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Published on: February 24, 2023
Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race
Katherine A Lawson-Michod1,2,3, Courtney E Johnson4, Mollie E Barnard2,3,5
1Fred Hutchinson Cancer Center, Seattle, Washington.
Insights
Homologous recombination deficiency (HRD) impacts ovarian cancer survival differently across races. Characterizing HRD in diverse populations is crucial for equitable precision medicine and improved outcomes.
Area of Science:
- Genomic medicine
- Oncology
- Population health
Background:
- Half of ovarian high-grade serous carcinomas (HGSC) exhibit homologous recombination deficiency (HRD).
- HRD is less understood in Black individuals, who face poorer HGSC survival rates.
- Disparities in HGSC outcomes necessitate research into racial differences in HRD.
Purpose of the Study:
- To characterize HRD features in ovarian HGSC.
- To investigate the association between HRD and survival in Black and White individuals.
- To identify racial disparities in HRD characterization and its clinical implications.
Main Methods:
- Whole-exome and RNA sequencing were used to identify HRD features in an HGSC cohort.
- Survival analyses were performed using age- and stage-adjusted hazard ratios, stratified by self-reported race.
- Germline and somatic variants were analyzed for racial differences in annotation and significance.
Main Results:
- Any HRD was linked to a 32% reduced mortality risk in Black individuals versus a 62% reduction in White individuals.
- A higher proportion of unannotated or variant of uncertain significance (VUS) germline (65% vs. 45%) and somatic (62% vs. 50%) variants were found in Black individuals.
- Black individuals with germline unannotated/VUS variants were more likely to have HRD scarring and a family history of breast or ovarian cancer.
Conclusions:
- HRD testing is vital for precision medicine in ovarian cancer, but higher VUS rates in Black individuals may hinder access to care.
- Genomic research must prioritize diverse participant recruitment to accurately characterize VUS and reduce outcome disparities.
- Further research is needed to understand and address the clinical impact of VUS in diverse populations for equitable cancer care.
Background:
Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race.
Methods:
HRD features were identified using matched tumor-normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race.
Results:
Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43-1.09; White HR = 0.38; 95% CI, 0.14-1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%).
Conclusions:
HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals.
Impact:
Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.
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