Keira Smith: Welcome to Oncology Data Advisor^TM, where we explore the latest advances in cancer research and treatment. I'm Keira Smith. In this podcast, Dr. Sara Tolaney from Dana-Farber Cancer Institute will be discussing strategies for improving the management of patients with metastatic breast cancer. Thank you for joining us, Dr. Tolaney.

Sara Tolaney, MD, MPH: Thanks so much for having me. I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute here in Boston.

Keira Smith: So what are some of the most challenging aspects of managing patients with metastatic breast cancer?

Dr. Tolaney: I think we've made incredible progress for our patients with metastatic breast cancer, particularly over the last two to three years, where we've seen approvals for several new agents that really have a significant impact on patient outcomes. But I think the challenges that we're faced with are trying to balance quality of life with different therapeutic decisions and then trying to figure out optimal sequencing of therapy. As we get all these new drugs, we are now faced with what order we give them in order to really optimize someone's outcome and if having had one agent will potentially impact their ability to benefit from another. This introduces lots of challenges when making treatment decisions.

In particular, I think, the challenge I often have is really trying to make decisions with the patient, because it is critical that we make these decisions with the patient involved so that they're able to have a voice in weighing potential risks and benefits of each treatment.

Keira Smith: Do you have any advice for optimizing the use of genetic testing for these patients?

Dr. Tolaney: I think we've learned, particularly over the last couple of years, that understanding if someone has a germline genetic alteration—particularly a BRCA alteration—is really important when making treatment decisions for patients. For example, we know that when someone has metastatic disease, poly–adenosine diphosphate ribose polymerase (PARP) inhibitors improve progression-free survival. Knowing who has a germline BRCA mutation is critical so that we know if PARP inhibition is a treatment option for them. Now in early-stage disease, we even know that patients who have germline BRCA mutations and high-risk disease can benefit from adjuvant PARP inhibition, which can prevent recurrences. In my mind, this means that we really need to be doing genetic testing on all metastatic breast cancer patients and all patients who have early-stage cancers with high-risk disease for whom PARP inhibition may be appropriate.

Then on the other side, there are also patients who just have strong family history and may not be candidates for PARP, but obviously, understanding if they have a genetic mutation can have serious implications on decisions with regards to prophylactic surgery or more intensive surveillance, which we do in patients who have high risk for developing breast cancer. Again, there's some thought about moving towards more universal testing, but for now, I think that we at least need to be testing metastatic patients, high-risk early-stage patients, and patients who have strong family histories and early-age onset of breast cancer.

Keira Smith: Last year, the FDA issued an alert warning against the use in paclitaxel in place of nab-paclitaxel for patients with triple-negative breast cancer. What are some of the potential reasons why this combination is not effective?

Dr. Tolaney: The reason for that FDA alert was really based on data that emerged from IMpassion 131. This was a trial that had looked at paclitaxel in combination with atezolizumab and found that there was no improvement in progression-free or overall survival when using that combination, compared with paclitaxel alone. This is really the opposite of what we found with nab-paclitaxel plus atezolizumab, where we did find that adding atezolizumab to nab-paclitaxel did extend progression-free survival. It did lead to clinically meaningful improvements in overall survival. Because of these discordant results, using paclitaxel with atezolizumab is really contraindicated at this time. The preference would be to use nab-paclitaxel with atezolizumab.

Keira Smith: Speaking a little bit about the management of these patients, what are some of the considerations for patients with central nervous system (CNS) metastases?

Dr. Tolaney: In breast cancer, unfortunately, we do see prevalent CNS metastases, particularly in patients who have human epidermal growth factor receptor (HER2)–positive and triple-negative breast cancer. This definitely does have therapeutic implications where many of our drugs do not penetrate into the CNS. In essence, it leaves the CNS as a reservoir for cancer cells to be able to sort of set up shop in the brain. There's been a lot of work being done about developing agents that can penetrate into the brain and have benefit in the CNS. In fact, we now have an agent, the very first agent, that extends overall survival in patients with brain metastases, and that is tucatinib for patients who have HER2-positive breast cancer, where there was a benefit in patients who have active CNS metastases. This is, again, the very first approval we've ever seen for an agent that can actually extend overall survival in patients with brain metastases.

I think we're making very important headway here, and I think it also really highlights the need for us, when we're developing clinical trials, to include patients with CNS metastases. They have classically been excluded from registrational trials, but knowing how much of a problem CNS metastases can be for our patients, it's important that we study benefits of agents particularly in patients who have CNS metastases.

Keira Smith: Looking ahead to the future of metastatic breast cancer treatment, what are some of the agents currently in clinical trials that you think are the most promising?

Dr. Tolaney: I think there are lots of really interesting agents that are in development. One class of agents that I think we're all awaiting data from are oral selective estrogen receptor degraders (SERDs). These are oral agents that degrade the estrogen receptor. We've been used to using fulvestrant (Faslodex^®), which is an intramuscular SERD which works for our patients, but generally has pretty poor bioavailability. I think we're very excited about these oral agents that have better bioavailability and may potentially even work better than fulvestrant. We are awaiting data from randomized registrational trials in metastatic disease, and there are now trials that are being developed to use these in the early-stage setting, as well. I think these agents carry a lot of promise.

Another area of drug development that we're all excited about is the antibody-drug conjugates (ADCs). We do have approval now for three different ADCs in breast cancer, ado-trastuzumab (T-DM1) being the first one that we had. Then subsequently, we saw approvals for sacituzumab govitecan and trastuzumab deruxtecan. Now there are also other antibody-drug conjugates in development. We saw some really exciting data from DS-1062, which is a new antibody-drug conjugate targeting Trop-2. We have seen a press release about positive data from SYD985. I think in the future, there are going to be a lot of questions about how we can sequence antibody-drug conjugates, because some of these ADCs are targeting the same receptors. Some even have payloads that have similar mechanisms of activity. This is going to raise a lot of questions as we get more and more potent ADCs approved, about how we can optimally use them and sequence them. Again, there are a lot of exciting new agents coming, which is great for our patients.

Keira Smith: Well, thank you so much, Dr. Tolaney, for joining us today and for sharing all this valuable information with us.

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

Keira Smith: Thank you for listening to Oncology Data Advisor. Be sure to subscribe to the podcast so you'll never miss an episode! In addition to our podcast, the Oncology Data Advisor site features expert perspectives and news stories on the latest in cancer research and treatment, all found at oncdata.com.

About Dr. Tolaney

Sara Tolaney, MD, MPH, is the Associate Director of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, where is she is also the Director of Clinical Trials in Breast Oncology and the Director of Breast Immunotherapy Clinical Research. In addition, she is an Associate Professor of Medicine at Harvard Medical School. Dr. Tolaney's research focuses on the development of novel therapies for breast cancer, and she has served as principal investigator of numerous clinical trials.

For More Information

CLICK HERE to gain additional perspectives from Dr. Tolaney by completing the complimentary CME/NCPD-approved activity.

This transcript has been edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.