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

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

Authors :
Konstantinopoulos, Panagiotis A.
da Costa, Alexandre André B. A.
Gulhan, Doga
Lee, Elizabeth K.
Cheng, Su-Chun
Hendrickson, Andrea E. Wahner
Kochupurakkal, Bose
Kolin, David L.
Kohn, Elise C.
Liu, Joyce F.
Stover, Elizabeth H.
Curtis, Jennifer
Tayob, Nabihah
Polak, Madeline
Chowdhury, Dipanjan
Matulonis, Ursula A.
Färkkilä, Anniina
D'Andrea, Alan D.
Shapiro, Geoffrey I.
Source :
Nature Communications; 9/22/2021, Vol. 12 Issue 1, p1-8, 8p
Publication Year :
2021

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. A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20411723
Volume :
12
Issue :
1
Database :
Complementary Index
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
152580563
Full Text :
https://doi.org/10.1038/s41467-021-25904-w