Patients who have a BRCA mutation, and with a tumor that has a high mutational burden, may respond better to immunotherapy. This is suggested by a study conducted by researchers from the University of Oklahoma Health Sciences Center and published in Jama Network Open. The result can be important, because identifying the “right” patients, that is, those who are most likely to benefit from new drugs, is one of the challenges of precision oncology.
“The authors note that in tumors with BRCA 1 and 2 mutation associated with the mutational load (Tumor Mutational Burden, TMB, the amount of acquired mutations present in tumor cells, ed.), The response to immunotherapy with immune checkpoint inhibitors is better, “he explains Michele Maio, director of the Immuno-Oncology Center of the Sienese University Hospital (CIO): “It is a piece of information that adds to what we are studying and experimenting even in the clinic, a small piece that adds to the knowledge needed to succeed to identify patients who benefit most from immunotherapy, who are more likely to respond to these treatments. For example, we know that 30% of those with lung cancer respond well to immunotherapy: we need to understand why these 30 respond and why the other 70 do not. We need to understand the molecular mechanisms of resistance and sensitivity. The identification of patients is therefore fundamental: the reasons are also economic, we are talking about expensive treatments for health systems, and of course ethical ”.
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I study
The researchers then evaluated whether the mutated BRCA1 and BRCA2 genes may or may not be biomarkers predicting a positive response to treatment. And they concluded that yes: in combination with the tumor mutational burden, they have some potential. The study we are talking about was conducted on over 39,000 samples of different types of cancer (from melanoma to bladder cancer, from ovarian to lung cancer) taken from more than 37,000 patients. 5.3% had a BRCA 1/2 alteration. At the same time, the mutational load of each sample was also measured. It should be noted that the tumors with the altered BRCA genes were those with a higher mutational load.
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The authors then enrolled 1,661 patients undergoing immunotherapy, of which 141 (8.5%) with BRCA1 / 2 alteration. Survival for those with BRCA2 impairment was greater than for those without. The survival of those with low mutational load and altered BRCA2 was comparable to survival of patients with high mutational load, and both had better survival than patients with tumors with mutated BRCA2 but low mutational load.
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“Only a few years ago – continues Maio – it was not known that there was a relationship between the molecular profile of cancer and the response to therapy. But we now know that tumors produce neo-antigens, which are molecules which they then expose on the surface of their cells, which are effectively recognized by the immune system. So we know that cancer can be tackled with immunotherapy. In some tumors it has been found that the higher the number of mutations, the better the response to immunotherapy. But – concludes the expert – it will also be crucial to study the microenvironment of the tumor, because the ecosystem that cancer creates around itself can modify the response of the immune system “.
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