@article{0b18918483164d2797e4dc1804dc72b4,
title = "53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer",
abstract = "Objective: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting. Methods: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. Results: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r = 0.050; p = 0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r = −0.69, p = 0.004). Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.",
keywords = "53BP1, DNA damage, HR-deficiency, Ovarian cancer, PARP inhibitors",
author = "Hurley, {Rachel M.} and {Wahner Hendrickson}, {Andrea E.} and Visscher, {Daniel W.} and Peter Ansell and Harrell, {Maria I.} and Wagner, {Jill M.} and Vivian Negron and Goergen, {Krista M.} and Maurer, {Matthew J.} and Oberg, {Ann L.} and Meng, {X. Wei} and Flatten, {Karen S.} and {De Jonge}, {Maja J.A.} and {Van Herpen}, {Carla D.} and Gietema, {Jourik A.} and Koornstra, {Rutger H.T.} and Agnes Jager and {den Hollander}, {Martha W.} and Matthew Dudley and Shepherd, {Stacie P.} and Swisher, {Elizabeth M.} and Kaufmann, {Scott H.}",
note = "Funding Information: The work was supported in part by NIH grants P50 CA136393 (S.H.K., A.E.W.H., and D.W.V.) and R01 CA190423 (S.H.K., A.E.W.H., E.M.S., and D.W.V.), and DOD Translational Synergy Grant W81XWH-13-1-0485 (to E.M.S. and S.H.K.) as well as a fellowship (to R.M.H.) and support (S.H.K.) from the Mayo Foundation for Medical Education and Research . A.E.W.H., E.M.S., and S.H.K. were supported by Stand Up To Cancer – Ovarian Cancer Research Fund Alliance – National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15 ). Stand Up to Cancer is a program of the Entertainment Industry Foundation ; research grants are administered by the American Association for Cancer Research , a scientific partner of SU2C. Funding Information: P.A. and M.D. are employed and hold stock and intellectual property from Abbvie. S.H.K. receives royalties from Millipore and Topogen for unrelated technology and is an inventor on a patent held by Mayo Clinic regarding NHEJ proteins in ovarian cancer. S.P.S. holds stock through and was previously employed at Abbvie. The Phase I trial was funded by Abbvie, but no funding was provided for the follow-up biomarker study presented here. Funding Information: The work was supported in part by NIH grants P50 CA136393 (S.H.K., A.E.W.H., and D.W.V.) and R01 CA190423 (S.H.K., A.E.W.H., E.M.S., and D.W.V.), and DOD Translational Synergy Grant W81XWH-13-1-0485 (to E.M.S. and S.H.K.) as well as a fellowship (to R.M.H.) and support (S.H.K.) from the Mayo Foundation for Medical Education and Research. A.E.W.H., E.M.S., and S.H.K. were supported by Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15). Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C. Funding Information: The work was supported in part by NIH grants P50 CA136393 (S.H.K., A.E.W.H., and D.W.V.) and R01 CA190423 (S.H.K., A.E.W.H., E.M.S., and D.W.V.), and DOD Translational Synergy Grant W81XWH-13-1-0485 (to E.M.S. and S.H.K.) as well as a fellowship (to R.M.H.) and support (S.H.K.) from the Mayo Foundation for Medical Education and Research. A.E.W.H., E.M.S., and S.H.K. were supported by Stand Up To Cancer?Ovarian Cancer Research Fund Alliance?National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15). Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = apr,
doi = "10.1016/j.ygyno.2019.01.015",
language = "English (US)",
volume = "153",
pages = "127--134",
journal = "Gynecologic oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",
number = "1",
}