Research Shows that tumors with mutations in the BRCA2 gene respond better to checkpoint blockade immunotherapy than tumors with mutations in the BRCA1 gene.
Immunotherapy, or treatments that harness a person's immune system, can significantly improve some cancers' outcomes. One of the more recent study areas includes the activation of the body's immune system by treatments. Researchers are learning more about why some cancers respond better than others to immune-activating drugs.
Findings show that one major factor for different responses is the tumor mutation burden (TMB), or the number of DNA changes in a tumor. Studies have shown that tumors with high TMB tend to respond better to immune checkpoint inhibitors.
In 2017, the US Food and Drug Administration (FDA) approved the checkpoint inhibitor pembrolizumab (Keytruda®) for the treatment of tumors with a type of genetic defect called mismatch repair (MMR) deficiency.
MMR is one of several DNA repair pathways that cells use to fix mistakes, or mutations, in a person's DNA. Mutations in this pathway lead to faulty DNA repair and, therefore, to higher TMB.
After MMR, the most commonly mutated DNA repair pathway is called homologous recombination, which repairs double-strand breaks in DNA, or when both sides of the DNA "ladder" are broken. The often-discussed cancer-predisposition genes known as BRCA1 and BRCA2 belong to this pathway. When BRCA1 and BRCA2 are mutated, DNA damage accumulates, and one's risk increases for developing several types of cancer, including breast, ovarian, prostate, and pancreatic cancers.
Research now shows that mutations in the BRCA2 gene instead of the BRCA1 produce tumors that have a better response to immunotherapy.
"When we started this work, we assumed that tumors with both types of homologous recombination deficiency would respond to immunotherapy based on having a high mutation burden," says physician-scientist Nadeem Riaz from Memorial Sloane Kettering Hospital (MSK). "But we found instead that BRCA2-mutated tumors responded much better than BRCA1 tumors."
These results, which were published in the journal Nature Cancer (11/20), may have implications for the types of treatments that people with BRCA mutations should consider.
A Striking Divergence
This discovery was made using both human data and mouse model data. When researchers compared tumor mutations and clinical information from patients treated with immunotherapy at MSK, they found a direct correlation between mutations in BRCA2 and better survival after treatment.
Researchers confirmed these findings by creating genetically engineered mouse models of BRCA1 and BRCA2 mutant breast and colorectal cancers. In both cases, they found that only the BRCA2 mutated tumors responded to treatment with checkpoint inhibitors immunotherapy drugs.
While these findings still need to be confirmed by others and validated in clinical trials, they suggest that people with BRCA2-mutant tumors may wish to consider discussing with their doctors enrolling in clinical trials of immunotherapy, specifically trials utilizing checkpoint inhibitors.
Memorial Sloan Kettering Cancer Center. "For people with certain BRCA mutations, activating the immune system could be promising treatment." ScienceDaily. ScienceDaily, 1 December 2020. <www.sciencedaily.com/releases/2020/12/201201144034.htm>.
