The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Ngoi, Natalie Yl; Tan, David Sp

doi:10.1016/j.esmoop.2021.100144

Cited by 95 publications

(101 citation statements)

References 80 publications

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“…High-grade serous ovarian cancer (HGSOC) is the most common type of EOC, accounting for 75% of all EOC, 15-20% of which western patients have germline BRCA1 or BRCA2 mutations. The BRCA mutation rate observed in our cohort was 35.8%, which was near the higher boundary of the previously reported range of 5 to 35% (14,22). Similar to other studies, we also observed BRCA1 mutations occurring more frequently than BRCA2 mutations in Chinese ovarian cancer patients (23,24).…”

Section: Discussionsupporting

confidence: 89%

“…FoundationFocus ® CDx mainly evaluates HRD by loss of heterozygosity (LOH) with 16% as the threshold value that has been used for companion diagnostic (CDx) of rucaparib (11), while Myriad myChoice ® CDx includes LOH, telomere allele imbalance (TAI), and large fragment migration (LST) with 42 as the threshold value that has been widely applied for CDx of niraparib and olaparib (4,6,10,12). Approximately 50% of patients with high-grade serous ovarian cancer are HRD positive in the western population (13,14).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Homologous Recombination Deficiency Associated With Response to Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer Patients: The First Real-World Evidence From China

Guo

Zhao

et al. 2022

Front. Oncol.

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Homologous recombination deficiency (HRD) is an approved predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of positive HRD in the real world and the relationship between HRD status and PARPi in Chinese ovarian cancer patients remain unknown. A total of 67 ovarian cancer patients who underwent PARPi, either olaparib or niraparib, were enrolled and passed inclusion criteria from August 2018 to January 2021 in the Affiliated Cancer Hospital of Nanjing Medical University. HRD status correlation with Progression-free survival (PFS) was analyzed and summarized with a log-rank test. Univariate and multiple cox-regression analyses were conducted to investigate all correlated clinical factors. Approximately 68.7% (46/67) patients were HRD positive and the rest 31.3% (21/67) were HRD negative. The PFS among HRD-positive patients was significantly longer than those HRD-negative patients (medium PFS 9.4 m vs 4.1 m, hazard ratio [HR]: 0.52, 95% CI: [0.38–0.71], p <0.001). Univariate cox-regression found that HRD status, Eastern Cooperative Oncology Group (ECOG) status, BRCA status, previous treatment lines, secondary cytoreductive surgery and R0 resection were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status and ECOG were the independent factors to predict PFS (HR: 0.67, 95% CI: [0.49–0.92], p = 0.01; HR: 2.20, 95% CI: [1.14–4.23], p = 0.02, respectively). In platinum sensitivity evaluable subgroup (N = 49), HRD status and platinum sensitivity status remain significant to predict PFS after multiple regression correction (HR: 0.71, 95% CI: [0.51–0.98], p = 0.04; HR: 0.49, 95% CI: [0.24–1.0], p = 0.05, respectively). This is the first real-world study of HRD status in ovarian cancer patients in China, and we demonstrate that HRD is an independent predictive biomarker for PARP inhibitors treatment in Chinese ovarian cancer patients.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Homologous Recombination Deficiency Associated With Response to Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer Patients: The First Real-World Evidence From China

Guo

Zhao

et al. 2022

Front. Oncol.

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“…Currently, there are five commercially available FDA-approved CDx tests for evaluating PARPi eligibility: BRACAnalysis CDx and MyChoice CDx from Myriad Genetic Laboratories, Inc., as well as FoundationOne CDx, FoundationFocus CDxBRCA, and FoundationOne Liquid CDx from Foundation Medicine ( 60 , 61 ). NGS-based CDx tests follow similar workflows: DNA is extracted from tissues and sequenced through NGS platforms, and then raw reads are processed through proprietary bioinformatics pipelines for variants calling and medical interpretation.…”

Section: Dna Damage Repair Pathways and Cancermentioning

confidence: 99%

“…The five CDx mentioned can all detect pathogenic or likely pathogenic variants of BRCA1/2. Among them, MyChoice CDx and FoundationOne CDx assays are prospectively validated assays for evaluation of HR deficiency status ( 61 ). The HR deficiency status can be assessed by checking the percentage of genomic regions with loss of heterozygosity (LOH) using single nucleotide polymorphism (SNP) sequencing or by calculation of the Genomic Instability Score (GIS) via coalescing three parameters: LOH, large scale transitions (LSTs) and telomeric allelic imbalance (TAI).…”

Section: Dna Damage Repair Pathways and Cancermentioning

confidence: 99%

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

Wong

Cheung

2021

Front. Oncol.

