Secondary mutation of a somatic BRCA2 mutation in an olaparib and carboplatin resistant ovarian tumour

Development of resistance to platinum and PARP inhibitors via secondary mutations that restore functional homologous recombination has been observed in a number of cancer types. Here we report a case of somatic BRCA2 mutation in a patient with high grade serous ovarian carcinoma. A secondary mutation predicted to restore the BRCA2 open reading frame was detected at low frequency in whole exome sequencing of a peritoneal biopsy at disease progression after treatment that included carboplatin and olaparib. We used digital droplet PCR (ddPCR) to verify the presence and frequency of this mutation in the biopsy sample and assess the presence of the secondary mutation in historical diagnostic biopsies, including at first relapse. We found no evidence of the secondary mutation prior to the final progression biopsy, suggesting that this mutation was acquired late in the course of treatment. ddPCR provides a sensitive and specific technique to investigate the presence of low frequency mutations in a time series of biopsies.