Benefits of Additional Chemo in Residual Breast Cancer

Kathy D. Miller, MD: Hi. I'm Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana.

We have all recognized that our patients who receive neoadjuvant therapy and have residual disease at the time of surgery have a high risk for recurrence. This is a group that could teach us a lot about drug resistance, and where novel therapies might have a role.

To give us a perspective on this really important area is a friend and colleague, Dr Bryan Schneider, who is associate professor of medicine and Vera Bradley Investigator at the Indiana University School of Medicine. He is also the director of the Indiana University Health Precision Genomics Program. Welcome, Bryan.

Bryan P. Schneider, MD: Thanks for having me, Kathy.

What Can Patients With Residual Disease Teach Us?

Dr Miller: Let's think first about what we could learn about biology and drug resistance in this group. There have been several studies that have looked at patients who have residual disease and have sequenced their tumors to try to understand why our best therapies didn't work. What have we learned about drug resistance from these patients?

Dr Schneider: Most of the work to date has been in patients with triple-negative breast cancer because, on the basis of ongoing work from a variety of groups, this is the population in which if patients get a pathologic complete response, they do quite well—whereas those who don't get a pathologic complete response do really poorly.

So what is that group [that does poorly], and what do they look like at the genomic level? There is really interesting work from Vanderbilt University that has shown that there are probably multiple distinct subgroups or populations, suggesting there may not be one unified way to attack them.^[1] Also, interesting work from Radovich and colleagues^[2] has shown that immune depletion seems to be really important for this group that has a lot of residual disease.

Dr Miller: How can we use that? Because the clinician in my brain just had a sinking feeling when you said there were a lot of different mutations and a lot of different problems, and one therapy is not likely to be helpful. Immune therapy sounded very appealing in this high-risk, triple-negative group. But if they have such immune depletion, it makes me wonder whether that is going to be useful in this area.

Dr Schneider: That brings up a couple of very good points—one of which is that the heterogeneity suggests, in part, why standard chemotherapy may not be the silver bullet for this group. It may allow us, using new high-throughput genomic technology, to try to identify the different subgroups, and potentially drugs for these subgroups.

The question of immunity is a great one. Does this imply that the immune system simply is going to be unhelpful here and the use of such drugs as checkpoint inhibitors won't be the way forward? Or does it imply that we really need to try to institute or invigorate an immune-based response to get maximal benefit for this population? It's hard to know at this point.

Dr Miller: I can bet that is going to be studied fairly soon, given the enthusiasm for immunology and the success of the checkpoint inhibitors in early trials in patients who have already crossed over that metastatic line.^[3,4,5]

Dr Schneider: I think it's fair to say that this will be a very vigorous area of investigation, and I think the real question moving forward will be: Even if successful, is it the whole population or just a subgroup of patients who will benefit from trying to invigorate the immune system?

CREATE-X Trial: Benefit of Capecitabine in Residual Disease?

Dr Miller: I want to ask you about a study that I think caught many of us by surprise at this meeting. Many of us have assumed that we would not do better in these patients by just adding more unselected, untargeted chemotherapy. To be fair, we have tried that in the neoadjuvant setting.^[6,7] We have tried that in the adjuvant setting, with several studies in particular that have looked at capecitabine or gemcitabine in addition to anthracycline and taxane-based therapies.^[8,9]

A lot of the work in post-neoadjuvant patients has looked at more targeted therapies or immune therapies.^[10,11] And then we heard about the Capecitabine for Residual Cancer As Adjuvant Therapy (CREATE)-X trial.^[12] Tell our audience about this important study.

Dr Schneider: In complete converse nature to what I just told you, this was a really cool study looking at a standard chemotherapy that we commonly use in metastatic breast cancer: capecitabine (Xeloda®). This was a randomized, phase 3 trial for patients who were human epidermal growth factor receptor 2 (HER2)-negative and, indeed, had residual disease after chemotherapy.

There was a fairly marked improvement in disease-free survival, from about 74% to 82%, and about a 5% improvement in overall survival for those patients who received capecitabine.

The patients were randomly assigned to receive about eight cycles of the standard, US Food and Drug Administration (FDA)-approved dosing of capecitabine vs the standard approach. What the investigators found was fascinating: There was a fairly marked improvement in disease-free survival, from about 74% to 82%, and about a 5% improvement in overall survival for those patients who received capecitabine. This really calls into question: Why did this happen when in the past, our attempts to do this in the neoadjuvant setting and adjuvant setting failed?

