BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges
BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphospha...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2024.1354427/full |
| _version_ | 1797263661868253184 |
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| author | Laetitia Collet Laetitia Collet Laetitia Collet Brunhilde Hanvic Brunhilde Hanvic Margherita Turinetto Isabelle Treilleux Nicolas Chopin Olivia Le Saux Olivia Le Saux Isabelle Ray-Coquard Isabelle Ray-Coquard |
| author_facet | Laetitia Collet Laetitia Collet Laetitia Collet Brunhilde Hanvic Brunhilde Hanvic Margherita Turinetto Isabelle Treilleux Nicolas Chopin Olivia Le Saux Olivia Le Saux Isabelle Ray-Coquard Isabelle Ray-Coquard |
| author_sort | Laetitia Collet |
| collection | DOAJ |
| description | BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate–ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients. |
| first_indexed | 2024-04-25T00:16:34Z |
| format | Article |
| id | doaj.art-4ce29ee231a040ebb2aded80b23eceb5 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-25T00:16:34Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4ce29ee231a040ebb2aded80b23eceb52024-03-13T04:30:22ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-03-011410.3389/fonc.2024.13544271354427BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challengesLaetitia Collet0Laetitia Collet1Laetitia Collet2Brunhilde Hanvic3Brunhilde Hanvic4Margherita Turinetto5Isabelle Treilleux6Nicolas Chopin7Olivia Le Saux8Olivia Le Saux9Isabelle Ray-Coquard10Isabelle Ray-Coquard11Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, BelgiumMedical Oncology Department, Centre Léon Bérard, Lyon, FranceUniversity Claude Bernard Lyon 1, Lyon, FranceMedical Oncology Department, Centre Léon Bérard, Lyon, FranceUniversity Claude Bernard Lyon 1, Lyon, FranceMedical Oncology Department, Centre Léon Bérard, Lyon, FranceDepartment of Pathology, Centre Léon Bérard, Lyon, FranceDepartment of Surgery, Centre Léon Bérard, Lyon, FranceMedical Oncology Department, Centre Léon Bérard, Lyon, FranceUniversity Claude Bernard Lyon 1, Lyon, FranceMedical Oncology Department, Centre Léon Bérard, Lyon, FranceUniversity Claude Bernard Lyon 1, Lyon, FranceBRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate–ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.https://www.frontiersin.org/articles/10.3389/fonc.2024.1354427/fullhigh grade ovarian cancerBRCA1/2 mutationreversion mutationPARP inhibitorresistancehomologous recombination deficiency |
| spellingShingle | Laetitia Collet Laetitia Collet Laetitia Collet Brunhilde Hanvic Brunhilde Hanvic Margherita Turinetto Isabelle Treilleux Nicolas Chopin Olivia Le Saux Olivia Le Saux Isabelle Ray-Coquard Isabelle Ray-Coquard BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges Frontiers in Oncology high grade ovarian cancer BRCA1/2 mutation reversion mutation PARP inhibitor resistance homologous recombination deficiency |
| title | BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges |
| title_full | BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges |
| title_fullStr | BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges |
| title_full_unstemmed | BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges |
| title_short | BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges |
| title_sort | brca1 2 alterations and reversion mutations in the area of parp inhibitors in high grade ovarian cancer state of the art and forthcoming challenges |
| topic | high grade ovarian cancer BRCA1/2 mutation reversion mutation PARP inhibitor resistance homologous recombination deficiency |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2024.1354427/full |
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