Epithelial ovarian cancer (EOC) is one of the leading causes of cancer-related death in women worldwide, and is characterized by a high rate of recurrence after surgery and chemotherapy. We sought to implement a circulating tumor DNA (ctDNA)–based blood test for more accurate post-operative surveillance of this disease. We analyzed 264 plasma samples collected between June 2016 and September 2021 from 63 EOC patients using tumor-guided plasma cell-free DNA analysis to detect residual disease after treatment. Assay specificity was verified using cross-patient analysis of 1,195 control samples. ctDNA was detected in 51 of 55 (93%) samples at diagnosis, and 18 of 18 (100%) samples at progression. Positive ctDNA in the last on-treatment sample was associated with rapid progression (median 1.02 versus 3.38 yr, HR = 5.63,P< 0.001) and reduced overall survival (median 2.31 versus NR yr, HR = 8.22,P< 0.001) in patients with high-grade serous cancer. In the case of 12 patients, ctDNA assays detected progression earlier than standard surveillance, with a median lead time of 5.9 mo. To approach the physical limits of ctDNA detection, five patients were analyzed using ultra-sensitive assays interrogating 479–1,856 tumor mutations, capable of tracking ctDNA fractions down to 0.0004%. Our results demonstrate that ctDNA assays achieve high sensitivity and specificity in detecting post-operative residual disease in EOC.

Purpose: To evaluate the feasibility, efficacy, and safety of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).Methods: Eleven patients with CP/CPPS were enrolled in this prospective clinical study. rTMS was performed for 5 consecutive days in 20-minute sessions. Patients were evaluated at baseline, after treatment, and at 1, 4, 8, and 12 weeks after the last session with questionnaires concerning pain (numerical rating scale [NRS], the National Institutes of Health Chronic Prostatitis Symptom Index [NIH-CPSI], and the Short Form-36 [SF-36]), urinary symptoms (NIH-CPSI, Danish Prostatic Symptom Score [DAN-PSS-1]), quality of life (NIH-CPSI, SF-36), and psychometrics (Beck Depression Index [BDI]). Telephone-based interviews were used to evaluate side effects, subjective response, and changes in drug consumption.Results: All patients completed the planned treatment and follow-up according to protocol. No patients experienced serious side effects or significant pain increase during or after treatment. Mild transient tension headache responsive to oral pain medication was reported by 2 patients. Decreased pain was observed on the NRS after treatment and at 1 and 8 weeks (P=0.019, P=0.006, P=0.042, respectively) and on the NIH-CPSI pain domain at 1 week (P=0.04). Improvement in lower urinary tract symptoms was observed after treatment in the NIH-CPSI urinary domain (P=0.02) but not with the DANPSS-1. No significant changes in the BDI were observed. Nine patients reported a positive overall subjective response (82%) and 6 patients (55%) were able to reduce pain medication. Higher age was associated with lower NRS scores after treatment (R=0.605, P=0.048) and at 8 weeks (R=0.659, P=0.028).Conclusions: rTMS for patients with CP/CPPS seemed to be well tolerated, at least moderately effective in pain reduction, and might be of interest in patients with chronic pelvic pain resistant to conventional treatment. These findings remain to be confirmed by a randomized trial.

Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiology remain incompletely understood. We assembled a meta-cohort of 3048 plasma cell-free DNA and matched leukocyte DNA samples from 1751 mCRPC patients, accrued from eight clinical trials and a regional biobank. Samples were sequenced with successive generations of a custom targeted hybridization capture panel with extensive coverage of the AR locus and 71 prostate cancer genes, enabling comprehensive characterization of AR genotypes including enhancer and gene copy number amplification, and mutations or structural rearrangements. Somatic AR alterations, detected in 84% of mCRPC, were shaped by underlying genomics, including TP53 and DNA repair defects. Wnt-mutant tumors showed unique AR amplification structures characterized by preferential incorporation of an alternative downstream enhancer and low copy number. AR mutations were present in 19.7% of mCRPC, often subclonal, and enriched in tumors with AR enhancer-only gain. We establish a functional hierarchy of AR genotypes based on treatment responses and identify a specific class of AR rearrangements truncating the ligand-binding domain within intron 4 or exon 4 (ALTR4) that are under robust positive selection and strongly impact AR pathway inhibitor outcomes, distinct from other rearrangements arising as byproducts of AR amplification. We provide evidence that a subset of AR amplifications arise through breakage-fusion-bridge cycles with associated Xq loss. Some 16% of mCRPC lacked detectable AR alterations and had reduced frequency of ETS gene fusions, with many demonstrating robust responses to AR pathway inhibitors. This study provides the most comprehensive resource to date characterizing somatic alterations at the AR locus. Our clinicogenomic analysis establishes the repertoire and clinical relevance of AR genotypes in mCRPC, informing efforts to target renewed AR dependency.