Expert Predicts TNBC Will Evolve to Include More Subsets, Tailored Therapies

Lisa A. Carey, MD

The term triple-negative breast cancer (TNBC) is not helping researchers and physicians in the field to properly diagnose and provide optimal treatment for patients with the disease, explains Lisa Carey, MD.

“One of the key elements in TNBC is the promise of a targeted therapy, because triple-negative disease is defined by what it doesn’t have, which is a targetable protein such as hormone receptor and HER2,” says Carey.

However, early evidence suggests that some TNBC tumors are heterogeneous—and that a sample of these cancers are immunogenic, making them possible candidates to positively respond to immunotherapy. Updated results of the phase Ib KEYNOTE-012 study, which were presented at the 2016 San Antonio Breast Cancer Symposium, showed that treatment with pembrolizumab (Keytruda) in heavily pretreated patients with PD-L1—positive metastatic TNBC led to a median progression-free survival and overall survival of 1.9 months and 11.3 months, respectively (Nanda R, et al. Abstract P6-10-03).

In an interview with OncLive, Carey, an associate director of Clinical Research at UNC Lineberger Comprehensive Cancer Center, and the Richardson and Marilyn Jacobs Preyer Distinguished Professorship for Breast Cancer Research at UNC-Chapel Hill, discussed the current state of the science in TNBC, the potential for immunotherapy, and future treatment approaches she anticipates in the coming years.

OncLive: How would you currently describe the field of TNBC?

Carey: The truth is, with TNBC, we have a number of options with traditional chemotherapy and there are actually data about the best first-line drug being taxanes or platinum drugs. In patients who have inherited breast cancer with germline BRCA1/2 mutations, they may actually do better longer with platinum drugs first.

However, there are also a number of drugs—eribulin mesylate (Halaven) and capecitabine, for example—that are perfectly reasonable drugs to sequence later. One of the take-home messages is that patients can do well for quite a while—1 year in some cases—and one of the strategies that has to be front and center for metastatic TNBC is to balance trying to control the disease with quality of life. It’s important to pick the drugs that the patient has the least toxicity to, can tolerate, and maintain their quality of life for their own lifestyle. Those are really important variables, in addition to picking drugs.

The emerging evidence about molecular heterogeneity in TNBC is giving us real ideas of things within subsets we might be able to do. Some of the most interesting data are coming out around the androgen receptor (AR) as a possible target in some, but not all, TNBC. There are some studies that are being done to try and capitalize on that and formally test it.

The other thing, of course, is the idea of using immunotherapy and immune checkpoint inhibitors. We know that TNBC has activated immune cells in the primary tumor. We also know there’s emerging data for the various checkpoint inhibitors with similar findings: that there is a small but really proportionate number of patients who do exceptionally well with these drugs.

This is an area that is likely to be the next advance, but not for all patients with TNBC. TNBC is going to be one of those where we’re going to have a lot of improvements within subsets and, together, that’s going to raise survival in the disease as a whole. TNBC itself is not a monolithic thing. We need to keep that in mind.

You mentioned the importance of balancing treatment with quality of life. Anecdotally, how have you seen certain treatments affect patients?

Some of the most obvious examples of needing to take toxicity into account are patients who have neuropathy after their adjuvant taxane. While taxanes are among the most effective drugs for first-line metastatic TNBC, if a woman has difficulty buttoning her shirt, restarting a taxane or another neurotoxic drug might not be in her best interest—especially if you have other options, which we do.

There are patients in whom gastrointestinal toxicity is very troublesome. On the other hand, there are patients for whom adherence is difficult. They have trouble remembering to take their pills or trouble swallowing their pills. At that point, intravenous therapy is a much more controlled situation. We talk about molecularly individualizing therapy but, from the standpoint of tolerability and preference, this is also a compelling reason to individualize therapy.

What potential is there, truly, for immunotherapy in TNBC?

It is clear that some triple-negative patients have immune activation and others do not. We know that plays out prognostically. The truth is, also, that TNBCs have some evidence of clonal restrictions. Therefore, there is some actual evidence of immune reaction to an antigen from the tumor from correlative studies that have been done.

Of all the breast cancer subtypes, this is one where immunotherapy is probably the best place to start. That’s probably why there are a number of studies in TNBC and all 3 of the current immune checkpoint inhibitors that are furthest along, have shown effectiveness in a subset.

The questions that still remain are, “How do you select? How do you pick the ones that are most likely to benefit? Is it better used as monotherapy or in combination with chemotherapy? Which ones?” This is a very hot area right now, and I don’t know what’s going to be the best option. But, I am just thrilled that we have a number of them, all of which are showing evidence of having real activity in TNBC.

How do you see the landscape evolving?

In general, I am betting that in the landscape of breast cancer we are going to move away from estrogen receptor (ER), progesterone receptor, and HER2 as defining characteristics. This is not just for TNBC, but in general. We are going to be much more reliant, as we are already in ER-positive and HER2-negative disease.

In early breast cancer, we already use genomic tests to help us gauge appropriate therapy. That’s going to be the story for breast cancer in general. That will also happen in TNBC. To be honest, the name may go away because the name “TNBC” itself doesn’t help us very much; it just tells us what the disease isn’t.

Now that we are getting a better sense of what they are, the landscape is likely to involve more tailored choices of chemotherapy. There will also be tumor microenvironment-directed therapy. Immunotherapy is one obvious example, and will probably be in combination. There will be patients getting both. There may be hormonal pathways that are targetable in TNBC. The AR is one, but it is also true that some TNBCs show up as luminal, so they may be ER-driven and things like that.

That’s my sense and hope that we are able to do this. We will get to a place where we can be less aggressive with TNBC because we will understand the biology better.