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Review
. 2020 Aug 25;12(9):2414.
doi: 10.3390/cancers12092414.

Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives

Thibaut Reverdy  1 , Christophe Sajous  1 , Julien Péron  1 , Olivier Glehen  2   3 , Naoual Bakrin  2   3 , Witold Gertych  3   4 , Jonathan Lopez  5 , Benoit You  1   3 , Gilles Freyer  1   3
Affiliations
Review

Front-Line Maintenance Therapy in Advanced Ovarian Cancer-Current Advances and Perspectives

Thibaut Reverdy et al. Cancers (Basel). .

Abstract

Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic BRCA mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date.

Keywords: BRCA 1/2; PARP inhibitors; anti-angiogenics; front-line maintenance therapy; homologous recombination deficiency; immunotherapy; ovarian cancer.

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Conflict of interest statement

J.P. has been involved as a consultant for AZ, Roche and Lilly, Olivier Glehen is consultant for Gamida, B.Y. has been involved as a consultant for AZ, GSK, NOVARTIS, BAYER, ROCHE, CLOVIS, AMGEN, MSD, ECS Progastrin and has received accommodation from AZ, MSD and BAYER, G.F. has been involved as a consultant for Clovis, GSK, AZ, MSD, BMS, Roche and Lilly. The rest of the authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PARP inhibitor mechanisms. (A) DNA single strand break damage (SSB) appears and induce stress on the replication fork duplicating DNA in S phase. (B) Physiologically, the base excision repair (BER) pathway intervene through PARP enzyme. (C) SSB is fixe and replication proceed. (D) At the end of phase S the cell has 2 copies of DNA and mitosis continues. (E) However in the presence of PARP inhibitor (PARPi) the BER mechanism does not detect SSB and the PARP enzymes bind on the SSB are trapped. (F) The replication fork collapses in response to unrepaired SSB and PARP entrapment. (G) PARP trapping leads to double strand-break (DSB). In case of homologous repair-deficiency (HRd) phenotype, the DSB can be resolved by the non-homologous end-joining (NHEJ), which generates numerous mutations, resulting in genome instability and cell death.
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