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

Joyce F Liu, Geoffrey I Shapiro, Alan D D'Andrea, Anniina Färkkilä, Ursula A Matulonis, Dipanjan Chowdhury, Madeline Polak, Nabihah Tayob, Jennifer Curtis, Elizabeth H Stover, Panagiotis A Konstantinopoulos, Elise C Kohn, David L Kolin, Bose Kochupurakkal, Andrea E Wahner Hendrickson, Su-Chun Cheng, Elizabeth K Lee, Doga Gulhan, Alexandre André B A da Costa

Journal: Nature communications 2021;12(1):5574

PMID: 34552099

Free Full Text on Nature Publishing Group View on PubMed

Abstract

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

Address: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. [email protected].; Department of Medical Oncology, AC Camargo Cancer Center, São Paulo, SP, Brazil.; Department of Biomedical Informatics and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.

DOI: 10.1038/s41467-021-25904-w

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MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Biomarkers, Tumor, DNA Replication, Deoxycytidine, Female, Humans, Isoxazoles, Mutation, Oncogenes, Ovarian Neoplasms, Progression-Free Survival, Protein Kinase Inhibitors, Pyrazines, Recombinational DNA Repair, Retinoblastoma Binding Proteins, Gemcitabine