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Open AccessArticle

Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer

1
Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj Napoca, Romania
2
The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj Napoca, Romania
3
INSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, France
4
Gustave Roussy Cancer Center, Department of Pathology, Université Paris-Saclay, 94805 Villejuif, France
5
Gustave Roussy Cancer Center, Department of Medical Oncology, Université Paris-Saclay, 94805 Villejuif, France
6
Gustave Roussy Cancer Center, Department of Surgery, Université Paris-Saclay, 94805 Villejuif, France
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 707; https://doi.org/10.3390/cancers12030707
Received: 24 February 2020 / Revised: 8 March 2020 / Accepted: 11 March 2020 / Published: 17 March 2020
Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0–300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1−/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi). View Full-Text
Keywords: ovarian cancer; DNA damage repair; temporal heterogeneity; survival ovarian cancer; DNA damage repair; temporal heterogeneity; survival
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Kubelac, P.; Genestie, C.; Auguste, A.; Mesnage, S.; Le Formal, A.; Pautier, P.; Gouy, S.; Morice, P.; Bentivegna, E.; Maulard, A.; Adam, J.; Achimas-Cadariu, P.; Leary, A. Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer. Cancers 2020, 12, 707.

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