Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer
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: RA...
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doaj-df939f5088464a3da48c51d92d1dc85e2020-11-25T02:10:43ZengMDPI AGCancers2072-66942020-03-0112370710.3390/cancers12030707cancers12030707Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian CancerPaul Kubelac0Catherine Genestie1Aurelie Auguste2Soizick Mesnage3Audrey Le Formal4Patricia Pautier5Sebastien Gouy6Philippe Morice7Enrica Bentivegna8Amandine Maulard9Julien Adam10Patriciu Achimas-Cadariu11Alexandra Leary12Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj Napoca, RomaniaINSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, FranceINSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, FranceINSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, FranceINSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Medical Oncology, Université Paris-Saclay, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Surgery, Université Paris-Saclay, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Surgery, Université Paris-Saclay, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Surgery, Université Paris-Saclay, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Surgery, Université Paris-Saclay, 94805 Villejuif, FranceGustave Roussy Cancer Center, Department of Pathology, Université Paris-Saclay, 94805 Villejuif, FranceDepartment of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj Napoca, RomaniaINSERM U981, Gustave Roussy Cancer Center, 94805 Villejuif, FranceOvarian 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, <i>p</i> = 0.009 and HR 2.78, <i>p</i> = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, <i>p</i> = 0.05 and HR 2.38, <i>p</i> = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, <i>p</i> = 0.038 and HR 2.04, <i>p</i> = 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).https://www.mdpi.com/2072-6694/12/3/707ovarian cancerdna damage repairtemporal heterogeneitysurvival |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paul Kubelac Catherine Genestie Aurelie Auguste Soizick Mesnage Audrey Le Formal Patricia Pautier Sebastien Gouy Philippe Morice Enrica Bentivegna Amandine Maulard Julien Adam Patriciu Achimas-Cadariu Alexandra Leary |
spellingShingle |
Paul Kubelac Catherine Genestie Aurelie Auguste Soizick Mesnage Audrey Le Formal Patricia Pautier Sebastien Gouy Philippe Morice Enrica Bentivegna Amandine Maulard Julien Adam Patriciu Achimas-Cadariu Alexandra Leary Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer Cancers ovarian cancer dna damage repair temporal heterogeneity survival |
author_facet |
Paul Kubelac Catherine Genestie Aurelie Auguste Soizick Mesnage Audrey Le Formal Patricia Pautier Sebastien Gouy Philippe Morice Enrica Bentivegna Amandine Maulard Julien Adam Patriciu Achimas-Cadariu Alexandra Leary |
author_sort |
Paul Kubelac |
title |
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer |
title_short |
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer |
title_full |
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer |
title_fullStr |
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer |
title_full_unstemmed |
Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer |
title_sort |
changes in dna damage response markers with treatment in advanced ovarian cancer |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-03-01 |
description |
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, <i>p</i> = 0.009 and HR 2.78, <i>p</i> = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, <i>p</i> = 0.05 and HR 2.38, <i>p</i> = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, <i>p</i> = 0.038 and HR 2.04, <i>p</i> = 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). |
topic |
ovarian cancer dna damage repair temporal heterogeneity survival |
url |
https://www.mdpi.com/2072-6694/12/3/707 |
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