Kathy D. Miller, MD; Hope Rugo, MD


December 20, 2013

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Kathy D. Miller, MD: Hi. I'm Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2013 San Antonio Breast Cancer Symposium. Today we are going to look at the role of platinum agents in triple-negative breast cancer (TNBC). Joining me for this discussion is Dr. Hope Rugo, Professor of Medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. Welcome, Hope.

Hope Rugo, MD: Thank you.

Why Platinum for Triple-Negative Disease?

Dr. Miller: Let's go back to the beginning. Remind us where the interest in platinum for the treatment of TNBC came from. Ten years ago, these drugs were not thought about outside of the HER2-positive population.

Dr. Rugo: My interest in treating triple-negative disease with DNA-damaging agents such as platinum came from just casting about for another drug with a leukemia background -- trying a different drug and having patients respond. More than a decade ago, I remember being very impressed with the fact that these patients with very bad disease would respond to a platinum combination but to nothing else. Then they would relapse and die of their disease. Of course, the science behind that came along, and it has been intriguing to see that story develop for all of us.

It came from the idea that patients with BRCA1 mutations were more likely to have triple-negative cancer and BRCA codes for the DNA repair gene. Perhaps if you damage the DNA, the cancer cell wouldn't be able to recover and you could get a better antitumor affect. That led to an interest in poly ADP-ribose polymerase (PARP) inhibitors as another arm of the DNA repair mechanism -- the 2 big arms being BRCA and homologous recombination. There was great interest in the PARP inhibitors, and then the idea came along that if you combined both arms, you would kill cancer cells. It is a very simplistic way of looking at a very complicated process.

Dr. Miller: It did seem simplistic to me. If you have a BRCA mutation, you don’t repair DNA very well, so a DNA-damaging agent ought to work. The big leap to me seemed to be the assumption that because this is the type of cancer that patients with BRCA mutations tend to get, sporadic cancers that just happen to look similar under a pretty crude microscope must have the same response. That seems to me like a big leap of faith.

Dr. Rugo: We thought that maybe we could pick out specific treatments for BRCA-positive disease but not for sporadic triple-negative disease. But we started testing platinum compounds in triple-negative disease before we knew the information that supported their use, which was the fact that there are acquired defects in DNA repair occurring in these triple-negative sporadic cancers. We also knew that if you do expression phenotyping and look at gene arrays, you can't tell the difference between a BRCA-associated cancer and a sporadic triple-negative cancer. They both look basal-like. So if that has anything to do with response to treatment, it seems as though one might be able to use a similar strategy.

We were waylaid en route with the iniparib experience,[1] but iniparib is now understood not to inhibit PARP in the concentrations and schedule that we were using it in, but it didn't diminish the excitement about the carboplatin. That regime seemed to work well -- the gemcitabine-with-carboplatin combination. Then the idea was to test it in earlier-stage breast cancer and see whether we can show a better response.


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