Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

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Proton chemical shift data have been used in three ways to estimate the aromatic character of the 2-pyridone ring. The results are reasonably consistent and indicate that 2-pyridones have ca. 35% of the aromaticity of benzene, as defined by ability to sustain an induced ring current. The formally related 1,2-dihydro-2-methylenepyridine system is not aromatic : this conclusion has bearing on the constitution of adducts from pyridine and 3-picoline with acetylenedicarboxylic ester.* It is emphasised that (A) and (B) are fixed-bond model structures.aza-cyclohexatriene, and is not meant to represent a hybrid structure.