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Figure.  Overall Survival in Carriers of BRCA Pathogenic Variants Diagnosed With Breast Cancer Who Were Aware of Their BRCA Status Before vs After Cancer Diagnosis
Overall Survival in Carriers of BRCA Pathogenic Variants Diagnosed With Breast Cancer Who Were Aware of Their BRCA Status Before vs After Cancer Diagnosis

Kaplan-Meier curves of overall survival in BRCA1/BRCA2 carriers diagnosed with breast cancer. PreDx-BRCA indicates carriers who were aware of BRCA status before their breast cancer diagnosis; postDx-BRCA, carriers who became aware of their BRCA status only after their breast cancer diagnosis. Vertical hatches represent censored individuals. Overall survival was higher in preDx-BRCA vs PostDx-BRCA carriers: 5-year survival rates were 94% (SE 4%) in pre-Dx-BRCA carriers and 78% (SE 5%) in postDx-BRCA carriers (P = .03). The hazard ratio for overall mortality for BRCA-preDx carriers vs BRCA-postDx carriers, controlled for calendar year at diagnosis, was 0.20 (95% CI, 0.04-0.93) (P = .04). Controlled for age, SI (socioeconomic index), family history, calendar year at diagnosis and variant gene, the hazard ratio was 0.16 (95% CI, 0.02-1.4; P = .10). Log-rank test was used to examine statistical differences in survival curves. Hazard ratio was calculated using Cox regression.

Table.  Comparison of PreDx vs PostDX Awareness of BRCA Carrier Status in Women With Breast Cancer
Comparison of PreDx vs PostDX Awareness of BRCA Carrier Status in Women With Breast Cancer
1.
Gabai-Kapara  E, Lahad  A, Kaufman  B,  et al.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.   Proc Natl Acad Sci U S A. 2014;111(39):14205-14210. doi:10.1073/pnas.1415979111PubMedGoogle ScholarCrossref
2.
Marchetti  C, De Felice  F, Palaia  I,  et al.  Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers.   BMC Womens Health. 2014;14(1):150. doi:10.1186/s12905-014-0150-5PubMedGoogle ScholarCrossref
3.
Heemskerk-Gerritsen  BAM, Jager  A, Koppert  LB,  et al.  Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.   Breast Cancer Res Treat. 2019;177(3):723-733. doi:10.1007/s10549-019-05345-2PubMedGoogle ScholarCrossref
4.
Metcalfe  K, Eisen  A, Senter  L,  et al; Hereditary Breast Cancer Clinical Study Group.  International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.   Br J Cancer. 2019;121(1):15-21. doi:10.1038/s41416-019-0446-1PubMedGoogle ScholarCrossref
5.
Daly  MB, Pilarski  R, Yurgelun  MB,  et al; National Comprehensive Cancer Network.  NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.   J Natl Compr Canc Netw. 2020;18(4):380-391. doi:10.6004/jnccn.2020.0017PubMedGoogle ScholarCrossref
6.
Domchek  S, Robson  M.  Broadening criteria for BRCA1/2 evaluation: placing the USPSTF recommendation in context.   JAMA. 2019;322(7):619-621. doi:10.1001/jama.2019.9688PubMedGoogle ScholarCrossref
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    Research Letter
    July 9, 2020

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

    Author Affiliations
    • 1Breast Surgery Unit, Department of Surgery, Shaare Zedek Medical Center, Jerusalem, Israel
    • 2Department of Obstetrics & Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel
    • 3Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
    • 4Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    • 5Breast Imaging Unit, Department of Imaging, Shaare Zedek Medical Center, Jerusalem, Israel
    • 6Departments of Radiation Oncology and Medicine, University of Colorado, Anschutz Medical Campus, Aurora
    JAMA Oncol. 2020;6(9):1460-1463. doi:10.1001/jamaoncol.2020.2059

    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.

    Methods

    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.

    Results

    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).

    Discussion

    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

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    Article Information

    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.

    References
    1.
    Gabai-Kapara  E, Lahad  A, Kaufman  B,  et al.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.   Proc Natl Acad Sci U S A. 2014;111(39):14205-14210. doi:10.1073/pnas.1415979111PubMedGoogle ScholarCrossref
    2.
    Marchetti  C, De Felice  F, Palaia  I,  et al.  Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers.   BMC Womens Health. 2014;14(1):150. doi:10.1186/s12905-014-0150-5PubMedGoogle ScholarCrossref
    3.
    Heemskerk-Gerritsen  BAM, Jager  A, Koppert  LB,  et al.  Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.   Breast Cancer Res Treat. 2019;177(3):723-733. doi:10.1007/s10549-019-05345-2PubMedGoogle ScholarCrossref
    4.
    Metcalfe  K, Eisen  A, Senter  L,  et al; Hereditary Breast Cancer Clinical Study Group.  International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.   Br J Cancer. 2019;121(1):15-21. doi:10.1038/s41416-019-0446-1PubMedGoogle ScholarCrossref
    5.
    Daly  MB, Pilarski  R, Yurgelun  MB,  et al; National Comprehensive Cancer Network.  NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.   J Natl Compr Canc Netw. 2020;18(4):380-391. doi:10.6004/jnccn.2020.0017PubMedGoogle ScholarCrossref
    6.
    Domchek  S, Robson  M.  Broadening criteria for BRCA1/2 evaluation: placing the USPSTF recommendation in context.   JAMA. 2019;322(7):619-621. doi:10.1001/jama.2019.9688PubMedGoogle ScholarCrossref
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