Predictive Markers Help Guide Evolving Field of Triple-Negative Breast Cancer


With the proven predictive value of PD-L1 expression and BRCA mutations in patients with metastatic triple-negative breast cancer, immunotherapy, PARP inhibitors and antibody-drug conjugates are changing the treatment landscape.

Drugs that work by taking advantage of a cancer’s genetic mutations are proving to be effective in patients with triple-negative breast cancer (TNBC) that has spread to distant locations in the body.

Used based on a cancer’s expression of the protein PD-L1 or mutations in the patient’s BRCA gene, immunotherapy, PARP inhibitors and antibody-drug conjugates (ADCs) are showing a clinical benefit in patients with metastatic TNBC, according to Dr. Howard A. "Skip" Burris, III.

The triple-negative breast cancer space has undergone an evolution as oncologists look to supplement standard chemotherapies with novel agents. These include the immunotherapy Tecentriq for patients whose cancers overexpress the protein PD-L1 and PARP inhibitors for the numerous patients with TNBC who also carry the BRCA 1 and 2 mutations.

PD-1 and PD-L1-targeting immunotherapies work by inhibiting the activity of proteins designed to keep the immune system in check; this takes the brakes off the immune system so that it can fight cancer. PARP inhibitors interfere with the ability of cancer cells to repair their DNA when damaged; this can kill the cells.

“The biggest take-home message in TNBC is the importance of molecular profiling and biological assessment. These patients must be assessed for BRCA mutations or other mutations in the DNA damage repair pathway,” explained Burris in an interview with OncLive®, a sister publication of CURE®, at the 2020 OncLive® State of the Science Summit™ on Breast Cancer. “We need to know whether these patients have PI3K and AKT alterations, and we need to know whether they overexpress PD-L1. It’s an important tack to take as you're (determining) what therapy to give to these patients.”

Antibody-drug conjugates (ADCs) are targeted drugs attached to chemotherapies that, together, are potent and precise in reaching and fighting cancer cells. While there is still a lot to learn about their use in TNBC, some signs have been promising.

“Recently, we saw some very encouraging data with sacituzumab govitecan, a novel ADC,” Burris said. “The result is a novel chemotherapeutic that has been shown to be very successful — more than one-third of patients are responsive to this drug.” An advantage of ADCs is that they release chemotherapy within the body over a longer period of time, which allows patients to tolerate it better. According to Burris, many biopharmaceutical companies are adopting this approach to reduce the incidence of major side effects for patients.

Burris, who is also the 2019-2020 president of the American Society of Clinical Oncology and a 2014 OncLive® Giant of Cancer Care® in the drug development category, highlighted his positive experience with immunotherapies in combination with chemotherapy. However, he pointed out that only 40.9% of patients with triple-negative breast cancer overexpress PD-L1, according to the results of the IMpassion130 trial, meaning that more than half of patients in this population are less likely to respond to immunotherapy.

“It's important to test patients for PD-L1 overexpression. I’ve found that about one-third of my patients overexpress PD-L1,” Burris said. “Certainly, we don't want to waste the patient's time by using a therapy that might not benefit them. However, in the context of PD-L1 positivity, a well-tolerated (immunotherapy)and the chemotherapy backbone with which it's combined tends to work well for the patient in terms of (safety) and quality of life.”

Subsets of patients with BRCA 1 and 2 mutations show a sensitivity to PARP inhibitors, yet further study is needed of the wider use of these agents and whether or not they can be effectively combined with immunotherapy for patients who overexpress PD-L1 and have a BRCA 1 and 2 mutation.

“PARP inhibitors are interesting,” Burris said. “Many experts in the field, and chemists, in particular, would talk about these drugs as being cytotoxics and not too dissimilar from chemotherapy. (PARP inhibitors) are oral agents that are certainly better tolerated (than chemotherapy) in many settings.”

This article was adapted from an article that originally appeared on OncLive titled, "Metastatic TNBC Paradigm Continues to Evolve With Novel Treatments".

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