Every year several thousands of cancer researchers converge on south Texas for fajitas, margaritas, and the latest in breast cancer science (not necessarily in that order, though the fajitas and margaritas are outstanding). The San Antonio Breast Cancer Symposium is the world’s premier breast cancer meeting, and (along with the ASCO Annual Meeting) the place where important clinical trial data are most likely to be presented.
This year the buzz was all about the biologics. This has been a fascinating change from a decade ago, when the podium was still crowded with chemotherapy trials. Now one barely ever sees a chemotherapy question making it to an oral session: we’ve quite lost interest.
My bias was that the two top talks involved the BOLERO-2 and CLEOPATRA trials. Since these two trials tell us a great deal about where breast cancer is going, let’s spend some time on each.
BOLERO-2 was first presented a few months ago at a European meeting, so this represented an update, though it was the first time many of us had seen the data. BOLERO-2 addressed the issue of resistance to aromatase inhibitor therapy in ER-positive metastatic breast cancer. If you think about treatments for ER-positive breast cancer in recent decades, most of the attacks have involved the estrogen receptor itself. Whether we were speaking of fulvestrant, or aromatase inhibitors, or SERMs or steroid hormones, the target was always the estrogen receptor.
BOLERO-2 involved the combination of the aromatase inhibitor exemestane with the mTOR (molecular target of rapamycin) inhibitor everolimus in a population of patients who had previously received a nonsteroidal AI. Patients receiving the combination remained progression-free an average 4.1 months longer than patients receiving exemestane alone. Overall survival data are insufficiently mature: more on this down the road.
CLEOPATRA looked at patients with front-line HER2-positive metastatic breast cancer, a population essentially trapped in amber since 1998. Patients were randomized to receive docetaxel and trastuzumab either with or without pertuzumab. Pertuzumab represents what might be considered a “horizontal” attack as opposed to the “vertical” attack of an mTOR inhibitor, in that it prevents dimerization of HER2 to other HER receptors at the cell surface.
Pertuzumab is somewhat of a dud as a single agent in HER2-positive patients who have received prior trastuzumab. But combine it with trastuzumab, as occurred in CLEOPATRA and in the earlier TAMRAD randomized Phase II trial, and it looks very potent indeed. In CLEOPATRA median progression-free survival was improved by over 6 months. While overall survival has not yet passed the O’Brien-Fleming statistical boundaries, a first peak at the data suggests we will soon see the first improvement in overall survival in front-line HER2-positive metastatic disease with a new agent.
Neither everolimus nor pertuzumab cures metastatic breast cancer. But it is reasonable to ask what will happen when these agents are moved up front into the adjuvant setting. Adjuvant trials are ongoing, and the early neoadjuvant data with pertuzumab looks promising. HER2-positive disease is likely to be a very different creature within the next few years. We may be close to the magical 90% long-term distant disease-free survival point, where the trials become prohibitively large and the advances increasingly small. A good problem to have, and I hope we have it soon.
The other big story from San Antonio involved adjuvant bisphosphonates. There were four randomized adjuvant bisphosphonate trials presented, and depending on your frame of mind you could be delighted or depressed or (like me) just plain confused. The ABCSG12 trial in younger women continues to show a disease-free survival benefit for zoledronic acid, as well as a small but statistically significant overall survival advantage. A German trial (GAIN) with adjuvant ibandronate was flat-out negative. The NSABP’s adjuvant clodronate trial (B-34) had a negative primary endpoint for disease-free survival, but a positive subset in postmenopausal women. The ZO-FAST trial randomized patients to initial or delayed zoledronic acid (based on a bone mineral density endpoint) and (in an exploratory subgroup analysis in postmenopausal women) showed reductions in bone metastasis rates and improved survival.
How much these positive subset analyses represent biologic reality, and how much the ability of researchers to waterboard data until it confesses, is unclear to me. I await the peer-reviewed publication of these very interesting studies, though I did speak to colleagues who considered the postmenopausal theme a compelling one. It will also be interesting to see how the regulatory agencies will view the adjuvant bisphosphonate question. I’m sure we’ll hear more about these issues in coming months.
And by the way, is there any particular reason why American cooperative oncology group trials have to be so boringly named? B-34 or BOLERO: which has a zippier sound to it? Which one is more memorable? Not to mention CLEOPATRA. Do we have to be so excruciatingly banal?