Kathleen M. Darcy

Inactivating mutations in TP53 and ATRX are key alterations defining the genomic landscape of uterine leiomyosarcoma (uLMS), creating chronic replication stress and increasing dependency on Ataxia telangiectasia and Rad3-related kinase (ATR) signaling for survival. ATR-CHK1 signaling limits the efficacy of standard-of-care gemcitabine by facilitating the stabilization of stalled replication forks and preventing lethal DNA strand breaks in checkpoint-deficient cells. Here, we show that ATR inhibitors (elimusertib, ceralasertib, berzosertib) preferentially synergize with gemcitabine over docetaxel or doxorubicin, across a panel of TP53-mutant/ATRX-wildtype uLMS models. When simultaneously administered, gemcitabine/elimusertib demonstrated enhanced synergy and efficacy compared to standard-of-care gemcitabine/docetaxel. This combination benefit was absent in a TP53-wildtype uterine sarcoma control line, highlighting TP53 mutation status as a critical predictive biomarker. Combined gemcitabine/ATRi treatment demonstrated reciprocal potency enhancement at low-nanomolar concentrations and significantly increased apoptotic populations compared to monotherapy. Gemcitabine monotherapy induced CHK1 (S345) phosphorylation and a corresponding S-phase arrest. Elimusertib abrogated this checkpoint, transforming protective S-phase arrest into a cytotoxic response characterized by a marked increase in the sub-G1 population. This transition was driven by the inhibition of gemcitabine-induced CHK1 phosphorylation, resulting in marked accumulation of unrepaired DNA damage (γH2AX) and the induction of apoptosis as evidenced by cleaved caspase-3 expression. These findings demonstrate that elimusertib strongly potentiates gemcitabine-induced damage to kill TP53-mutant uLMS in vitro, outperforming standard gemcitabine/docetaxel when concurrently administered. This combination strategy broadens the clinical utility of ATR inhibitors to uLMS harboring the prevalent TP53-mutant/ATRX-wildtype genotype and supports the clinical evaluation of gemcitabine/ATRi combinations as a novel therapy for uLMS.

BRCA -associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), residual disease after primary surgery has limited prognostic effect in g BRCA pv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2 -deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA , RAD21 and MYC amplification define BRCA2 -deficient HGSC with exceptionally short survival. Patients with BRCA1 -deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1 -deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

The journal retracts the article, “Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro”

Importance: Three-year pelvic recurrence rate in women with low-risk cervical carcinoma was not inferior following simple hysterectomy (SH) vs modified radical hysterectomy (MRH) or radical hysterectomy (RH) in the Simple Hysterectomy and Pelvic Node Assessment randomized clinical trial, but the survival analysis of the trial was underpowered.Objective: To evaluate long-term survival in low-risk cervical carcinoma following SH vs MRH or RH.Design, Setting, and Participants: This cohort study included women undergoing SH, MRH or RH in US Commission on Cancer–accredited facilities participating in the National Cancer Database who received a diagnosis between January 2010 and December 2017 of International Federation of Gynecology and Obstetrics 2009 stage IA2 or IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix (≤2 cm) and clinically negative lymph nodes.Exposure: SH, MRH, or RH following diagnosis of stage IA2 or IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.Main Outcomes and Measures: Survival was the primary end point, evaluated with and without propensity score balancing. Survival rates, survival distributions, adjusted hazard ratio (aHR) of death, and restricted mean survival times (RMST) were analyzed as of September 2024. Two multivariable models were fitted. Model 1 included the hysterectomy type and 9 baseline factors (age, comorbidity score, race and ethnicity, insurance status, treatment facility, stage, histologic subtype, tumor grade, and surgical approach). Model 2 included the model 1 variables plus 4 additional clinical factors (surgical margin, LVSI, pathologic LN metastasis, and adjuvant treatment).Results: This cohort study evaluated 2636 women (mean [SD] age, 45.4 [11.4] years; median [IQR] follow-up, 85 [64-110] months), including 982 with SH, 300 with MRH, 927 with traditional RH, and 427 with unspecified MRH or RH. Survival was similar following SH vs MRH or RH (7 year survival rate, 93.9%; 95% CI, 91.9%-95.4% vs 95.3%; 95% CI, 94.0%-96.3%%; P = .07) and SH vs MRH vs RH (7 year survival rate, 93.9%; 95% CI, 91.9%-95.4% vs 94.2%; 95% CI, 90.1%-96.7% vs 95.4%; 95% CI, 93.6%-96.6%; P = .15). Risk of death following either SH vs MRH or RH, SH vs RH, or MRH vs RH remained similar after adjusting for baseline covariates alone or baseline covariates plus clinical factors. Survival remained similar within subsets by age, comorbidity score, race and ethnicity, facility type, stage, histologic subtype, tumor grade, surgical approach, and year of diagnosis. Adjusted survival remained similar in patients with SH vs MRH or RH after propensity score balancing for baseline covariates (aHR, 1.19; 95% CI, 0.86-1.65; P = .31) with similar 3-year (98.3%; 95% CI, 97.2%-99.0% vs 97.6%; 95% CI, 96.6%-98.2%), 5-year (95.9%; 95% CI, 94.3%-97.1% vs 96.5%; 95% CI, 95.5%-97.3%), 7-year (94.5%; 95% CI, 92.5%-95.9% vs 95.1%; 95% CI, 93.7%-96.1%), and 10-year (89.8%; 95% CI, 86.3%-92.5% vs 91.7%; 95% CI, 89.4%-93.4%) survival rates. Sensitivity analysis for patients who received a diagnosis between 2010 and 2013 documented similar 10-year RMST following SH vs MRH or RH, SH vs RH, SH vs MRH, and MRH vs RH.Conclusions and Relevance: In this cohort study, long-term survival was similar following SH vs MRH or RH, supporting the use of SH in select patients with low-risk early-stage cervical carcinoma.

Patients with high-grade serous ovarian carcinoma (HGSC) are usually diagnosed with advanced-stage disease, and the tumors often have immunosuppressive characteristics. Together, these factors are important for disease progression, drug resistance, and mortality. In this study, we used a combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, we found that untreated primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation; this, in turn, was correlated with expression changes in the interferon α and γ pathways in epithelial cells, showing that cross-communication between the epithelial and immune compartments is important for immune suppression in HGSC. These findings could have implications for the design of clinical trials with immune-modulating drugs.

We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.

Purpose: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. Methods: Patients diagnosed with stage IVB cervical cancer during 2013–2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. Results: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64–0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. Conclusions: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer.