Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer

Abstract

While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.

Figure 1

Cohort treatment overview. Swimmer plot showing the treatments received by the 26 HGSC patients in the cohort. Each asterisk represents a cycle of treatment or for PARPi the start, stop or cycle dates (see “Methods”), the colour of the symbol represents the type of treatment as indicated in the figure legend. The x-axis represents the timing of treatment in weeks from diagnosis. Arrow represents only living patient at time of data extraction.

Figure 2

Schematics of the mutations in the cohort. (a) The position of each BRCA1 mutation is represented in the lollipop plot, with the number of dots on the lollipop indicating the number of patients in which the mutation is observed, the colour of the bar and point indicates the type of mutation. The blue lollipop with 2 dots denotes the Cys61Gly mutation. Schematic constructed based on lollipop plot generated from GenomePaint. Note only 15 of 16 mutations are depicted, as one was annotated in AOCS but not detected in our sequencing. (b) Reversion mutations detected in three patients, the variant allele frequencies depicted as pie charts. Note that for 15295_10-00451, one reversion is not shown as it is a large deletion and the VAF not accurately estimable.