Kathy D. Miller, MD; Andrew N. J. Tutt, MBChB, PhD


December 22, 2014

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Teasing Out Effective Agents in Triple-Negative Disease

Kathy D. Miller, MD: I'm Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights, from the 2014 San Antonio Breast Cancer Symposium. Triple-negative breast cancer is a therapeutic challenge, one that has received increasing attention over the past several years. With some early studies, enthusiasm has increased for platinum compounds and poly (ADP ribose) polymerase (PARP) inhibitors.

Joining me to discuss these data and this important area of research is Dr Andrew Tutt, professor of oncology at the Institute of Cancer Research, and consultant clinical oncologist at Guy's and St. Thomas' Hospital in the National Health Service Foundation Trust in London. Welcome, Andy. Tell us first the background biology. Why the interest in platinums and PARP inhibitors in this subgroup of our patients?

Andrew N.J. Tutt, MBChB, PhD: Triple-negative breast cancer is a heterogeneous disease, but there has been this long-noted association between subgroups of triple-negative breast cancer and the BRCA1 mutation carrier phenotype, and also the knowledge that other ways in which the BRCA pathway can be dysregulated—for instance, methylation of the BRCA1 promoter that leads to tumors that have this estrogen, progesterone, and HER2-receptor-negative phenotype. Both in terms of targeting germline mutation carriers with triple-negative disease and in seeking those who might have a BRCAness phenotype, people have been interested in platinums because they require the BRCA pathway for their repair.

Dr Miller: We have had some tantalizing, early neoadjuvant studies that found a real but rather modest improvement in pathologic complete response.[1,2,3] We have only had small, single-arm trials of platinums in the metastatic setting,[4,5,6] but with that biology and enthusiasm—at least in my practice—I have seen many more patients coming to me in the metastatic setting having received a platinum or a platinum combination very early in their course, often as their first line of chemotherapy. That led to a clinical trial,[1] which you reported at this meeting.

TNT: Platinums Are Silver Lining for BRCA Carriers

Dr Tutt: We reported on behalf of the Triple Negative Breast Cancer Trial (TNT) investigators, a randomized controlled phase 3 trial[7] testing platinum-based treatment, six cycles of carboplatin at the full AUC6 [area under the curve 6 mg/mL x min], against a standard of care in first-line therapy, the licensed dose of docetaxel. We recognized that this was a heterogeneous population, so we particularly wanted to have prespecified subgroup analyses for these distinct populations in whom we believed there might be the particular DNA repair defect, namely those with germline mutations in BRCA1 and BRCA2 and those with basal-like phenotypes, whether that be by immunohistochemical analysis or by PAM50 intrinsic subtyping. We tried to get comparative data in a large number of patients about the activity of a platinum salt in comparison with a standard of care, because those data do not currently exist.

Dr Miller: How large a trial are we talking about?

Dr Tutt: We had 376 patients, 29 of whom were recruited as BRCA1/2 mutation carriers. Patients could enter the study with triple-negative breast cancer but also as BRCA mutation carriers with other phenotypes of the disease—with ER-positive disease, for instance. Of those 29 patients with BRCA mutations, 13 were not triple-negative; they had ER-positive, HER2-negative disease.

Dr Miller: In this entire population, was there any benefit to platinum or docetaxel as the first therapy? Did it matter?

Dr Tutt: It didn't matter. The two drugs had similar performance. The trial was designed as a superiority trial, so the hypothesis was that carboplatin might have a 15% greater objective response after three or six cycles than docetaxel. And that was not the case. It was not superior to docetaxel. The actual performance estimates were very similar at approximately 35% in both arms. In the crossover experience, because you could cross over at progression, the performance of the two drugs was also similar in that setting and in the overall unselected populations.

The Critical BRCA Carrier Subgroup

Dr Miller: You mentioned some important subsets that you were interested in. You recruited 29 patients who were known BRCA carriers. Do you know how many other BRCA carriers might have been hidden in that group whose status wasn't known when they entered the trial?

Dr Tutt: We had asked whether patients would consent to have research testing for BRCA1 and BRCA2 in the study. We were able to test all samples in two independent laboratories—the Institute of Cancer Research and at Myriad Genetics—and no discrepancies were found in the results. That led us to have a population of 43 patients in total, including those 29 entered as BRCA mutation carriers, as the BRCA mutation-positive cohort for our preplanned subgroup analysis.

Dr Miller: That is a much smaller subgroup, so your ability to see differences is hampered, but that is also the group in whom this initial enthusiasm for platinum started. In the known BRCA mutation carriers, were there still no differences or did things start to change?

Dr Tutt: Things started to change, so in a prespecified analysis we found that the objective response rate to carboplatin was 68%, and to docetaxel it was slightly more than 30%, so there was more than twice the response activity for carboplatin over docetaxel. We were able to look in the wild-type population of this study with the BRCA mutation carriers removed, and to look at the performance of the drugs in a wild-type population, where they were similar. The testing interaction was positive. There is clear evidence that carboplatin is the more active agent in those with a BRCA1 or BRCA2 mutation.

Dr Miller: Let me break this down for myself and for the folks who are trying to figure out what to do in their clinics on Monday morning. If I have somebody I know is a mutation carrier, she is probably better served by a platinum regimen as her first therapy. If she's not known to be a carrier, then activity is similar, and we can individualize those treatment choices on the basis of potential toxicities, costs, and other patient factors.

