AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida

Ovarian cancer patients with BRCA mutations show improved survival

Kelly Bolton (National Cancer Institute, Maryland, USA)

Kelly Bolton, you’ve been conducting a study to look at BRCA1 and 2, well known breast cancer susceptibility genes, in their implications for ovarian cancer. What is it you were looking at and why?

We’ve known that BRCA1 and 2 mutations, as you said, are important risk factors for both breast and ovarian cancer and there have been some suggestions in literature that survival between BRCA1 and BRCA2 carriers that have ovarian cancer may be different. But a lot of these studies were limited both because of methodological issues and also because of sample sizes.

What about the differences in survival between BRCA1 and 2 carriers and patients who don’t have that mutation?

Those studies, as I said, they have been conducted and there is some suggestion that carriers have an improved survival relative to non-carriers. But our goal was to perform a large multi-centre study so that we could assess this in a well-powered manner and also that we could directly compare the survival of BRCA1 and BRCA2 carriers which has been something that previous studies, which have mostly been smaller studies, haven’t been able to assess.

Could you describe the study to me then?

Yes, we collected data from about twenty studies that were centred across the world, we had about 3,500 ovarian cancer patients both with and without mutations in BRCA1 and BRCA2 and we compared their survival, both for the carriers compared to the non-carriers but also BRCA1 to BRCA2 carriers.

And there’s quite a difference, isn’t there?

Yes, we found that both BRCA1 and BRCA2 carriers had a significantly improved survival relative to non-carriers and interestingly we found that BRCA2 carriers appeared to have a better survival than BRCA1 carriers and that was significant.

What might be going on because this gene is in fact associated with a risk for ovarian cancer so how can it be giving protection?

No-one is actually certain as to the mechanism that drives this but there is suggestion from in vitro work in animals and also from retrospective clinical studies that BRCA1 and BRCA2 carriers actually might have an improved response to platinum based chemotherapy. So the mechanism is that BRCA1 dysfunction or BRCA2 dysfunction causes problems in repairing DNA damage and in particular this certain type called double stranded DNA damage. Platinum based therapies cause double stranded DNA damage so if you have this defect in this repair pathway your tumour is more susceptible to damage with a platinum based agent. So that’s the thought but we don’t know if that’s driving our survival improvement but that’s what we’re hypothesising.

So, in other words, patients who get properly treated with the right chemotherapy may benefit more from that chemotherapy?

They might, yes, but we need to assess this in a large scale randomised trial, that would be the next step.

Here at the meeting in Orlando, we’ve been hearing a lot about looking for the right targets and getting drugs which act at those particular targets. There was a word about PARP inhibition in this context wasn’t there? What do you make of that?

PARP inhibitors are targeted for patients that have BRCA dysfunction, in particular people that have germline mutations in BRCA1 or BRCA2. For our study it suggests that it would be interesting for these clinical trials to look at BRCA1 and BRCA2 carriers separately, like it’s two separate groups, because we’ve shown that they do have different survival patterns.

What then, finally, are the clinical implications?

We don’t have any immediate clinical implications for our results but, as I said, they could be important for clinical trial design, both for PARP inhibitors and for just agents that don’t target BRCA carriers. They also could be used for clinical predication so they could be incorporated into other studies that are developing models for clinical prediction of ovarian cancer survival.

Now this is a massive study between the NCI and Cambridge University, what’s the next step in exploring the genetics of ovarian cancer and why do you think doctors all over the world should be interested in this sort of work?

In terms of the genetics of ovarian cancer survival, especially for our study, for BRCA mutations and survival, the next step would be to do randomised clinical trials and to possibly separate BRCA1 and BRCA2 carriers in these trials to see if they have similar responses to therapy. In a broader sense both we and others are looking at other genetic risk factors that could also influence ovarian cancer survival and that will be coming up in the next few years.

Well, thank you very much for joining us here on ecancer.tv.

Thanks.