By Deborah Borfitz 

January 6, 2021 | Despite having similar levels of tumor mutational burden (TMB), cancers associated with BRCA1 and BRCA2 alterations respond quite differently to immunotherapy. Counterintuitively, the tumor type that typically harbors the fewer number of immune cells—BRCA2—appears to be more immunogenic and the reason may be that the mutation process generates foreign-looking peptides readily detected by the body’s DNA repair engine, according to Nadeem Riaz, M.D., radiation oncologist at Memorial Sloan Kettering (MSK) Cancer Center.

In a study recently published in Nature Cancer (DOI: 10.1038/s43018-020-00139-8), which Riaz co-authored with Mount Sinai’s Robert Samstein, M.D. and his MSK colleagues in The Timothy Chan Lab, researchers found a direct and striking correlation between mutations in BRCA2 and better survival after treatment. Patients with BRCA2 mutations who are running out of treatment options “may want to think about enrolling in a clinical trial with immunotherapy,” he says. 

“Immunotherapy has played an important role in revolutionizing the treatment of patients who have cancer and we’re starting to understand some of the determinants of response,” says Riaz. “Increased tumor mutational burden significantly improves the ability of the immune system to recognize the tumor source and things that increase mutational burden, like UV light and smoking, are associated with improved response to immunotherapy.” 

Defects in DNA damage response have likewise been associated with better treatment response, he adds. The new study focuses specifically on a hereditary syndrome (homologous recombination deficiency) that is commonly due to genetic alterations affecting BRCA1 or BRCA2.

Although BRCA1 and BRCA2 mutations are often lumped together for therapeutic purposes, they are in fact distinct phenotypes that may benefit from personalized treatments, Riaz notes. BRCA2 is much more strongly associated with estrogen receptor-positive breast cancer, prostate cancer and pancreatic cancer, while BRCA1 is linked primarily with triple-negative breast cancer and ovarian cancer.

Across all cancers, BRCA1 and BRCA2 mutations (both germline and somatic) account for between 2% and 5% of all cancers and occur at roughly the same frequency relative to one another, continues Riaz. 

The focus on BRCA genes was prompted by the discovery of the link between TMB and improved outcomes from immunotherapy—a connection initially made a few years ago by the Chan Lab—and a similarly positive correlation with cancer-damaged DNA repair genes, Riaz says. BRCA1 and BRCA2 mutations both disrupt normal DNA damage response and lead to a slightly higher number of DNA changes relative to other tumor types.

Out of 2,000 patients treated with immunotherapy, researchers identified about 100 having BRCA1 or BRCA2 mutations and compared their outcomes, says Riaz. Patients with BRCA2 mutations had a statistically significant 50% reduction in risk of dying after receiving immunotherapy compared to patients without BRCA2 mutations, whereas BRCA1 mutations had no beneficial effect.

Genetically engineered mouse models validated that the BRCA mutations were responsible for improved immunotherapy response among the BRCA2 group. The findings still need to be validated in prospective clinical studies before changes in clinical practice can be recommended, the authors note. 

Exploration Continues 

Riaz theorizes that the divergent outcomes are related to the fact that BRCA2-related cancers are more frequently linked to mutations called “indels” that in turn prompt frameshift mutations responsible for creating the long stretches of peptides the body recognizes as intruders. That makes them similar to mismatch repair (MMR) deficient tumors, another DNA repair process associated with improved response to immunotherapy. 

In 2017, the U.S. Food and Drug Administration approved the immune checkpoint inhibitor pembrolizumab (Keytruda) specifically for MMR deficiency. Homologous recombination is the next most commonly mutated DNA repair pathway responsible for fixing double-strand breaks in DNA.

Another possible explanation for the differing outcomes is that the microenvironment of BRCA1 and BRCA2 tumors triggers different kinds of immune reactions, Riaz continues. The research team is currently evaluating if BRCA1 tumors have distinct cell subsets upregulating immunosuppressive molecules that are hampering treatment response.

At the same time, they will continue to prospectively validate findings of the Nature Cancer paper in large groups of patients with BRCA1 or BRCA2 tumors to evaluate long-term outcomes. Several such studies are already underway at MSK and elsewhere, often involving a combination of poly (ADP-ribose) polymerase (PARP) agents with programmed cell death protein 1 (PD-1) inhibitors.

Currently, cancer patients often don’t learn they have a BRCA mutation unless they have a strong family history of cancer or they’re out of treatment options, says Riaz. But as the genetics of tumors become better understood, the list of reasons for individuals to get their tumor sequenced grows. “Every year, we peel off another 2% of patients where sequencing would identify something that might… change their treatment” and guide them to a trial option, or standard therapy that’s most likely to be effective.