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

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.

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

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.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.

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

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.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.

In neoadjuvant treatment, what is the optimal regimen?

Androgen receptors are another subtype that appears to comprise a fair number of these TNBC. That's a target that there are drugs that can actually attack, so we're starting to identify some targets — DNA repair, androgen receptor, immunologic abnormalities – that we can start to think about using other approaches than just standard chemotherapy.We all agree that we tend to use either an anthracycline-based regimen with a taxane, or a combination of those drugs either in sequence or concurrently. A three-drug regimen is the standard of care—an anthracycline, an alkylating agent with cytoxan, and a taxane. One of the big questions has been what the best taxane to use is, and I showed data recently looking at whether nab paclitaxel is superior to standard paclitaxel in this patient population. There's been some thought that this could be the case because of a protein called SPARC present in some breast cancers that might help bring that chemotherapy into the tumor cell more effectively than standard paclitaxel.

You mentioned in a recent talk that there were neoadjuvant trials showing pathologic complete responses, that didn’t translate to better overall survival. Can you elaborate on that?

I think what we saw were some controversial and conflicting data on this issue. It does not appear that nab paclitaxel is necessarily better than paclitaxel, but it also appears that it's a very reasonable alternative. Many women have allergic reactions to paclitaxel that limits their ability to take the drug. Because nab paclitaxel is not formulated within the same vehicle that induces allergic reactions, patients who had an allergic reaction to one can take the other with no difficulty. So it's nice to have that alternative so we don't have to abandon a taxane for patients who are having an allergic reaction.It's a trick issue, and I think we've been really trying to understand this. Why is it that there's such a huge difference between patients who have no complete pathologic response and those who do, but once we start adding drugs it becomes hard to see a benefit. That really has to do with the fact that we are looking at simply increasing the proportion of patients who get a pathologic complete response. In terms of event free survival, there's a very large difference if you compared patients. Once you start making comparisons where one arm of the trial has a certain pathologic response rate, and the other arm has maybe only slight higher of a pathologic response rate, that small difference in PCR ultimately doesn't have the power to show a significant difference in event free survival. It's something that we have to pay attention to, and I think we need to think about how to design our neoadjuvant trials such that they're going to have the ability to give us the long term outcome data.

What do you see as the biggest questions that need to be answered in TNBC?

For many years, we would see the results of neoadjuvant trials that just showed us the path CR rates. That's not enough anymore. We really need to follow patients on these trials and power these trials to look at event-free survival later on.This understanding of the difference biologically between chemotherapy sensitive TNBC and chemotherapy insensitive TNBC is the question of our time. Because the patients who are chemosensitive have such good outcomes, we want everybody to have that opportunity. We want to give enough therapy to the patients who are sensitive that they have a good outcome, and we want to identify the patients who aren't sensitive so we can try something different.

In the neoadjuvant setting, we can get a sense of what a patient's response is. What's coming next, I believe, is the ability to say "okay, we're going to give a certain amount of therapy and see if this patient is responding to standard therapy or not." Then we can either finish them on that therapy, or we could not waste time giving something that's not working. Let's switch to something that might work. Using response in the neoadjuvant setting to actually pivot when a patient is not responding to try other things will help them gain a response. This is the essence of personalized medicine. It's not simply comparing two arms with different drugs. It's looking at a strategy and figuring out how to study the strategy of assessing response and then evaluating whether making the change will improve that response. That's the frontier of clinical trials.