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Carey Explains the Challenges of Treatment De-Escalation in TNBC

Shannon Connelly
Published Online:9:10 AM, Wed August 9, 2017

Lisa Carey, MD
Escalating treatments when necessary can be easy, but de-escalating treatments where they are not needed is where it becomes a little bit tougher. Due to the lack of non-chemotherapy options in triple-negative breast cancer (TNBC), this cancer type is one of the most challenging areas in which to de-escalate treatment. However, Lisa Carey, MD, says, there are ways it can be accomplished.

In an interview with Targeted Oncology, Carey, professor of medicine, University of North Carolina, discussed strategies that can be used to de-escalate treatment in patients with TNBC and the steps toward developing further strategies in this area.

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

Carey: One of the hardest places to [de-escalate treatment] is in TNBC, because we have fewer non-chemotherapy 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 non-randomized 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 1 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.

I have to say that the future here [also depends on] the effective development of biomarkers to help us strategize, as opposed to just clinical extensive disease. That includes immune biomarkers, like tumor infiltrating lymphocytes, and the incorporation of non-cytotoxic options, of which we really don't have any, but I think we are all very hopeful that we will in the near future.

TARGETED ONCOLOGY:  Are there any biomarker-based studies currently being done?

Carey: 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.

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

Carey: The history of breast cancer therapy has been 1 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.

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, or should it, because it's not ready for that. But these things tend to happen quickly. 

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

Carey: 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.

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