A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer

• DOI: 10.1038/s41467-021-25904-w
• Publication Date: 2021-09-22T10:03:10Z
• Authors: Panagiotis A. Kon...; Alexandre André B...; Doga Gulhan; Elizabeth K. Lee; Su-Chun Cheng; Andrea E. Wahner ...; Bose Kochupurakkal; David L. Kolin; Elise C. Kohn; Joyce F. Liu; Elizabeth H. Stover; Jennifer Curtis; Nabihah Tayob; Madeline Polak; Dipanjan Chowdhury; Ursula A. Matulonis; Anniina Färkkilä; Alan D. D’Andrea; Geoffrey I. Shapiro
• Keywords: DNA Replication; Science; Ataxia Telangiectasia Mutated Proteins; Deoxycytidine; Article; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; CLINICAL ASSAYS; Protein Kinase Inhibitors; SIGNATURES; Gynaecology and paediatrics; Ovarian Neoplasms; 0303 health sciences; Q; Recombinational DNA Repair; PHASE-III TRIAL; Isoxazoles; Oncogenes; CHEMOTHERAPY; Gemcitabine; PEGYLATED LIPOSOMAL DOXORUBICIN; Progression-Free Survival; 3. Good health; Biomedicine; Retinoblastoma Binding Proteins; DNA-DAMAGE; Pyrazines; CELLS; Mutation; Female; Cancers

Abstract In a trial of patients with high grade serous ovarian cancer (HGSOC), addition the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared alone but biomarkers predictive treatment are lacking. Here we report candidate biomarker response versus combined and therapy in HGSOC cancer. Patients replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related loss RB pathway regulation and/or oncogene-induced achieve significantly prolonged PFS (HR 0.38, 90% CI, 0.17–0.86) on monotherapy those without such alterations (defined RS-low, n 30). However, benefits only RS-low (gemcitabine/berzosertib HR 0.34, 0.13–0.86) not RS-high 1.11, 0.47–2.62). Our findings support notion that exacerbation by is adequate for lethality tumors. Conversely, berzosertib-mediated inhibition necessary occur. Independent prospective validation this required.