Genetic testing for epithelial ovarian cancer

Amin, Noa; Chaabouni, Narda; George, Angela

doi:10.1016/j.bpobgyn.2020.01.005

Cited by 18 publications

(14 citation statements)

References 82 publications

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“…For OC patients with BRCA1/2 cancer driver mutations, PARP inhibitors are the standard of care rather than immunotherapy. Genetic counseling of the relatives of cancer patients is essential [39]. In addition, we identified RET, CBL, and DDR2 driver mutations as potential response markers in hypermutated cancers.…”

Section: Discussionmentioning

confidence: 99%

Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Lin

Yeh

Hsu

et al. 2021

Cancers

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Tumor heterogeneity results in more than 50% of hypermutated cancers failing to respond to standard immunotherapy. There are numerous challenges in terms of drug resistance, therapeutic strategies, and biomarkers in immunotherapy. In this study, we analyzed primary tumor samples from 533 cancer patients with six different cancer types using deep targeted sequencing and gene expression data from 78 colorectal cancer patients, whereby driver mutations, mutational signatures, tumor-associated neoantigens, and molecular cancer evolution were investigated. Driver mutations, including RET, CBL, and DDR2 gene mutations, were identified in the hypermutated cancers. Most hypermutated endometrial and pancreatic cancer patients carry genetic mutations in EGFR, FBXW7, and PIK3CA that are linked to immunotherapy resistance, while hypermutated head and neck cancer patients carry genetic mutations associated with better treatment responses, such as ATM and BRRCA2 mutations. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and DNA repair defects are mutational drivers that are signatures for hypermutated cancer. Cancer driver mutations and other mutational signatures are associated with sensitivity or resistance to immunotherapy, representing potential genetic markers in hypermutated cancers. Using computational prediction, we identified NF1 p.T700I and NOTCH1 p.V2153M as tumor-associated neoantigens, representing potential therapeutic targets for immunotherapy. Sequential mutations were used to predict hypermutated cancers based on genomic evolution. Using a logistic model, we achieved an area under the curve (AUC) = 0.93, accuracy = 0.93, and sensitivity = 0.81 in the testing set. The sequential patterns were distinct among the six cancer types, and the sequential mutation order of MSH2 and the coexisting BRAF genetic mutations influenced the hypermutated phenotype. The TP53~MLH1 and NOTCH1~TET2 sequential mutations impacted colorectal cancer survival (p-value = 0.027 and 0.0001, respectively) by reducing the expression of PTPRCAP (p-value = 1.06 × 10−6) and NOS2 (p-value = 7.57 × 10−7) in immunity. Sequential mutations are significant for hypermutated cancers, which are characterized by mutational heterogeneity. In addition to driver mutations and mutational signatures, sequential mutations in cancer evolution can impact hypermutated cancers. They characterize potential responses or predictive markers for hypermutated cancers. These data can also be used to develop hypermutation-associated drug targets and elucidate the evolutionary biology of cancer survival. In this study, we conducted a comprehensive analysis of mutational patterns, including sequential mutations, and identified useful markers and therapeutic targets in hypermutated cancer patients.

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Section: Discussionmentioning

confidence: 99%

Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Lin

Yeh

Hsu

et al. 2021

Cancers

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“…Only about 15% of patients with advanced serous ovarian cancer have germline BRCA mutations, 6% have somatic BRCA mutations ( Amin et al, 2020 ), and approximately 50% of patients have HRD-positive mutations ( Ibrahim et al, 2020 ). The National Comprehensive Cancer Network (NCCN) recommends the detection of HRD as a biomarker of PARPis in patients with advanced serous ovarian cancer ( Miller et al, 2020 ), indicating the effectiveness of clinically recognized PARPis in an HRD-positive population.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer

Gao

Chen

et al. 2021

Front. Pharmacol.

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Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC).Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated.Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively.Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.

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“…Since then, the clinical relevance of PARPis has been confirmed in a number of studies including a larger group of patients, namely patients with somatic BRCA1/2 mutations, HRD and genetic or epigenetic aberrations that result in a "BRCAness" profile (19,20). This broad group of patients appears to respond better to platinum-based chemotherapies, as well as to PARPis, ultimately demonstrating improved progression-free and overall survival rates (21)(22)(23)(24).…”

Section: Parp Inhibitors In Ovarian Cancermentioning

confidence: 99%

“…Around 50% of HGSOC exhibit a defect in the HR repair mechanism, whereas low-grade serous carcinomas harbor HR defects less frequently (3-11%) (23,25). As far as endometrioid and clear-cell carcinomas is concerned, incidence of HR defects varies widely, ranging between 8-37.6% and 3-26% respectively (22,23,(31)(32)(33). Endometrioid histology, instead, has been strongly associated with Lynch syndrome (21,34,35).…”

Section: Parp Inhibitors In Ovarian Cancermentioning

confidence: 99%

The evolving role of PARP inhibitors in advanced ovarian cancer

Levva

Skolariki

Sogka

et al. 2021

Forum of Clinical Oncology

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The field of ovarian cancer has been revolutionized with the use of poly (ADP-ribose) polymerase (PARP) inhibitors, which present greater inhibition effect in epithelial subtype due to high rates of homologous recombination deficiency. PARP inhibition exploits this cancer pitfall by disrupting DNA repair, leading to genomic instability and apoptosis. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with epithelial ovarian cancer, while others are under development. Among women with BRCA1/2 mutations, maintenance PARP therapy has led to a nearly fourfold prolongation of PFS, while those without BRCA1/2 mutations experience an approximately twofold increase in PFS. Differences in trial design, patient selection and primary analysis population affect the conclusions on PARP inhibitors. Limited OS data have been published and there is also limited experience regarding long-term safety. With regard to toxicity profile, there are no differences in serious adverse events between the experimental and control groups. However, combining adverse event data from maintenance phases, a trend towards more events in the experimental group, compared with controls, has been shown. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair are discussed as well. PARP inhibitors play a pivotal role in the management of ovarian cancer, affecting the future treatment choices. Defining exactly which patients will benefit from them is a challenge and the need for HRD testing to define ‘BRCA-ness’ will add additional costs to treatment.

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Genetic testing for epithelial ovarian cancer

Cited by 18 publications

References 82 publications

Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer

The evolving role of PARP inhibitors in advanced ovarian cancer

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