Dr. Sledge is a Distinguished Professor at the Indiana University of Medicine and the co-leader of the Breast Program. In January 2013, he will move to Stanford University where he will be the Chief of Oncology.
What is the most important news about TNBC coming out of this meeting?
To be honest, there isn't any one study or one group of studies that represents a major change in the way we treat TNBC today. The real news has been more directed at ER+ and HER2 positive breast cancers. In the last year and a half though, we are seeing some very promising work that I believe will lead to significant improvements in treatment and outcomes over the next five years.
These include some excellent work presented yesterday by Jennifer Pietenpol whose group has identified six distinct subtypes of TNBC. This provides the opportunity to develop therapies that are targeted to the specific genetic profiles of these subtypes.
Some of these cell lines may respond very well, for example, to platinum based chemotherapy. For years, we have been using these drugs and seeing some patients respond very well, and others, not at all. It is very possible that these differences can be explained by identifying the subtype of TNBC that is involved.
Other subtypes may respond to PARPs that inhibit the cancer cell's ability to repair DNA damage. One subtype, which Dr. Pietenpol calls Luminal Androgen Receptor positive actually has a target receptor that we can shut down. The biology is going to be therapeutically very relevant in the future.
Why is TNBC so complicated?
Triple negative breast cancer is a genomic grab bag, a large collection of different diseases. In addition, it really is genomic chaos. When you do sequencing on these tumors, you find multiple genetic mutations that occur in different combinations. This means that it is a very complex group of diseases-and it makes designing clinical trials very complicated as well.
Why can't you target these mutations the way you do with other cancers?
First, we have to identify the driver mutations, and then they have to be actionable. That means we need a drug that targets the specific mutation. One complicating feature of TNBC is that many of the mutations represent a loss of function or cell regulation. It is much harder to fix something that is lost than it is to shut down something is being over expressed, the HER2 gene, for example. We know that a mutation in the P53 gene is linked to a number of cancers, including TNBC-but we don't have a way yet of turning that into something biologically actionable, in other words a treatment.
We also know that TNBC is linked to the loss of the cell's normal ability to repair damage to its DNA-and that is a very hard thing to fix. It also contributes to the large number of diverse mutations that we see in these tumors.
The other thing to remember is that the molecular profiles of cancers change. I tell my oncology fellows that cancers are like criminals tying to escape. If you set up a roadblock but only at one point, they will find a different way out. To outsmart the cancer, we need multiple roadblocks-and frankly, right now, we are not very good at doing that.
Why does this make clinical trials so hard to design and do?
When you have multiple subtypes and multiple driver mutations, it becomes increasingly difficult to design trials that will have achievable end points and involve a sufficient number of patients. The logistics are difficult, obtaining patient consent and participation is difficult, persuading drug companies to fund these trials is difficult. We may know that there are as many as five driver mutations involved in TNBC, but we have never done a trial in which we inhibited more than two.
What are the most promising areas?
Kinases have been the golden road to progress against cancer in the last decade. We can continue to work hard in that area, developing combination therapies that combine our knowledge of genetics with drugs-just like we do for HER+ cancers. Or we can look at different approaches, including immunologic therapies. If you had asked me even three years ago whether immunotherapy would be promising, I would have said no way, but there is very interesting work right now in that area.
I also think that PARP inhibitors have promise for TNBC. Two years ago, the big news was the failure of the PARP inhibitor trial, but that turns out to be more of a drug failure than a concept failure. I think these drugs will prove useful in the BRCA 1 and BRCA2 populations.
I also see some rapid therapy advances using the new information about subtypes. The key will be to define the subpopulations that will respond to specific approaches.
What is the importance of having a global approach to tackling TNBC?
TNBC really does have a huge global impact. In sub-Saharan Africa, it is the dominant type of breast cancer-and that is true in many low and middle income countries throughout the world. In those countries, you have young women being diagnosed with this disease. They have no access to screening or early diagnosis, it can take literally months to get into the medical system and get a biopsy-and no one has thousands of dollars to pay for treatment. So, it is devastating, and presents a real world challenge.
A final word?
We don't need a magic bullet for TNBC. We need a magic shotgun. It is going to be a long haul and it's not going to be easy-but I really believe that we will see real progress on multiple fronts in the next few years.
Christine Wilson for TNBC Foundation
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