneous. It isn't all the same in all patients who have triple-negative disease. I think we've come a long way from where we used to be, where we used to think that there was no target on triple-negative breast cancer and that we really just had chemotherapy. But as this program will address, there are lots of novel therapies that really have come out that have changed outcomes for patients, which is really important.

Oncology Data Advisor: Definitely. As you mentioned about these novel therapies, what are some of the most promising ones that have been developed over the past few years, and how have they impacted treatment?

Dr. Tolaney: I think we've been really fortunate to see so many new drugs come out. Particularly over the last two to three years, we've seen immunotherapy, we've seen poly-ADP ribose polymerase (PARP) inhibitors, and we've seen antibody-drug conjugates emerge. I think all of these have really had tremendous outcomes. That being said, these agents are for specific subsets of triple-negative disease. Just like we said, not all triple-negative breast cancers are the same. It is important to understand a person's individual triple-negative cancer and then figure out what therapy works for them.

For example, with immunotherapies, we've learned that if someone has metastatic triple-negative breast cancer and that the cancer has the programmed death ligand 1 (PD-L1) receptor on it, then immunotherapy added to chemotherapy really does dramatically improve outcomes. We need to know if the triple-negative breast cancer is PD-L1–positive, which is about 30% to 40% of all triple-negative cancers.

Then for PARP inhibitors, we know that these agents work in patients who have germline BRCA mutations and that they have better disease control for longer in patients when compared with chemotherapy. It's really important to know germline BRCA status. But as it turns out, they also work in patients who have somatic BRCA mutations or germline PALB2 mutations. It's really important to understand this information in order to know if they're a candidate for PARP inhibition.

Additionally, for antibody-drug conjugates, we have sacituzumab govitecan and we have trastuzumab deruxtecan. Trastuzumab deruxtecan, at least for now, seems to work best in those patients who have what we call HER2-low breast cancer, meaning that the cancer has a little bit of the HER2 protein on it. It's not a cancer that's truly HER2-amplified and HER2-positive. But rather, if you look at the cancer, it's either 1+ or 2+ by immunohistochemistry and not fluorescence in situ hybridization (FISH)–amplified, which is about a third of triple-negative breast cancer patients. As can see, there are lots of drugs, but we do need to understand the individual biomarkers on that cancer, as well as germline mutational status, to be able to figure out what agent is the best choice for the individual patient at that particular time.

Oncology Data Advisor: Absolutely. It's great to hear about all the new options. What are some of the notable toxicities that have come along with these novel treatments, and how do you approach managing them?

Dr. Tolaney: Yes, it's a very important question. These therapies all have different side effects that we do have to be mindful of. For example, with immunotherapy, these agents are really looking to take the brakes off the immune cells, so your immune cells then sometimes can get a little over-revved up and potentially attack normal tissue. This can cause an inflammation in that normal tissue.

For example, very commonly in breast cancer patients getting immunotherapy, about 20% of patients will develop thyroid toxicity, which is something we can monitor by checking thyroid function tests routinely when someone's getting immunotherapy and then institute thyroid hormone replacement if someone develops hypothyroidism. We also see that people can get other organs inflamed. The lungs, if inflamed, can cause pneumonitis; in the liver, you can get hepatitis; in the colon, you can get colitis. You can also get other endocrine toxicities, such as adrenal insufficiency and hypopituitarism. All those things do need to be carefully monitored in patients getting immunotherapy.

For PARP inhibition, the things to be mindful of are issues with nausea—which we can use antiemetics as needed, certainly—and then impact on blood counts, with a particular impact on the red blood cells. We can see anemia, which sometimes can even result in the need for transfusion in patients getting PARP inhibition. It's something, again, to be tracking and monitoring.

Then for antibody-drug conjugates, there are some unique toxicities. In fact, these are, in truth, chemotherapy agents; they are delivering chemotherapy. With sacituzumab, we do see that patients lose their hair. Alopecia, unfortunately, is very common. Neutropenia is common. About half of the patients getting sacituzumab govitecan will develop grade 3-4 neutropenia, and about half of them require growth factor support. Mild diarrhea can also happen with sacituzumab, but as-needed loperamide works very well.

For trastuzumab deruxtecan (T-DXd), that agent can also cause some neutropenia. It causes less in the way of alopecia, so maybe about 20% of patients or so will actually completely go bald from using T-DXd, but most people keep their hair. Then the one side effect that we do have to be mindful of with T-DXd is interstitial lung disease (ILD), which happens in about 10% to 15% of patients. It's important to let patients know that they could get this inflammatory reaction in their lungs from T-DXd, so they do need to look out for shortness of breath, dyspnea, exertion, cough, or any type of upper respiratory symptoms. That does need to get evaluated promptly if they become symptomatic from it. Again, there are unique toxicities depending on which agent there is.

