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BOLERO-2: Exciting Results for ER-positive Breast Cancer

Nov 07, 2011

Numerous superlative studies were presented at the recent 2011 European Multidisciplinary Cancer Congress; however, significant attention has been paid to the phase III BOLERO-2 study, in which 724 women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer were randomly assigned to receive exemestane/placebo or exemestane/everolimus. Principal investigator José Baselga, MD, of Massachusetts General Hospital and Harvard Medical School, discussed the highly positive results and his work in experimental therapeutics with ASCO Connection.

AC: What was the basis behind the BOLERO-2 study, and what were your results?
 “What we observed, and the basis for all the buzz, was a dramatic improvement in progression-free survival in the experimental arm.”
-José Baselga, MD

Dr. Baselga:
We had some data that one of the mechanisms of resistance to anti-estrogen therapy in breast cancer was the activation of the mTOR pathway. The estrogen receptor can be activated by ligand binding, or you can have additional pathways of activation which are non-ligand-dependent. We had a lot of clinical evidence that mTOR activation would be responsible for resistance and we did a number of studies that seemed to confirm that with mTOR inhibitors.

Then we launched the BOLERO-2 study, a phase III study of patients who are ER-positive who had been treated in the past and progressed on a non-steroidal aromatase inhibitor, either letrozole or anastrozole. Those patients received either exemestane (another aromatase inhibitor) plus placebo or exemestane plus the mTOR inhibitor everolimus. The primary study endpoint was progression-free survival. What we observed, and the basis for all the buzz, was a dramatic improvement in progression-free survival in the experimental arm. The patients on the exemestane arm had a progression-free survival per investigator of 2.8 months, and in the combination arm it went up to 6.9 months (which gives us a hazard ration of 0.43 and a p-value less than 0.0001). When we look at the central review, which was confirmatory, the progression-free survival for the exemestane arm was 4.1 months and 10.6 months for the exemestane/everolimus arm (a hazard ratio of 0.36).

This is a very positive result in a patient population that didn’t respond to one AI. To me, it’s proof that the mTOR pathway does interfere with response to anti-estrogen therapy, which is fascinating. I could see a number of ways that we could make these results even better, and this combination could become a new standard of care in this patient population.

AC: Were you and your team surprised by the strength of your findings?
Dr. Baselga:
Yes. I was convinced that we would have a difference in favor of everolimus—everything was pointing in that direction—but the magnitude of that effect was surprising. The gasps at the presentation came from the strength of the data and the size of the benefit.

AC: How did you become interested in breast cancer?
Dr. Baselga:
During my fellowship I worked under past ASCO President Larry Norton, one of the world’s experts in breast cancer. My interest has always been in experimental therapeutics, and breast cancer became a very important area for this. I was involved in the early days of trastuzumab, back to 1990. The beauty of breast cancer, from the point of view of science, is that we’ve mapped out a lot of the signaling pathways involved in tumor progression. It’s a very fertile soil for looking for new therapies.

AC: What are you currently working on?
Dr. Baselga:
I’m going to be presenting results from the CLEOPATRA trial at San Antonio, which examined pertuzumab and trastuzumab in HER-positive breast cancer. Pertuzumab and trastuzumab are anti-HER2 antibodies, and when given together, we observed a very high response rate in patients with advanced HER2 positive breast cancer refractory to trastuzumab. The next thing we did was a huge phase III randomized trial in the first-line setting: the CLEOPATRA study.

I’m also working on the whole set of new inhibitors of the PI3 kinase pathway, which is where the mTOR pathway is (mTOR is downstream), and we have a new set of very promising compounds that hit the PI3K. I’m leading some of these phase I studies and we’ve seen some responses, which is very exciting. I’m also working on the mechanisms of resistance to these therapies, both HER2 and PI3 kinase.

I’ve been at Massachusetts General Hospital for a year, and we are building a new state-of-the-art facility for experimental therapeutics. Our dream is to consolidate our hospital as the place to do these new trials. We are working on clinical trials that have an interactive design—we are giving therapies, then we do biopsies to see what genes are being turned on or off, and based on that information, we decide what to do next. We are entering a new era of clinical trial designs. As part of our routine medical care we can genotype tumors, and that information is in the patient’s chart. We have about 60 clinical trials going, many of them first in human and for genotype-specific tumors. We’re making an effort to bring, whenever we can, personalized medicine to clinical trial development.
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