Abstract
Leveraging genomic instability scores (GIS) to investigate BRCA variants of unknown significance (VUS) in ovarian cancer: An analysis of 14,513 patients in the Myriad Collaborative Research Registry (MCRR).
Author
person
John Nakayama
Allegheny Health Network, Pittsburgh, PA
info_outline
John Nakayama, Lauren Lenz, Jeff Jasper, Brent Mabey, Brandon Ulm, Shanell Hatcher, Alexander Gutin, Kirsten Timms, Martins Ayoola, Dana Meredith Chase, Thomas C. Krivak, Andrew Berchuck
Full text
Authors
person
John Nakayama
Allegheny Health Network, Pittsburgh, PA
info_outline
John Nakayama, Lauren Lenz, Jeff Jasper, Brent Mabey, Brandon Ulm, Shanell Hatcher, Alexander Gutin, Kirsten Timms, Martins Ayoola, Dana Meredith Chase, Thomas C. Krivak, Andrew Berchuck
Organizations
Allegheny Health Network, Pittsburgh, PA, Myriad Genetics, Inc., Salt Lake City, UT, Myriad Genetics Inc, Salt Lake City, UT, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California, Los Angeles, Los Angeles, CA, Division of Gynecologic Oncology, Duke University School of Medicine, Durham, NC
Abstract Disclosures
Research Funding
Myriad Genetics, Inc.
Background:
In ovarian cancer, use of homologous recombination deficiency (HRD) and
BRCA
mutation (
BRCA
m) status is essential in guiding PARP inhibitor (PARPi) therapy, with the greatest survival benefit in patients harboring
BRCA
m pathogenic variants (PVs). In other indications, PARPi are only approved for patients with BRCAm or homologous recombination repair mutations (HRRm). Genomic instability scores (GIS), an HRD proxy, are also predictive of PARPi benefit in patients without
BRCA
m or HRRm, suggesting that other DNA alterations without definitive classification, such as
BRCA
VUS or variants of Special Interpretation (SI), may be contributing to HRD. Here, we evaluated the association of
BRCA
VUS and SI variants that have complex clinical interpretation with reduced penetrance.
Methods:
Retrospective analysis was conducted using de-identified genetic testing data from the MCRR. Eligible patients with ovarian, fallopian tube or primary peritoneal cancer were tested with the MyChoice CDx HRD test between 2016 and 2023, with HRD+ defined as GIS≥42 or presence of
BRCA
m PV. Patient
BRCA
m and HRRm status were defined using the most clinically significant variant observed in BRCA1/2 and an HRR 13-gene set, respectively. GIS distributions were compared using Kolmogorov-Smirnov tests and decomposed using mixture models.
Results:
Overall, 31.9% (4,628/14,513) of patients were HRD+ with 9.3% (N=1,344) having
BRCA
m PVs. An additional 3.7% (N=538) had a
BRCA
VUS [N=83 uncharacterized large rearrangement (LR), N=455 non-LR]. The distributions of GIS in both non-LR and LR VUS were significantly different from the distributions in
BRCA
m PVs and
BRCA
wildtype tumors (ps < 0.001), likely representing a spectrum of pathogenic and benign variants. Mixture models estimated that 28.8% [95% confidence interval (CI) 21.9, 35.8] of non-LR VUS and 55.8% (95% CI 40.0, 70.4) of LR VUS exhibited GIS similar to
BRCA
m PVs. Of the 15 non-LR VUS observed more than once, two were observed only in tumors with low GIS and are therefore presumed benign.
BRCA
SI variants (N=6) were observed in 16 patients and had a distribution of GIS significantly different from
BRCA
wildtype tumors (p < 0.001), but not significantly different from
BRCA
m tumors (p = 0.1). Two SI variants had high GIS in multiple patients and are therefore presumed pathogenic. One SI variant had low GIS in two patients and is therefore presumed benign.
Conclusions:
The
BRCA
VUS GIS distribution spanned across the
BRCA
m PV and
BRCA
wildtype GIS distributions, which suggests that
BRCA
VUS represent a mix of benign variants and PVs. In these patients, GIS is able to correctly classify HRD status. Additional data are needed to further characterize these uncertain
BRCA
variants and the appropriate therapeutic and preventive strategies required for these patients.
1 organization
Organization
Myriad Genetics Inc