27 August 2019

Immune checkpoint inhibitors are generally most effective against tumours with more genetic mutations, although the relationship isn’t always true. According to a new study published in Clinical Cancer Research, BRCA 1/2 mutation status in patients with breast cancer may not be directly predictive of response to checkpoint inhibitor therapy.

By using a set of The Cancer Genome Atlas (TCGA) genomic data and comparing this to breast cancer with and without germline or somatic BRCA 1/2 mutations the researchers reported that higher levels of genomic instability are associated with lower immunogenicity meaning immune checkpoint inhibitors are less effective in patients with these tumours.

Checkpoint inhibitor drugs, such as Bristol-Myers Squibb’s nivolumab (Opdivo) and Merck’s pembrolizumab (Keytruda), work by blocking protein receptors that regulate the activity of T cells and other immune system components, thus boosting these cells’ antitumor activity. It’s not yet clear why more tumour mutations are linked with improved treatment outcomes. One popular theory is that a higher tumour mutational burden (TMB) makes a tumour cell appear more different from a normal cell by creating an abundance of abnormal proteins, which the immune system then recognizes and reads as a signal to destroy the tumour.

Further research is needed to examine the biological mechanisms underpinning response to immune therapies, which might further shape treatment strategies and clinical trial design for patients.

Reference: ESMO