Oncology Data Advisor: Thank you. That was a great overview of all the considerations. Looking ahead to the future, of the therapies that are currently in development, which do you think will have the greatest potential to impact treatment in the coming years?

Dr. Tolaney: It's nice to see there are so many new agents that are in the pipeline that hopefully will continue to really impact outcomes for patients. We touched upon two of the antibody-drug conjugates (ADCs), sacituzumab govitecan and trastuzumab deruxtecan, but there are other ADCs in development.

One that hopefully come out more near-term is datopotamab deruxtecan (dato-DXd), which is a Trop2-directed ADC, also with a deruxtecan payload—very similar in that sense to T-DXd, but instead with a different target. This agent is being studied in the first-line setting for triple-negative disease, so hopefully there is more to come. That study is currently enrolling, but we've already seen initial data that looks very promising in pretreated triple-negative disease. There are other ADCs as well. Patritumab deruxtecan, which is a HER3-directed ADC, also with the deruxtecan payload, looks very promising as well in pretreated triple-negative breast cancer.

But I think this leads to the question of, how can we have all these ADCs with somewhat similar payloads, especially if they're all targeting or having a topoisomerase 1 payload. Are they going to work one after the other? We don't know. We need more data here. I think that is going to be a question as these new agents really move forward. How do we sequence these drugs? Can you use them sequentially? What's the efficacy? Are there biomarkers that can help us predict which patients will continue to derive benefit as we better understand resistance to these drugs?

There are certainly other agents that are in development, including some targeted drugs for AKT inhibition, which we're currently waiting on data for. Other novel immunotherapies are also in development, such as things like TIGIT. Again, there will be more to come as these other agents move forward.

Oncology Data Advisor: Definitely looking forward to hearing more about all of these trials as they progress. Switching gears, since you're presenting the webinar next week along with Dr. Ira Bleiweiss, who is a pathologist, what are some insights that you have learned from pathologists over the years that have benefited your practice?

Dr. Tolaney: One is how critical the pathologists are, which is becoming more and more important as time goes on—particularly not just to make a diagnosis of triple-negative disease, but now as we're getting all these biomarkers, it is becoming very complicated. With PD-L1, we've seen lots of different antibodies be used to test for PD-L1. Right now, since we're using pembrolizumab in PD-L1–positive triple-negative disease, we have to use a 22C3 antibody and use combined positive score (CPS) testing and get a score greater than or equal to 10 to make someone eligible for immunotherapy.

There are a lot of challenges with reading that PD-L1 assay, so it's really important to partner with your pathologist to make sure you're getting the right assay for the checkpoint inhibition you're going to utilize that for HER2 testing. That's been quite an evolving space as we now need to understand if someone has HER2-low disease. We never really thought about that before, but now that is quite critical. We've seen the challenges with reading HER2-low in terms of challenges getting concordance between pathologists reading the same scoring.

I think this is going to evolve even further because we will soon better understand if patients can have ultra-low HER2 status, meaning somewhere between 0 and 1+, and benefit from T-DXd, and maybe even eventually see if HER2 0 patients benefit from T-DXd. We need better quantitative assays. I think these are just two little examples of how complicated testing has become in breast cancer and how critical our pathology partners are. Again, having a better understanding of these biomarkers is critical, and our pathologists plays such an important role there.

Oncology Data Advisor: Absolutely, they definitely do. is there anything else covered in the webinar that you're looking forward to discussing?

Dr. Tolaney: I think really the most fun that I have is trying to figure out what the right therapy is for the individual patient at that particular time. We have all these pieces in the armamentarium, if you will, that we could utilize to treat the patient. It does take understanding what exactly is going on with the patient at that time. How they respond to prior therapy can sometimes help you understand how they're going to respond to a future therapy. Where is their cancer—is it visceral, non-visceral, what biomarkers do they have, and what germline genetic mutations they have?

Putting all the pieces together helps us better understand how to tailor treatment to the individual patient. We have some cases that will discuss, which I think are really helpful in putting everything into context.

Oncology Data Advisor: Definitely, and I'm looking forward to hearing more about all of these topics during the webinar. Thank you so much for coming on today. This is a really great preview, and I'm definitely looking forward to learning more about it.

Dr. Tolaney: Thank you so much for having me.

Dr. Tolaney: Thank you.

About Dr. Tolaney

Sara M. Tolaney, MD, MPH, is Chief of the Division of Breast Oncology and Associate Director of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute. She is also an Associate Professor of Medicine at Harvard Medical School. Dr. Tolaney's research focuses on the development of novel therapeutic strategies for breast cancer, including de-escalation of therapies for patients with low-risk HER2-positive disease, and she has been instrumental in the development of CDK4/6 inhibitors and immunotherapies for breast cancer.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.