Presymptomatic Awareness of Germline Pathogenic BRCA Variants and Associated Outcomes in Women With Breast Cancer

Individuals who carry pathogenic BRCA variants are often identified only after a cancer diagnosis because about half of these persons lack relevant family history (FH),¹ and BRCA screening is not routinely performed. Unaffected carriers of pathogenic variants unaware of their genetic status cannot undertake recommended surveillance and prevention measures, including risk-reduction bilateral mastectomy (RRBM), which reduces breast cancer risk in carriers of pathogenic BRCA variants² and overall mortality in BRCA1 carriers.³ However, worldwide, most carriers decline RRBM.⁴ We hypothesized that among carriers who decline RRBM and ultimately develop breast cancer, knowing their BRCA status before cancer diagnosis might lead to breast cancer downstaging at diagnosis and measurable downstream benefits.

We performed a single-institution retrospective review of a cohort of BRCA1/BRCA2 carriers diagnosed with breast cancer (2005-2016). All received guideline-based surveillance and prevention recommendations, including RRBM and risk-reduction salpingo-oophorectomy.⁵ Demographic, clinical, and pathological data were extracted from medical records, and vital status from the Israel National Cancer Registry. The t test was used for continuous variables, and χ² for categorical variables. Logistic regression was used for multivariate analyses. Kaplan-Meier survival analysis was performed, with the log-rank test to examine differences beween survival curves. Hazard ratios were calculated using Cox regression. All P values are 2-sided with 95% CIs. The study was approved by the Shaare Zedek Medical Center institutional review board, waiving patient written informed consent for deidentified data.

Of the 105 women BRCA pathogenic variant carriers diagnosed with breast cancer, 83% were Ashkenazi Jewish, mean (SD) age, 50.4 (13.3) years. Of these, 42 were aware of their genotype before diagnosis (BRCA-preDx carriers) and 63 only after diagnosis (BRCA-postDx carriers) (Table). The BRCA-preDx carriers had significantly more suggestive FH and higher socioeconomic index (SI) than BRCA-postDx carriers (Table). Forty of the 42 BRCA-preDx carriers were followed up at the institutional high-risk clinic. Mean age at diagnosis was identical in both groups (50.4 years), but BRCA-preDx carriers were significantly more likely to be diagnosed by magnetic resonance imaging and to present with ductal carcinoma in situ (noninvasive disease) or lower-stage invasive disease (Table). There were no significant differences in grade, hormone receptor, or ERBB2 (formerly HER2) expression (Table). BRCA-preDx carriers also had significantly lower rates of axillary dissection and chemotherapy delivery, with none requiring neoadjuvant chemotherapy (Table). Despite their earlier-stage disease, most BRCA-preDx carriers elected bilateral mastectomy as first surgery, significantly more than BRCA-postDx carriers (Table). Logistic regression controlling for age, SI, calendar year at diagnosis, FH, and variant gene indicated that timing of carrier status identification significantly predicted more advanced stage (≥II) at diagnosis. The odds ratios (OR) for BRCA-postDx vs BRCA-preDx carriers were 12.1 (95% CI, 2.7-54.0; P = .001) for advanced clinical stage (cT2-4 or cN+) and 8.1 (95% CI, 2.2-29.4; P = .002) for advanced pathological stage (pT2-4 or pN+, non-NAC patients). Lower SI was also significantly associated with advanced clinical stage (OR, 1.5; 95% CI,1.1-1.9; P = .002) but not with advanced pathological stage (OR, 1.2; 95% CI, 0.99-1.5; P = .06).

