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[Abnormalities of DNA repair and gynecological cancers].

Authors
  • Auguste, Aurélie1
  • Leary, Alexandra2
  • 1 Gustave-Roussy, Inserm U981, Gynecological Tumors Translational Research Lab, 114, rue Edouard-Vaillant, B2M - p130, 94805 Villejuif, France. Electronic address: [email protected] , (France)
  • 2 Gustave-Roussy, Inserm U981, Gynecological Tumors Translational Research Lab, 114, rue Edouard-Vaillant, B2M - p130, 94805 Villejuif, France; University Paris-Saclay, Gustave Roussy Cancer Center, Department of Medical Oncology, 94805 Villejuif, France. , (France)
Type
Published Article
Journal
Bulletin du cancer
Publication Date
Oct 17, 2017
Identifiers
DOI: 10.1016/j.bulcan.2017.09.007
PMID: 29054544
Source
Medline
Keywords
License
Unknown

Abstract

The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer. Furthermore, several recent trials in OC have demonstrated that the benefit of PARPi may not be limited to patients with BRCA mutations. These data, combined with genomic studies suggesting that a significant proportion of OC may harbor somatic and germline alterations in other HR genes open huge perspectives for exploiting DNA repair as a therapeutic strategy. The current priorities are to (i) determine whether new biomarkers of homologous recombination deficiency may identify the BRCA wild-type subset likely to derive benefit from PARPi; (ii) to determine whether the efficacy of PARPi can be improved by combinatorial strategies (with chemotherapy, radiotherapy, immunotherapy, anti-angiogenesis or DNA repair inhibitors) and (iii) to develop new approaches exploiting DNA repair deficiencies in ovarian and other gynecological tumors.

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