Modification of Homologous Recombination Deficiency Score Threshold and Association with Long-Term Survival in Epithelial Ovarian Cancer.
Jeffrey How,Amir A. Jazaeri,Bryan Fellman,Molly S. Daniels,Suzanna Penn,Cara Solimeno,Ying Yuan,Kathleen M. Schmeler,Jerry S. Lanchbury,Kirsten Timms,Karen H. Lu,Melinda S. Yates +11 more
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TL;DR: In this paper, a series of 300 consecutive EOC patients were enrolled, and they underwent neoadjuvant chemotherapy (n = 172) or primary cytoreductive surgery(n = 128), and all patients underwent germline testing for HRD-related gene mutations.
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Abstract: New therapies, such as poly-ADP ribose polymerase inhibitors (PARPi), and immunotherapy treatments have generated great interest in enhancing individualized molecular profiling of epithelial ovarian cancer (EOC) to improve management of the disease. In EOC patients, putative biomarkers for homologous recombination deficiency (HRD), microsatellite instability (MSI), and tumor mutational burden (TMB) were characterized and correlated with survival outcomes. A series of 300 consecutive EOC patients were enrolled. Patients underwent neoadjuvant chemotherapy (n = 172) or primary cytoreductive surgery (n = 128). Molecular profiling and survival analyses were restricted to the primary cytoreductive surgery cohort due to tissue availability. All patients underwent germline testing for HRD- and MSI-related gene mutations. When sufficient tissue was available, screening for somatic BRCA1/2 mutations, BRCA1 promoter methylation, HRD score (a measure of genomic instability), MSI, and TMB testing were performed. HRD score ≥33 was associated with improved overall survival on multivariable analysis. In the era of biomarker-driven clinical care, HRD score ≥33 may be a useful adjunctive prognostic tool and should be evaluated in future studies to predict PARPi benefits.
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OUP accepted manuscript
27 Jan 2022
TL;DR: In this article , a consortium of project partners from key healthcare sectors have discussed the lack of consistency in the way homologous recombination deficiency (HRD) is defined and methods for measuring HR status.
CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
Takuya Tsujino,Tomoaki Takai,Kunihiko Hinohara,Fu Gui,Takeshi Tsutsumi,Xiao Bai,Chenkui Miao,Chao Feng,Bin Gui,Zsofia Sztupinszki,Antoine Simoneau,Ning Xie,Ladan Fazli,Xuesen Dong,Haruhito Azuma,Atish D. Choudhury,Kent W. Mouw,Zoltan Szallasi,Lee Zou,Adam S. Kibel,Li Jia +20 more
TL;DR: The authors performed genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identified previously unknown genes whose loss has a profound impact on PARP inhibitor response.
The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks
Lise M van Wijk,Claire J H Kramer,S. Vermeulen,Natalja T. ter Haar,Marthe M de Jonge,Judith R. Kroep,Cor D. de Kroon,Katja N. Gaarenstroom,Harry Vrieling,Tjalling Bosse,Maaike P.G. Vreeswijk +10 more
TL;DR: In this paper, the authors further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients.
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RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox?
TL;DR: An overview of currently available HRD tests can be found in this article , where the authors discuss the pros and cons of different methodologies including their sensitivity for the identification of HRD tumors, their concordance with other HRd tests, and their capacity to predict therapy response.
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Homologous recombination deficiency (HRD) as an ovarian cancer biomarker in a real-world cohort - validation of decentralized genomic profiling.
Carsten Denkert,Marcel Romey,Bradley D. Swedlund,Akira Hattesohl,Julia Teply-Szymanski,Stefan Kommoss,Kristine A. Kaiser,Annette Staebler,Andreas du Bois,Albert Grass,Christiane Knappmeyer,Florian Heitz,Cara Solimeno,T Ebel,Philipp Harter,Frederik Marmé,Paul Jank,Timo Gaiser,Chris Neff,Uwe Wagner,Kirsten Timms,Fiona R. Rodepeter +21 more
TL;DR: In this article , the authors evaluated homologous recombination deficiency (HRD) in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS).
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