Dr Miller: And there were two full adjuvant trials with capecitabine that did not find an improvement.^[8,13]

Dr Schneider: Indeed. One wonders whether this is statistical enrichment because you have got a population here that is markedly more likely to relapse. Or, is there something biologically interesting that capecitabine somehow targets?

Dr Miller: On the biological front, there are a couple of potential hypotheses, now that I have had a day to think about these data. In the early days of capecitabine development, there were some studies suggesting that, in particular, the taxanes might result in upregulation, which would increase conversion of capecitabine to the active 5-fluorouracil. In the CREATE-X study, 85% or more of the patients received an anthracycline and a taxane in some way, so perhaps that selection was important.

Dr Schneider: Yes, maybe the investigators did something nice ahead of time to actually sensitize these tumors to capecitabine. But as you mentioned, about 90%-95% of the patients received the standard anthracycline and taxane-based backbone, so this was a population who received real neoadjuvant chemotherapy as we know it.

Are We Ready to Apply the CREATE-X Results to Practice?

Dr Miller: You have a clinical practice. You will be heading home this weekend, and because I know your clinic schedule, I know you will be in clinic on Monday morning, where you might run into such a patient. Are you ready to use these data when you see a patient in this setting?

Dr Schneider: This is a very tough question. I think it is a provocative clinical trial that provides real evidence of potential benefit for a population who does poorly, in general.

In this trial, about two thirds of the population were actually estrogen receptor-positive (ER+). If you look at this subgroup, the hazard ratio suggested about a 15% improvement for the addition of capecitabine. We also had good hormonal therapy for this population, so I don't think I am compelled to consider doing additional capecitabine for patients that fall into this ER+ subgroup.

For those patients with triple-negative breast cancer, these are provocative data, and I think they warrant the discussion of the risks and benefits with almost a 40-plus percent improvement in the hazard ratio for the overall outcome.

Dr Miller: We should talk a little bit about the negative things that come with any additional chemotherapy. There are toxicities that come with this chemotherapy, although it is encouraging for this population that I didn't see toxicities that looked unusual or more than what you would expect.

Dr Schneider: No. These are the standard side effects one sees with capecitabine, especially at the doses they used, which was the dose in the FDA-approved package insert. These patients received almost a half-year of therapy, so you see the standard diarrhea, hand/foot syndrome, and neutropenia, which are things that those of us who treat breast cancer are well aware of. About one quarter of the population didn't finish therapy. The other three quarters did.

I do agree that it does require a really careful discussion of risk-to-benefit ratio. There are good data to suggest that the degree of nonpathologic complete response may also be important. Clearly for those patients with maybe a few millimeters of disease who have really struggled from their neoadjuvant therapy, I am maybe less inclined to push them, whereas for those with heavy nodal burden where the risk for distant relapse is high, I think the discussion will be more in a positive tone.

Postsurgical Radiation, or More Chemotherapy?

Dr Miller: Now the other thing that we would have to consider is that many of those patients will need and would benefit from postsurgical radiation therapy. In a younger patient who did quite well with her neoadjuvant therapy, but still has a lot of triple-negative disease remaining where you might want to discuss these data with her, what comes first? Radiation, or more chemotherapy?

My bias is that radiation should come first, with consideration of chemotherapy down the road.

Dr Schneider: I think the data for post-therapy radiation are compelling, and in particular post-mastectomy radiation therapy has a clear survival benefit.^[14] My bias is that radiation should come first, with consideration of chemotherapy down the road.

Dr Miller: To be fair, that is not a question that the CREATE-X trial was able to investigate, but it is one that our listeners are going to have to consider as they think about how these data might affect their patients.

Dr Schneider: Absolutely.

Dr Miller: I want to take you to the land of precision genomics for a moment, because that is another passion of yours. Given what we learned from the sequencing of these tumors, and given that many of our listeners may have patients whose tumors were sequenced, if they identify a mitogen-activated protein (MAP) kinase abnormality or phosphoinositide (PI)-3 kinase abnormality—which are among the more common ones—is that something we are ready to use in our practices?

Dr Schneider: I think the answer is absolutely no. In the curative setting, one has to be very careful about using agents that don't have very good safety and efficacy data. At the end of the day, we can end up hurting patients more than helping them by extrapolating this far from standard practice.

Dr Miller: This is another very fruitful area of research, so we will have you back to talk about when we are ready to make that leap. In the meantime, maybe we are not done with chemotherapy in this population. I think many of us had thought that there was no more to be gained with chemotherapy.

Dr Schneider: These are certainly provocative questions.

Dr Miller: Thank you for joining us, and thank you to our audience for joining us here at the 2016 San Antonio Breast Cancer Symposium.

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