Performance and clinical utility of homologous recombination deficiency (HRD) determined by genome-wide loss of heterozygosity (LOH).

Li, Chien‐Feng; Chen, Shu‐Jen; Tan, Kien Thiam; Tse, Ka-Po; Wang, Woei-Fuh

doi:10.1200/jco.2022.40.16_suppl.e15025

Cited by 2 publications

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“…ACTHRD assay, an enrichment-based targeted NGS assay, was designed to evaluate HRD status based on the detection of BRCA1/2 gene SNVs, INDEL variations, and the extent of genome-wide loss of heterozygosity (gLOH). The analytical robustness of ACTHRD assay has been validated to be highly consistent with the Food and Drug Administration (FDA)-approved myChoice CDx [15]. The assay employs HRD panel including the whole exons of 22 HRD-related genes (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCI, FANCL, PPP2R2A, PALB2, RAD51C, RAD51D, RAD51B, RAD54L, ATR , EMSY, FANCA, FAM175A, NBN, MRE11A, RAD50, and PTEN) and the whole exons and introns for BRCA1 and BRCA2.…”

Section: Brca /Hrr/hrd Status Analysismentioning

confidence: 94%

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Li,

Peng,

Zhu

et al. 2024

BMC Med

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Background The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. Methods HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan–Meier method was utilised to analyse progression-free survival (PFS). Results This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5–22.1) versus 9.2 months (95% CI: 7.5–13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4–18.2) versus 22.2 months (95% CI: 18.3–NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9–NA) versus 8.3 months (95% CI: 6.7–13.8)]. Conclusions HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. Trial registration NCT03534453. Registered at May 23, 2018.

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Section: Brca /Hrr/hrd Status Analysismentioning

confidence: 94%

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Li,

Peng,

Zhu

et al. 2024

BMC Med

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Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families

Kwong,

Ho,

et al. 2024

JPM

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Background: RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest. Methods: We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC). Results: We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD). Conclusions: Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.

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Performance and clinical utility of homologous recombination deficiency (HRD) determined by genome-wide loss of heterozygosity (LOH).

Cited by 2 publications

References 0 publications

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families

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