Jean H Siedel1, Kari L Ring2, Wei Hu1, Robert L Dood1, Ying Wang3, Keith Baggerly3, Kathleen M Darcy4, Thomas P Conrads5, Shannon Gallagher6, Placede Tshiaba6, Chris Neff6, Kirsten M Timms6, Selanere Mangala1, Shannon N Westin1, Russell Broaddus7, Gabriel Lopez-Berestein8, Karen H Lu1, Robert L Coleman1, George L Maxwell5, Anil K Sood9. 1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 2. Department of Obstetrics and Gynecology, Emily Couric Clinical Cancer Center, Charlottesville, VA, United States of America. 3. Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. 4. Gynecologic Cancer Center of Excellence, Department of Obstetrics & Gynecology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, United States of America; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, United States of America. 5. Gynecologic Cancer Center of Excellence, Department of Obstetrics & Gynecology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, United States of America; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, United States of America. 6. Myriad Genetics, Inc., Salt Lake, UT, United States of America. 7. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, United States of America. 8. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America. 9. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, United States of America. Electronic address: asood@mdanderson.org.
Abstract
BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. CONCLUSIONS: High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.
BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. CONCLUSIONS: High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.
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