clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women's Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

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.

Obesity is common in endometrial cancer and surgery for these patients is challenging. We compared total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) with respect to feasibility (operating time, estimated blood loss, length of hospital stay, and conversion to laparotomy) and safety (perioperative morbidity and mortality) in a retrospective analysis of 78 morbidly obese patients with endometrial cancer. Analysis is based on the intention to treat. The intention to treat was TLH in 47 patients and it could be successfully completed in 42 patients (89.4%). The mean weight for all patients was 118.7 kg, with patients in the TLH group weighing more and having higher ASA scores. Mean operating time and estimated blood loss were similar in both groups. Mean postoperative hospital stay was 4.4 (+/-3.9) days in the TLH group and 7.9 (+/-3.0) days in the TAH group (P < 0.0001). Wound infections occurred in 15 of 31 patients (48.4%) in the TAH group and in 1 of 47 patients (2.1%) in the TLH group. All other morbidity, as well as patterns of recurrence and survival were similar in both groups. These data justify a prospective randomized trial comparing TLH with TAH for the treatment of endometrial cancer.