BRCA reversion mutations

What is measured: a second mutation in BRCA1, BRCA2 (or PALB2, RAD51C, RAD51D) that restores a functional protein in a tumour that had lost it. How: sequencing of a progression biopsy or, more often, plasma cell-free DNA with a panel covering the whole gene; the reversion appears as a deletion or insertion that puts the reading frame back, or a change that undoes the original variant, and it is frequently polyclonal. It is found in 20 to 40 percent of ovarian cancers and metastatic prostate cancers that have become resistant to PARP inhibitors or platinum, and less often in breast cancer; other resistance routes (loss of 53BP1 or the Shieldin complex, drug efflux, PARP1 mutations) are invisible to this test. Germline carriers keep their germline mutation in normal cells; the reversion is somatic. What a result changes: it predicts non-response to further PARP inhibition and to platinum, so treatment moves to taxanes, antibody-drug conjugates (mirvetuximab for folate receptor alpha-high ovarian cancer) or trials of ATR and POLQ inhibitors; its appearance in blood precedes radiographic progression; its absence supports PARP inhibitor rechallenge (OReO). Where it matters: platinum-sensitive and platinum-resistant ovarian cancer, high-grade serous ovarian cancer and metastatic castration-resistant prostate cancer.