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Ovarian clear cell carcinoma (OCCC) is one of the major types of ovarian cancer and is of higher relative prevalence in Asians. It also shows higher possibility of resistance to cisplatin-based chemotherapy leading to poor prognosis. This may be attributed to the relative lack of mutations and aberrations in homologous recombination-associated genes, which are crucial in DNA damage response (DDR), such as BRCA1, BRCA2, p53, RAD51, and genes in the Fanconi anemia pathway. On the other hand, OCCC is characterized by a number of genetic defects rendering it vulnerable to DDR-targeting therapy, which is emerging as a potent treatment strategy for various cancer types. Mutations of ARID1A, PIK3CA, PTEN, and catenin beta 1 (CTNNB1), as well as overexpression of transcription factor hepatocyte nuclear factor-1β (HNF-1β), and microsatellite instability are common in OCCC. Of particular note is the loss-of-function mutations in ARID1A, which is found in approximately 50% of OCCC. ARID1A is crucial for processing of DNA double-strand break (DSB) and for sustaining DNA damage signaling, rendering ARID1A-deficient cells prone to impaired DNA damage checkpoint regulation and hence sensitive to poly ADP ribose polymerase (PARP) inhibitors. However, while preclinical studies have demonstrated the possibility to exploit DDR deficiency in OCCC for therapeutic purpose, progress in clinical application is lagging. In this review, we will recapitulate the preclinical studies supporting the potential of DDR targeting in OCCC treatment, with emphasis on the role of ARID1A in DDR. Companion diagnostic tests (CDx) for predicting susceptibility to PARP inhibitors are rapidly being developed for solid tumors including ovarian cancers and may readily be applicable on OCCC. The potential of various available DDR-targeting drugs for treating OCCC by drawing analogies with other solid tumors sharing similar genetic characteristics with OCCC will also be discussed.

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“…Mainly used as indirect measures are the LOH determined by SNP-Sequencing, telomeric allelic imbalance (TAI), and large-scale state transitions (LST) for which each HRD score has been developed (143)(144)(145). Currently, for clinical routine use, only two prospectively validated and commercially available tests for assessment of HRD status are available (146): the myChoice CDx (Myriad Genetics) calculates a score based on all three genomic instability features and also includes BRCA1/2 mutations. In contrast, the FoundationOne CDx (Foundation Medicine) only calculates the percentage of genomic LOH.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives

et al. 2021

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Mutated germline alleles in the DNA damage repair (DDR) genes “breast cancer gene 1” (BRCA1) and BRCA2 have originally been identified as major susceptibility genes in breast and ovarian cancers. With the establishment and approval of more cost-effective gene sequencing methods, germline and somatic BRCA mutations have been detected in several cancers. Since the approval of poly (ADP)-ribose polymerase inhibitors (PARPi) for BRCA-mutated cancers, BRCA mutations gained rising therapeutic implications. The impact and significance of BRCA mutations have been evaluated extensively in the last decades. Moreover, other genes involved in the DDR pathway, such as ATM, ATR, or CHK1, have emerged as potential new treatment targets, as inhibitors of these proteins are currently under clinical investigation. This review gives a concise overview on the emerging clinical implications of mutations in the DDR genes in gastrointestinal cancers with a focus on BRCA mutations.

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The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Cited by 95 publications

References 80 publications

Homologous Recombination Deficiency Associated With Response to Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer Patients: The First Real-World Evidence From China

Homologous Recombination Deficiency Associated With Response to Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer Patients: The First Real-World Evidence From China

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives

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