CDMRP Investigator Vignette

Premalignant Genetic and Epigenetic Alterations in Tubal Epithelium from Women with BRCA1 Mutations

Elizabeth Swisher, MD; University of Washington

I received from the DoD OCRP a Translational Research Award to study the fallopian tube in women who were known to be high risk for developing ovarian cancer but didn't necessarily yet have cancer and see if we could identify changes in the fallopian tube that were ultimately going to lead to cancer, sort of the earliest changes before we actually saw cancer arising.

Most women who present with ovarian cancer have advanced disease, and the mortality is very high. And it's not just a lack of screening; our screening is not effective so we don't pick up cancers early but also the biology of the disease is very aggressive and the window of time to identify it may be small. And we understand very little about how the cancer starts since most women already have an advanced cancer when they're diagnosed. So we don't know those early steps which are important if you want to try to catch it earlier or even prevent it.

We talk about translating research from the bench to the bedside but sometimes it works the other way. We make an observation clinically that then we test at the bench and ultimately bring back to the bedside. And that really was what happened here.

I was taking care of high risk women and they were undergoing preventive surgery. And usually when women present with ovarian cancer they have advanced surgery; the cancer is everywhere and you can't necessarily pinpoint exactly where it started.

But in these high risk women who had normal screening before they went through surgery sometimes we found an early cancer if we were careful to look at many sections for the pathology of it. And that very early cancer-sometimes less than a millimeter-was invariably in the fallopian tube and not the ovary. So we felt that-that provided potentially sort of the earliest window at looking at where a cancer could develop and that was a clinical observation that then we decided to test at the molecular level.

And at the time that was sort of breaking with the tradition of ovarian cancer. In fact, maybe ovarian cancer isn't really ovarian cancer. And other agencies-funding agencies thought that was sort of high risk. They don't want to fund an ovarian cancer project that's focusing on a different organ, the fallopian tube. Whereas the DoD was willing to take a risk with this idea that yes, you know if ovarian cancer is starting somewhere else that could change a lot of how we think about detecting it, preventing it; it would lead to a lot of new open pathways and even though that's sort of a high risk idea to follow they were willing to follow that path.

So we found that there were molecular alterations in the fallopian tube lining that mimicked the cancers that women were getting but smaller changes than you see in the actual cancers. And that gives us this idea of which are the early changes that are happening because we're just looking at a fewer changes which may allow us to target those changes for prevention or identify them as risks that they will go onto get cancer and then use targeted prevention for those women.

Since we have more confirmation that the fallopian tube is the origin of many of these cancers we're looking at new methods of screening using tiny flexible endoscopes to look into the fallopian tube and see if we could actually start screening the fallopian tube instead of the ovary which is what we have been doing.

The DoD is really critical as a separate funding source because it's much more flexible in considering alternative points of view. The idea that you want to study a different tissue and you don't think it's really ovarian cancer, that's a big change. And so people get very focused on what they think should be done and don't want to consider like broader alternatives.

So when the DoD funded this idea the NIH had already said oh that's too-that's too high risk. But by the time we finished our work with the DoD project, the NIH was very enthused about it and then funded it. So it allowed us to show enough data that the NIH was convinced that this was a successful pathway to follow.

So what we're trying to do now is take our laboratory findings and see if we could take those back to the clinic and maybe impact screening with a new method of screening.