The early promise of treating triple-negative and basal-cell breast cancers with poly (ADP-ribose) polymerase (PARP) inhibitors is yet to be realized, according to Lisa A. Carey, MD, who will be delivering a presentation on treatment options for these patients at the Miami Breast Cancer Conference this week.
Carey, an Associate Professor of Medicine and Medical Director of the UNC Breast Center Lineberger Cancer Center at the University of North Carolina, spoke with cancernetwork.com from her office in Chapel Hill, and shared her thoughts on the challenges of treating triple-negative and basal-cell breast cancers.
“The first thing we have to recognize is that triple-negative and basal-like breast cancers aren't the same thing. 'Triple negative' is really a term of convenience, meaning patients who do not have a hormone receptors or HER2 expression in their tumor. The basal-like molecular subtype of breast cancer makes up the majority, but not all of them. So, we do have to recognize that we use 'triple negative' as kind of a surrogate for the biology of basal-like breast cancer. We're always misclassifying some of these tumors in ways that might, in the future, become quite important.
“That said, regardless of how you examine these tumors, triple negative or basal-like, there are clearly prognostically different sub-groups within them. The easiest way to sort that out is to look at simple clinical variables. We know that a small node, triple-negative breast cancer has a far better prognosis than a much larger nodally-involved tumor. So there are things beyond just the triple-negative status that are very important in establishing prognosis.”
Dr. Carey will also be providing her audience with an overview on the current state of PARP inhibitors.
“The studies on PARP inhibitors have kind of fallen into two categories. There are a number of PARP inhibitor studies that have included BRCA mutation carriers, so BRCA1 or BRCA2 mutation carriers—women who have a familial form. In fact, these studies with drugs like Olaparib (AstraZeneca) or Veliparib (Abbot Laboratories), are small but they are fairly consistent in suggesting a role for these drugs—both of which are oral PARP inhibitors—in treating familial breast cancer and, for that matter, familial ovarian cancer, also; which fits really fits very strongly with the pre-clinical rationale for how these drugs work.
“So, people who have an inherited aberrancy in their DNA damage-response pathways should be sensitive to drugs that kind of kick out the other leg that the DNA damage-response is standing on. Now, when we get to triple negative, it's become a much more complicated story.
“There have been a number of pre-clincial studies that suggested that basal-like breast cancer, that molecular subtype that makes up most triple negatives, has elements and characteristics that are very reminiscent of BRCA1-associated breast cancer. In fact, when BRCA1 mutation carriers—women who carry one of these abnormal genes from birth—get breast cancer, they almost always get basal-like breast cancer.
“Because of those shared characteristics, people thought that whatever worked in BRCA mutation carriers would be more likely to work in triple negative than in other kinds of breast cancer.
“There was a study using a drug called Iniparib (BiPar Sciences, Sanofi Aventis), which is an IV drug with PARP activity. It is not totally clear if its mechanism of action is through that activity or through something else. Regardless, it was certainly initially thought of as being a PARP inhibitor. There was a Phase II randomized study with Iniparib that was published in the New England Journal of Medicine (2011; 364: 205-214) a couple months ago that showed what appeared to be very strong activity augmenting outcomes in patients treated with chemotherapy if you added this Iniparib to the chemotherapy.
“That story got more complicated because of two things. The studies with both Olaparib and Veliparib that have been done in triple negatives that don't have a familial component are small but have not, so far, shown us a great way forward in terms of this being a very effective strategy. We don't really know because they are very small and immature and Olaparib has been pulled from breast cancer development, so we won't be seeing any more data any time soon. But, they were not the kind of exciting data that we'd seen in mutation carriers.
“Separately, there was a Phase III study, the registration study, for Iniparib—which used to be called BSI 201—really hard on the heels of publication of the Phase II study. The first report of the Phase III came out as a press release that suggested that even though progression-free survival and overall survival were substantially and significantly improved in the Phase II setting this was not the case in the Phase III setting—for reasons that are entirely unclear at this point.
“The data have not, themselves, been released. I think the company is planning to present it at ASCO; if so, I think we'll have more to work with. But as of right now, the Phase III—which is, of course, the definitive study—did not replicate the Phase II. So, the role of Iniparib at this point is unclear.”
She will also be sharing the next steps beyond PARP inhibitors for treatment.
“For awhile, we've been looking in the direction of PARP inhibitors because of some of this early and exciting data. I think we're back to the drawing board, a little bit, for all the options for treating these subtypes of breast cancer.
“With basal-like breast cancer, and if you look at most triple negatives, there's a lot of heterogeneity. There may be so much heterogeneity in these tumors that it may be difficult to come up with a uniform approach using one or even a couple of drugs.
“The antiangiogenic strategies have shown some benefit in this group. The bevacizumab (Avastin, Genetech) studies, if anything, have shown as much benefit, if not more, in this subset than anything else. EGFR (epidermal growth factor receptor) and other sorts of signaling pathway-directed studies have shown modest activity—not enough to take to the bank—but they show there is some role for targeting that particular pathway. And there are a number of people looking at things like PI3 kinase signaling pathway and things like that, which are the likely future treatment directions.
“In my opinion, chemo will remain a mainstay of the treatment of this subtype for a long time. The ability to target it further will likely depend on our being much more sophisticated in genomic studies about how to identify what the Achilles' heel of a particular tumor is before we decide on treatment.”