Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 20;41(9):1703-1713.
doi: 10.1200/JCO.22.01239. Epub 2023 Jan 9.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Siddhartha Yadav  1 , Nicholas J Boddicker  2 , Jie Na  2 , Eric C Polley  3 , Chunling Hu  4 , Steven N Hart  2 , Rohan D Gnanaolivu  2 , Nicole Larson  2 , Susan Holtegaard  4 , Huaizhi Huang  5 , Carolyn A Dunn  4 , Lauren R Teras  6 , Alpa V Patel  6 , James V Lacey  7 , Susan L Neuhausen  7 , Elena Martinez  8 , Christopher Haiman  9 , Fei Chen  9 , Kathryn J Ruddy  1 , Janet E Olson  2 , Esther M John  10   11 , Allison W Kurian  10   11 , Dale P Sandler  12 , Katie M O'Brien  12 , Jack A Taylor  12 , Clarice R Weinberg  12 , Hoda Anton-Culver  13 , Argyrios Ziogas  13 , Gary Zirpoli  14 , David E Goldgar  15 , Julie R Palmer  14 , Susan M Domchek  16   17 , Jeffrey N Weitzel  18 , Katherine L Nathanson  16   17 , Peter Kraft  19 , Fergus J Couch  4
Affiliations

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Siddhartha Yadav et al. J Clin Oncol. .

Abstract

Purpose: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

Methods: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.

Results: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.

Conclusion: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

PubMed Disclaimer

Conflict of interest statement

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Cumulative incidence of CBC risk in PV carriers. Cumulative incidence plots for first contralateral breast cancers after primary breast cancer. Cumulative incidence is plotted against years since first breast cancer. Stepped plots for non-PV carriers (red), and carriers of variants are (A) ATM; (B) BRCA1; (C) BRCA2; (D) CHEK2, all pathogenic; (E) CHEK2 c.1100delC; and (F) PALB2. Numbers of carriers and noncarriers at each time point are displayed below the individual graphs. CBC, contralateral breast cancer; PV, pathogenic variant.
See this image and copyright information in PMC

References

    1. Gao X, Fisher SG, Emami B: Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: A population-based study. Int J Radiat Oncol Biol Phys 56:1038-1045, 2003 - PubMed
    1. Ramin C, Withrow DR, Davis Lynn BC, et al. : Risk of contralateral breast cancer according to first breast cancer characteristics among women in the USA, 1992–2016. Breast Cancer Res 23:24, 2021 - PMC - PubMed
    1. Kramer I, Hooning MJ, Mavaddat N, et al. : Breast cancer polygenic risk score and contralateral breast cancer risk. Am J Hum Genet 107:837-848, 2020 - PMC - PubMed
    1. Reiner AS, Sisti J, John EM, et al. : Breast cancer family history and contralateral breast cancer risk in young women: An update from the Women's Environmental Cancer and Radiation Epidemiology study. J Clin Oncol 36:1513-1520, 2018 - PMC - PubMed
    1. Chen Y, Thompson W, Semenciw R, et al. : Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8:855-861, 1999 - PubMed

Publication types

MeSH terms