The androgen receptor (AR) regulates mRNA-specific translation through 4EBP1, which is a druggable vulnerability in AR-deficient prostate cancer.

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation ( BRCA1 meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 ( BRCA mut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1 meth and BRCA mut states, BRCA1 meth uniformly associates with poor outcomes. Exposure of BRCA1 meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCA mut cancers, where BRCA loss is a genetically “fixed” deficiency state, BRCA1 meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.

Objective. Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC. Methods. EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity. Results. In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1 -12). Conclusion. Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC. (c) 2024 Published by Elsevier Inc.

PURPOSE: Homologous recombination DNA repair deficiency (HRD) is a therapeutic biomarker for sensitivity to platinum and poly(ADP-ribose) polymerase inhibitor therapies in breast and ovarian cancers. Several molecular phenotypes and diagnostic strategies have been developed to assess HRD; however, their clinical implementation remains both technically challenging and methodologically unstandardized. METHODS: We developed and validated an efficient and cost-effective strategy for HRD determination on the basis of calculation of a genome-wide loss of heterozygosity (LOH) score through targeted, hybridization capture and next-generation DNA sequencing augmented with 3,000 common, polymorphic single-nucleotide polymorphism (SNP) sites distributed genome-wide. This approach requires minimal sequence reads and can be readily integrated into targeted gene capture workflows already in use for molecular oncology. We interrogated 99 ovarian neoplasm-normal pairs using this method and compared results with patient mutational genotypes and orthologous predictors of HRD derived from whole-genome mutational signatures. RESULTS: LOH scores of ≥11% had >86% sensitivity for identifying tumors with HRD-causing mutations in an independent validation set (90.6% sensitivity for all specimens). We found strong agreement of our analytic approach with genome-wide mutational signature assays for determining HRD, yielding an estimated 96.7% sensitivity and 50% specificity. We observed poor concordance with mutational signatures inferred using only mutations detected by the targeted gene capture panel, suggesting inadequacy of the latter approach. LOH score did not significantly correlate with treatment outcomes. CONCLUSION: Targeted sequencing of genome-wide polymorphic SNP sites can be used to infer LOH events and subsequently diagnose HRD in ovarian tumors. The methods presented here are readily generalizable to other targeted gene oncology assays and could be adapted for HRD diagnosis in other tumor types.

Recurrent ovarian cancer (OC) is challenging to detect early using current methods like CA-125 and imaging. Circulating tumor DNA (ctDNA) may improve disease monitoring. Here, we assess the real-world clinical utility of serial ctDNA analyses in patients with recurrent OC. We analyzed serial plasma samples (N = 23) from six patients with recurrent OC using a tumor-informed next-generation sequencing assay targeting 68 cancer-related genes developed at the University of Washington. ctDNA variant allele frequencies (VAFs) were correlated with CA-125 levels, radiographic findings, and clinical outcomes. ctDNA levels generally reflected clinical status, accurately mirroring disease progression and therapeutic response. In one patient, rising ctDNA preceded clinical recurrence by four months, despite normal CA-125 and imaging, highlighting its potential advantage. Conversely, some patients exhibited clinical progression with undetectable ctDNA, indicating limitations in assay sensitivity, biological factors, or metastatic sites (e.g., brain metastases). ctDNA and CA-125 showed complementary value in most cases, suggesting potential combined use in clinical monitoring. Our findings demonstrate that ctDNA is a promising biomarker to complement existing monitoring approaches for recurrent OC. In some cases, capable of predicting relapse and treatment response ahead of current clinical indicators. However, identified discordances underscore technical and biological challenges that warrant further investigation. Larger prospective studies are necessary to refine ctDNA’s clinical utility and integration into personalized OC care.