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

Panagiotis A. Konstantinopoulos (), Alexandre André B. A. Costa, Doga Gulhan, Elizabeth K. Lee, Su-Chun Cheng, Andrea E. Wahner Hendrickson, 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 and Geoffrey I. Shapiro
Additional contact information
Panagiotis A. Konstantinopoulos: Dana-Farber Cancer Institute
Alexandre André B. A. Costa: AC Camargo Cancer Center
Doga Gulhan: Department of Biomedical Informatics and Ludwig Center at Harvard, Harvard Medical School
Elizabeth K. Lee: Dana-Farber Cancer Institute
Su-Chun Cheng: Dana-Farber Cancer Institute
Andrea E. Wahner Hendrickson: Department of Medical Oncology, Mayo Clinic
Bose Kochupurakkal: Dana-Farber Cancer Institute
David L. Kolin: Brigham and Women’s Hospital
Elise C. Kohn: National Cancer Institute
Joyce F. Liu: Dana-Farber Cancer Institute
Elizabeth H. Stover: Dana-Farber Cancer Institute
Jennifer Curtis: Dana-Farber Cancer Institute
Nabihah Tayob: Dana-Farber Cancer Institute
Madeline Polak: Dana-Farber Cancer Institute
Dipanjan Chowdhury: Dana-Farber Cancer Institute
Ursula A. Matulonis: Dana-Farber Cancer Institute
Anniina Färkkilä: University of Helsinki
Alan D. D’Andrea: Dana-Farber Cancer Institute
Geoffrey I. Shapiro: Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25904-w

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