Expert Highlights Ongoing Efforts for TNBC Treatment

David B. Page, MD

There are hundreds of targets and therapies in development for the treatment of patients with triple-negative breast cancer (TNBC), according to David B. Page, MD, a medical oncologist at Earle A. Chiles Research Institute of Providence Cancer Center.

Immunotherapy has garnered recent excitement in the field, with responses ranging from 10% to 26%, said Page. Although there are many new directions that are being explored, there is much to be discerned, he said, adding that more novel ways of delivering chemotherapy are also being investigated.

“Marrying the lab with the clinic is going to be the direction forward for immune therapy,” Page said.

OncLive: How has the treatment landscape evolved in TNBC?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Page discussed emerging treatment approaches for patients with TNBC.Page: There are so many new directions in the treatment of patients with metastatic TNBC. Immunotherapy is probably one of the most exciting directions. Immunotherapy is not 1 drug, but rather a broad class of medications. We are just seeing the tip of the iceberg. We're starting to see that PD-1 antibodies can reinvigorate immune responses against cancer. I presented some data that show response rates of approximately 10% to 26%.

This is very exciting because [antibodies were] the first drugs to really be evaluated in breast cancer. These are the combinations that are going to be the most promising. I read that there are [currently] 302 antibodies and immune therapy approaches that are being studied on ClinicalTrials.gov.

Also, people don't appreciate that hormone-directed strategies could be relevant for TNBC. There are some data to suggest that in about half of the patients with TNBC, the expression of androgen receptor (AR) is upregulated and could be relevant in the signaling process. Early data show that we can block androgens. There is some provocative evidence that we can stimulate immune responses and generate new T cells. [We may be able to do this] because the thymus, an organ that sits within the chest, is dependent on androgen signaling. If we block that signaling, we can induce new T cells to be produced. There are some studies evaluating this that show some interesting directions.

Another new direction is utilizing chemotherapy in novel ways. We acknowledge that chemotherapy is part of the backbone of standard treatment. We know that it is effective, but it is transiently and with toxicities that aren't ideal. Therefore, we’re trying to modify chemotherapy to be longer-acting. That way, we can use it in lower doses in a more sustainable fashion.

Will we continue to use the term TNBC as more specific subtypes are identified?

There are some promising chemotherapy modifications with pegylation that have been evaluated. Another strategy is combining chemotherapy with targeted therapy by conjugating antibodies to strong chemotherapies. This subsequently directs the chemotherapy to where it matters. That way, we can target the cancer and spare normal cells.As long as we have effective therapies for patients who don’t have TNBC, the designation for [TNBC] is going to be imperative. For patients with hormone-sensitive [breast cancer], we are going to use hormone blockers. I don't think that is going to disappear anytime soon.

[The landscape] is going to become much more complex; there will be multiple parameters that are not only looking at genes or specific protein expression, but potentially the immune dynamics of tumors. There might be some breast cancers that are labeled as triple negative, which have enriched immune signatures or certain types of immune cells that can be targeted differently.

How has olaparib helped patients with BRCA-positive breast cancers?

It will become much more complicated, but in a good way. Eventually, the number of parameters will require us to use computers to sort through these data. That is my prediction. We will have to harmonize medicine with statistics and informatics in order to treat patients appropriately. We have seen responses greater than 50%; we’ve seen responses that are somewhat durable, relative to some chemotherapies. We're trying to expand on that 10% benefit in understanding that BRCA is not the only relevant gene. There may be other genes that could confer sensitivity to olaparib (Lynparza). There are ways of categorizing a tumor based on its defects in repairing DNA.

How has the prognosis for TNBC changed in the past 5 to 10 years?

Depending on the assay you use, an upwards of 50% of patients with TNBC could have those defects. That may allow us to target that type of pathway. It remains to be determined. There are a lot of competing assays to see if we can predict who is going to respond to olaparib. We're still working out those details. I've been training in oncology for about that amount of time, and I haven't seen a lot of changes until recently. Until recently, [treatment] was chemotherapy. It’s quite sobering to see that patients could die—on average—in less than 1 year with chemotherapy. We hope that that will change. Immunotherapy is perhaps a provocative direction because some patients show durable responses.

Is there anything else you'd like to emphasize?

We have seen that in melanoma; patients who are treated with a couple of doses of certain immunotherapies can be cured of their metastatic disease. We hope that is true for breast cancer, though we don't really know. There are people who look at Kaplan-Meier survival curves of patients with TNBC who respond to immunotherapy. Those patients seem to have 100% survival rates. Because those are such small numbers, we can't know for sure how it's going to pan out. There are about 300 targets in development. We can inject vaccines into tumors to manipulate them, so the immune system can see the cancer. [The landscape] is going to become even more complicated. There are some interesting data showing that giving 2 immunotherapies together worsens the response, but giving them within 2 weeks of each other could double the response.

What ongoing trials are you excited about?

This is something that we saw with mice; the timing might matter. The immune system is highly complicated and responses have to be coordinated. If we put enough investment into exploring this preclinically with mice, we might be able to find strategies that work better in humans.[We’ll have to] look at agents that are already approved or have shown promise in breast cancer in combination with PD-1 [agents]. That is the next step and what we are going to start seeing more of. There are trials that are combing CDK4 inhibitors with PD-1 [agents]. This is less relevant for TNBC, but there are trials combining AR inhibitors with PD-1 inhibitors. The list goes on. Some of those combinations are almost certainly going to be fruitful.