Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis

Labidi-Galy, Sana Intidhar; Rodrigues, Manuel; Sandoval, José Luís; Kurtz, Jean‐Emmanuel; Heitz, Florian; Mosconi, Anna Maria; Romero, Ignacio; Denison, Ursula; Nagao, Shoji; Vergote, Ignace; Parma, Gabriella; Nøttrup, Trine Jakobi; Rouleau, Étienne; Garnier, G.; El‐Balat, Ahmed; Zamagni, Claudio; Martín-Lorente, Cristina; Pujade-Lauraine, Éric; Fiévet, Alice

doi:10.1016/j.annonc.2022.11.003

Cited by 25 publications

(23 citation statements)

References 60 publications

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“…The location of BRCA1/2 mutations is not only associated with risks for specific cancers, but has also been suggested to influence the magnitude of benefit from treatment with platinum salts and/or olaparib (plus bevacizumab). An exploratory analysis of the PAOLA-1 trial suggested that patients with mutations in the DBD region of BRCA2 might be extremely sensitive to platinum, whereas those with mutations in the DBD region of BRCA1 might be less sensitive to platinum but extremely sensitive to olaparib plus bevacizumab 33 . Currently, the biological mechanisms underlying domain-related sensitivity to PARPi are unknown.…”

Section: Discussionmentioning

confidence: 99%

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

Claes,

Fieuws,

Meulen

et al. 2023

Preprint

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Ovarian cancer is the most lethal gynecologic malignancy, mainly due to late-stage diagnosis, frequent recurrences, and eventually therapy resistance. To identify potentially actionable genetic variants, sequencing data of 351 Belgian ovarian cancer patients were retrospectively captured from electronic health records. The cohort included 286 (81%) patients with high-grade serous ovarian cancer, 17 (5%) with low-grade serous ovarian cancer, and 48 (14%) with other histotypes. Firstly, an overview of the prevalence and spectrum of the BRCA1/2 variants highlighted germline variants in 4% (11/250) and somatic variants in 11% (39/348) of patients. Secondly, application of a multi-gene panel in 168 tumors revealed a total of 214 variants in 28 genes beyond BRCA1/2 with a median of 1 (IQR, 1 to 2) genetic variant per patient. The ten most often altered genes were (in descending order): TP53, BRCA1, PIK3CA, BRCA2, KRAS, TERT promotor, RB1, PIK3R1, PTEN, and ERBB2 (HER2). Of note, the genetic landscape vastly differed between the studied histotypes. Finally, using ESCAT the clinical evidence of utility for every genetic variant was scored. Only BRCA1/2 pathogenic variants were classified as tier-I. Nearly all patients (151/168; 90%) had an ESCAT tier-II variant, most frequently in TP53 (74%), PIK3CA (9%) and KRAS (7%). In conclusion, our findings imply that although only a small proportion of genetic variants currently have direct impact on ovarian cancer treatment decisions, other variants could help to identify novel (personalized) treatment options to address the poor prognosis of ovarian cancer, particularly in rare histotypes.

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Section: Discussionmentioning

confidence: 99%

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

Claes,

Fieuws,

Meulen

et al. 2023

Preprint

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“…Moreover, deletion in DBD of BRCA2 increases olaparib and cisplatin sensitivity of engineered cell lines while deletion within the C-terminal domain retains partial HR activity and confers less sensitivity to DNA-damaging agents ( 33 ). Recently, ancillary analysis from the PAOLA-1 phase III clinical trial ( 29 ), assessing olaparib and bevacizumab first-line maintenance therapy, was the first large effort to assess the impact of the location of BRCA1/2 mutations on PARPi sensitivity in patients ( 6 ). Labidi-Galy and colleagues analyzed the location of BRCA1/2 mutation in 233 out of 806 randomized patients.…”

Section: Primary Resistance To Parpimentioning

confidence: 99%

“…Labidi-Galy and colleagues analyzed the location of BRCA1/2 mutation in 233 out of 806 randomized patients. Interestingly, they found that patients with BRCA1/2 mutation involving exon 11 derived greater benefit from the addition of olaparib compared to patients with mutation outside the exon 11 (HR = 0.2 [95% CI = 0.11–0.36] and HR = 0.41 [95% CI, 0.22–0.75], respectively) ( 29 ), as well as those with mutations in DBD of BRCA1 (HR = 0.08 [95% CI = 0.02–0.28]). These results are, however, surprising since previous studies reported worse outcomes and sensitivity to PARPi and platinum in cell lines with BRCA1 mutation inside versus outside exon 11 due to the presence of a hypomorphic BRCA1 protein ( 32 ).…”

Section: Primary Resistance To Parpimentioning

confidence: 99%

“…First described in cancer cell lines and patient-derived xenografts (PDX) models, reversion mutations have been identified and are currently increasingly studied in patients enrolled in clinical trials ( 27 , 28 ). Moreover, beyond the role of BRCA1/2 reversion mutations in PARPi resistance, the type and location of the original loss of function mutation have been recently associated with primary PARPi sensitivity ( 29 ). In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations.…”

Section: Introductionmentioning

confidence: 99%

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BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges

Collet,

Hanvic,

Turinetto

et al. 2024

Front. Oncol.

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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.

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“…The benefit of PARPi maintenance is higher in the BRCAm cohort, followed by BRCAwt/homologous recombination deficiency-positive, and then homologous recombination deficiency-negative patients. The type and location of mutations in the BRCA1/2 and homologous recombination repair genes are also prognostic in ovarian cancer patients but their predictive role in the maintenance decision-making needs to be further explored 9 10…”

Section: What Is the State Of The Art Of First-line Poly (Adp-ribose)...mentioning

confidence: 99%

Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer: lessons learned and future directions

Caruso

Tomao

Parma

et al. 2023

International Journal of Gynecological Cancer

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Poly (ADP-ribose) polymerase inhibitors (PARPi) represent a new standard of care in the upfront treatment of advanced epithelial ovarian cancer to the point that the vast majority of patients now receive a PARPi, alone or in combination with the anti-angiogenic bevacizumab, as part of their first-line maintenance therapy. The clinical benefit of PARPi is well established; however, much has changed since their introduction and several relevant questions have been raised and remain unresolved in the post-PARPi era. The decision-making process regarding the most appropriate first-line maintenance therapy could be challenging in clinical practice, especially in the homologous recombination-proficient setting, and several other factors need to be considered apart from the mutational status. Concerns regarding post-PARPi progression treatment have emerged, highlighting an unmet need to define a valid algorithm strategy. PARPi may not only compromise the response to further platinum due to cross-resistance mechanisms but the impact on subsequent non-platinum chemotherapy and surgery also remains unclear. Definitive results on the role of PARPi rechallenge are awaited, especially in the case of oligoprogression managed with locoregional treatment. Moreover, the updated overall survival data from the recurrent setting warrant caution in using PARPi as single agents for unselected patients. Several PARPi combination regimens are emerging for overcoming PARPi resistance and may become our new therapeutic armamentarium. This review discusses a set of clinically relevant issues in the PARPi era and provides a glimpse of future challenges and opportunities in ovarian cancer treatment.

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Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis

Cited by 25 publications

References 60 publications

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

Identification of potentially actionable genetic variants in epithelial ovarian cancer: A retrospective cohort study

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges

Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer: lessons learned and future directions

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