Awareness of genotype before diagnosis was associated with significantly better overall survival (Figure): 2 of 42 (4.8%) BRCA-preDx carriers and 16 of 63 (25.4%) BRCA-postDx carriers died, yielding 5-year overall survival of 94% (SE 4%) vs 78% (SE 5%), respectively (P = .03). Controlled for age, SI, calendar year at diagnosis, FH, and variant gene, the hazard ratio (HR) for overall mortality in BRCA-preDx vs BRCA-postDx carriers was 0.16 (95% CI, 0.02-1.4; P = .10). Factors associated with survival were higher SI (HR, 0.76; 95% CI, 0.6-0.97; P = .03), variant gene (BRCA2 vs BRCA1) (HR, 0.15; 95% CI, 0.03-0.75; P = .02) and age at diagnosis (HR, 1.047; 95% CI, 1.003-1.093; P = .04).

The findings of this study suggest that prior awareness of BRCA pathogenic variant carrier status may be beneficial even in carriers who decline RRBM and later develop breast cancer. Prediagnostic awareness was associated with diagnosis by magnetic resonance imaging, earlier-stage breast cancer, and less morbid axillary surgery and chemotherapy. To our knowledge, this is the first report to document a possible survival advantage for presymptomatic identification of BRCA carrier status in carriers who decline RRBM.

Study limitations include retrospective nature and limited sample size. Also, the data did not permit comparison of risk-reduction salpingo-oophorectomy rates. Nevertheless, the identical age at diagnosis in both groups suggests lack of substantial bias, and analyses were controlled for possible confounders.

These results provide further support for BRCA1/BRCA2 screening in unaffected women, particularly in populations such as Ashkenazi Jews, with high BRCA1/BRCA2 carrier rates.⁶

Corresponding Authors: Ephrat Levy-Lahad, MD, Medical Genetics Institute (lahad@szmc.org.il), and Tal Hadar, MD, Breast Surgery Unit, (talhadar@szmc.org.il), Shaare Zedek Medical Center, PO Box 3235, Jerusalem, 91031, Israel.

Published Online: July 9, 2020. doi:10.1001/jamaoncol.2020.2059

Author Contributions: Dr Hadar and Levy-Lahad had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mor, Amit, and Lieberman contributed equally to this work.

Concept and design: Hadar, Mor, Lieberman, Levy-Lahad.

Acquisition, analysis, or interpretation of data: Hadar, Amit, Lieberman, Gekhtman, Rabinovitch, Levy-Lahad.

Drafting of the manuscript: Hadar, Amit, Lieberman, Gekhtman, Rabinovitch, Levy-Lahad.

Critical revision of the manuscript for important intellectual content: Hadar, Mor, Lieberman, Rabinovitch, Levy-Lahad.

Statistical analysis: Lieberman.

Obtained funding: Hadar, Levy-Lahad.

Administrative, technical, or material support: Hadar, Mor, Levy-Lahad.

Supervision: Hadar, Levy-Lahad.

Conflict of Interest Disclosures: Dr Lieberman reported personal fees from AstraZeneca outside the submitted work. Dr Levy-Lahad reported grants from the Breast Cancer Research Foundation and grants from the Israel Cancer Association during the conduct of the study and personal fees from AstraZeneca outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the Breast Cancer Research Foundation (Dr Levy-Lahad) and by a gift from Ellie and David Werber to Shaare Zedek Medical Center (Drs Hadar and Levy-Lahad).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the following physicians from Shaare Zedek Medical Center, Jerusalem, Israel, for their contribution to data provision and collection and to critical review of the manuscript: Dr Ora Rosengarten, MD, Institute of Oncology; Dr Moshe Carmon, MD, Breast Surgery Unit, Department of Surgery; Dr Shalom Strano, MD, Breast Imaging Unit, Department of Imaging; Rachel Michaelson-Cohen, MD, MPH, Medical Genetics Institute and the Department of Obstetrics & Gynecology; and Dr Eliahu Golomb, MD, PhD, Department of Pathology, Dr Shani Paluch-Shimon, MBBS, MSc, Institute of Oncology. Dr Paluch-Shimon also assisted in study design and editing the manuscript. Prof Amnon Lahad, Clalit Health Services, Jerusalem, Israel, assisted in the statistical analysis. No compensation was received for these contributions.