Dr Tutt: Certainly the former. The evidence that a platinum is a more active drug for someone who has a mutation from this study at least seems clear, and it is consistent with high levels of activity for platinums in uncontrolled trials, as you described earlier. That is an option that ought to be available to discuss with a patient. It is a highly active option and probably more active than the alternatives. For the corollary—the non-mutation carrier—the standard of care is a taxane in that setting. I don't think our trial suggests that one should move away from those standards of care. Platinum has not shown to be the superior choice for people with triple-negative breast cancer in the absence of a mutation.

Choice of Platinums Depends on Mutation Status

Dr Miller: You just threw a big, old, wet blanket on the enthusiasm for the platinums, and we have two studies in the neoadjuvant setting that found small improvements in pathologic complete response.[8,9] In those cases, it was the addition of a platinum, rather than substituting a platinum one for the other, but where do we go in this area from here?

Dr Tutt: That is an important point, and I hope it's not throwing a wet blanket so much as confirming the fact that we are probably being oversimplistic about this disease as an entity. Being triple-negative and not being something else doesn't lead us to have a clear group of patients. To select a platinum for that diffuse group of patients, without knowledge of a BRCA mutation, isn't a sensible way forward. Our study says that one should carefully think about the age of the patient and the family history, and try to gain information about whether that patient has an underlying germline mutation in BRCA1 or BRCA2. If the patient does not have that, then this study says that enthusiasm for a platinum may not be well founded, and we need to work harder to find within that population those who will benefit from one drug or another. We haven't done that yet for the platinums.

In the neoadjuvant setting, clearly there is evidence of some additional activity when you add a platinum to established treatment,[8,9] but you also add toxicity. Although I suspect that it is probably driven by a mutation carrier population within those trials, I don't think we fully understand how that has been balanced between the arms of certain studies, and we need to study that better before we draw very firm conclusions about the role of platinums in neoadjuvant therapy across the whole disease.

An Assay for BRCAness?

Dr Miller: I want to ask you about some of the efforts to identify who those patients are who might benefit and who does not have the germline BRCA mutation. There has been a lot of talk over the years about a BRCAness. It has a similar phenotype and maybe a similar homologous recombination defect (HRD), just not driven by a germline mutation. A lot of work has been done trying to figure out whether we could develop an assay to identify who those patients might be. Are we there yet?

Dr Tutt: I don't think we are there yet. Our study seeks evidence of this population using a measure, a genome landscape scar of abnormal DNA repair. This was an HRD assay looking across the whole genome for a scar of recombination deficiency. It is clear that those scars from a number of data sources are able to detect people who have mutations, a hard-wired form of HRD. But when you ask the question in advanced breast cancer, analyzing the primary tumor DNA, does that kind of scar specifically pull out the patient who benefits more from a platinum than a taxane? A HRD scar does not seem to perform well in doing that in the way that a mutation performed well in identifying that, and that means that this is a work in progress. There are some potential explanations why in advanced disease that kind of biomarker might have challenges that are different from early disease, and we need to look at this biomarker separately in those two settings.

Dr Miller: Once again, a simple explanation that sounded lovely and elegant but just didn't match in reality in this complicated subset.

Dr Tutt: That's right. It's a valuable way of looking for abnormal DNA repair, for a recombination defect—a scar of the way that tumor has evolved, what repair mechanisms have functioned or not functioned in this case over its evolution. I think it is going to help us understand those cancers that, at some point, had a recombination defect. That may be enough in early disease, because it is treatment naive. In later disease, which has been selected against DNA damage in chemotherapy, it would seem to require a more complex biomarker that perhaps takes into account the fact that cancers can regain the ability to do recombination repair. We know that some of the ways of getting recombination deficiency are hard-wired mutations, but some are plastic—methylation, or epigenetic changes in BRCA1 or BRCA2. Those may be quite easily turned back on again, and so the cancer that looks like it's deficient in DNA repair, because of the scars it bears of its past life, could have reformed and changed. Those HRD tests are perhaps too simple in the advanced disease setting.

Dr Miller: So your chest x-ray might show that you are a smoker, but you quit 5 years ago and your chest x-ray can't tell you that.

Dr Tutt: Exactly; that kind of thing.

OlympiA to Examine PARP Inhibition

Dr Miller: In our last minute, I want to take you to the world of PARP inhibitors, another area where your research engendered early enthusiasm and has continued to help us understand. Can you make sure that our entire audience knows about a very important trial, the OlympiA trial?[10]

Dr Tutt: Thank you for that opportunity. Yes, PARP inhibition does target recombination deficiency. The focus at the moment in PARP inhibitor trials in breast cancer has been more hardcore proof-of-concept in patients who have mutations in BRCA1 and BRCA2. That is where the strongest signal comes, where we can be more confident that this is an appropriate intervention to test.

The OlympiA trial is recognizing that perhaps treating at the earliest point, but in the highest-risk situations, may get us the best ability to change the outcomes for these patients before resistance mechanisms might have kicked in.

OlympiA selects patients who have residual disease at the end of neoadjuvant chemotherapy in triple-negative breast cancer, but where they also have a BRCA mutation. It randomly assigned patients to placebo or exposure to olaparib for a year. The alternative route into the study is those who have had primary surgery and adjuvant chemotherapy, and where their cancer was a high-risk, triple-negative breast cancer with tumors that are > 2 cm in size or node-positive. The randomization is between placebo or a year of olaparib exposure. We will be testing for survival outcome in measures throughout the trial.

Dr Miller: It is a very important trial. I know that there are metastatic trials going on with the PARP inhibitors also focused on the mutation carriers, but OlympiA is one of the first, and perhaps most important, to try to move this treatment earlier into the course of the disease.

Thank you, Andy, for joining us and going over this evolving area. And to our audience, thank you for joining us in this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from the San Antonio Symposium in 2014.


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