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Biology of Triple-Negative Breast Cancer Crucial for Most Effective Treatment

Greg Kennelty
Published: Thursday, Sep 15, 2016

Angela DeMichele, MD

Angela DeMichele, MD

It is important to achieve a complete and thorough understanding of triple-negative breast cancer (TNBC) in order to most effectively treat patients, said Angela DeMichele, MD, professor of medicien and epidemiology, breast cancer oncologist, University of Pennsylvania.

In an interview with OncLive, DeMichele discusses the biology of the disease, DNA repair, chemotherapy sensitive versus insensitive TNBC, and the potential restructuring of neoadjuvant trials.

OncLive: What do you think are the optimal treatments for TNBC?

DeMichele: I think this is a really difficult time in terms of thinking about the optimal treatment for TNBC. In a recent talk I gave, I was focused on trying to make sense of the newest data we have on the optimal treatment regimen for this disease. We know that some patients are going to respond really well to chemotherapy, while others will be relatively chemo-insensitive, and those patients who do have a good response to chemotherapy will likely have a very good prognosis. So while many people worry that TNBC is generally a very poor prognosis disease, it turns out that some patents with TNBC will do very well.

If we can capture who those patients are and really optimize the therapy, then I think we will see that this disease will have better and better outcomes. That being said, there are various ways to go about doing that, and so we had new data this year looking at whether or not we should add a platinum-based chemotherapy to our regimen. We had data looking at what the ideal taxane drug would be in the regimen. Now we are starting to look at giving more therapy after neoadjuvant therapy in non-responders. These are all really wonderful studies because they help us think beyond the standards that we've typically used. However, with every new drug we add, there's toxicities. We have to weigh if we should give this new drug, which may have a small benefit, and if it's worth whatever cost there may be in terms of toxicities or cost.

I think for the individual patient who's sitting in front of us in the clinic, their questions are what's right for them. The more that we can understand who benefits based on the biology of the cancer, the better we'll be able to tailor the therapies to these patients.

What have you learned about the biology of TNBC that can help inform treatment decisions?

I think the most important area is the issue of DNA repair. That really underlies a lot of the work that's being done right now. There are several different subtypes that have emerged when you look at this entity of TNBC. It's not just the fact that it doesn't have estrogen receptors, and progesterone receptors, and HER2 receptors. That's what makes it triple negative, but what's positive? Well, there are some of these tumors that have lost their ability to repair their DNA. All of our cells in our body are experiencing DNA damage all of the time. We repair that DNA so that our cells can go on to replicate and do their jobs.

In patients that are born with an inherited mutation of BRCA1 or 2, those patients have a fundamental abnormality in the ability of the cell to repair its DNA. Some of these triple negatives cancers, in and of themselves, acquire the inability to repair their DNA. We can take advantage of that by further damaging the DNA so that the cells and the tumor can't recover. This is an important biological subtype of TNBC and there are assays being developed now, HRD assays, to try to identify which triple negative tumor have this inherent inability to repair their DNA. Those tumors may be more sensitive to drugs like platinum. That's one way that we can start to match the biological abnormalities in a subset of triple negative cancers to a particular therapy that might work for them.

Another area that's of great interest is immunological abnormalities within TNBC. I think this a crosscutting area, but in TNBC in particular, there does seem to be interaction for some of these tumors with the immune system. This may be a place where we can exploit some of the new checkpoint inhibitors and other types of therapies that are designed to help break down the barriers and allow the immune system to actually participate in killing the cancer cells.

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