Expert Discusses De-Escalation Difficulties, Other Topics in TNBC

Lisa Carey, MD

The lack of nonchemotherapy options in triple-negative breast cancer (TNBC) makes it difficult to de-escalate treatment in patients with these tumors, says Lisa Carey, MD.

OncLive: Why is it difficult to de-escalate treatment for patients with TNBC?

In an interview with OncLive at the 2017 St. Gallen International Breast Cancer Conference, Carey, professor of medicine, University of North Carolina, discussed the challenges with de-escalation in patients with TNBC and steps toward overcoming these obstacles.Carey: One of the hardest places to [de-escalate treatment] is in TNBC, because we have fewer nonchemotherapy options, but there are some things that we can do. We know that the use of neoadjuvant therapy can help us minimize surgery. It’s less clear that we can use it to tailor chemotherapy, but that’s an emerging arena. It’s also true that nonrandomized studies suggest that very small node-negative TNBCs may not benefit much from chemotherapy, so we can be thoughtful about T1a/N0-type tumors and not give them chemotherapy.

What is a little less clear, and what was one of the hopes, is that we could minimize anthracycline use. I think the current prospective data suggest that they still play a role in TNBC, so we haven’t quite managed to deliver on tailoring chemotherapy within that setting.

I think the flipside is that TNBC, at this point, is our poorest prognosis subset of breast cancers. Even in spite of standard-of-care cytotoxics, there is still a high relapse rate. Some of the initiatives that have been going on include use of platinums and residual disease strategies.

At the moment, platinums are still a work in progress because we know that they improve pathologic response rates in the neoadjuvant setting, but we don’t know if they translate into improvements in survival. There was a very interesting study that was presented 1.5 years ago—it hasn’t been published yet—that suggested that if you look at residual disease after chemotherapy, if you take those that still have cancer left after standard of care and give them additional chemotherapy—in this setting, it was capecitabine—you could impact relapse and survival. So that’s a way of tailoring it a little bit.

Are there any biomarker-based studies currently being done?

In the escalation phase, are there any agents that are promising?

I have to say that the future here [also depends on] the effective development of biomarkers to help us strategize…That includes immune biomarkers, like tumor infiltrating lymphocytes, and the incorporation of noncytotoxic options, of which we really don’t have any, but I think we are all very hopeful that we will in the near future.There are a ton of biomarker-based studies. In truth, there are 2 forms of biomarker-based studies. There are integral biomarkers, where we are testing them explicitly for clinical utility. In TNBC, we don’t have any biomarkers that are ready enough that we can use them for treatment decisions. What there are a lot of are studies that are incorporating biomarkers in a testing clinical validity realm, including tumor infiltrating lymphocytes and mRNA-based gene signatures, and things to try and help with identifying patients with BRCAness and with the potential benefit of platinums. There are a lot of studies in that realm. There are none that are level 1 evidence prospective trials, but I think we will get there.The history of breast cancer therapy has been one of escalating [treatments, according to a keynote speech by Martine Piccart, MD, PhD]. We’re good at escalating. De-escalating is more challenging. Taking away things is harder to do, both from a trial design standpoint and from a funding standpoint.

TNBC is the 1 area where there is as much emphasis on escalating as there is on de-escalating, because unlike HR-positive and HER2-positive breast cancer, we haven’t had big successes in terms of our strategy. We’ve had incremental benefits, and there’s no question that patients with TNBC are doing better now than they were 10 to 20 years ago, but we still have a lot of challenges.

I would say that the escalating part is still very appropriate in TNBC, probably much more than the other clinical subsets. Within the escalating realm, there’s 2 prongs. One is taking existing drugs, cytotoxics, and applying them thoughtfully and augmenting outcomes with the addition of novel drugs between anthracyclines and taxanes. That’s where the platinum stories come in, that’s where the capecitabine and other strategies in residual disease come in.

The other prong is the promissory note of novel agents—non-cytotoxic drugs—in TNBC, which is much earlier in development. It's still in the metastatic realm of testing, but of course those immune checkpoint inhibitors look promising in TNBC, and other targeted therapies for subsets within TNBC, like androgen receptor targeting.

What message would you want community oncologists to take away from this?

Part of our problem is that TNBC is an unhelpful category, because it’s so molecularly heterogeneous that to call something TNBC doesn’t help us very much, outside of using dumb drugs, like chemotherapy. It doesn’t help us with precision medicine initiatives, so part of what we need to do is to take TNBC and break it into its biologically relevant subsets and test those. That is all happening in the stage IV setting at the moment. It’s not yet happening in the early breast cancer setting, nor should it, because it’s not ready for that. But these things tend to happen quickly. I think there are 2 messages to drive home in TNBC. It is possible to de-escalate systemic therapy for a few patients, but not many. You can certainly de-escalate surgery, which is very useful for our patients. I think that the emerging evidence around the importance of immune activation in and around the tumor and how the cancer behaves is very tractable and will be a big future push. That will be a topic for future [breast cancer] meetings, without question. Additional chemotherapy thoughtfully applied is appropriate and can help patients. But, thoughtfully applied is the key element here. Clinical utility has to be proven, at least with modest strength.