CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer

Abstract

Purpose: We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.

Patients and methods: From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.

Results: CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only.

Conclusion: Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Fig 1.

Cumulative incidence of early death according to CHEK2*1100delC carrier status for all participants, separated by estrogen receptor status: (A) all patients; (B) estrogen receptor–positive patients; (C) estrogen receptor–negative patients. Patients were included at time of blood sampling following a first breast cancer and observed until death or end of follow-up, whichever came first. Multifactorially adjusted hazard ratio (HR) for early death in heterozygotes versus noncarriers stratified by study adjusted for age at diagnosis, year of diagnosis, body mass index, menopausal status, tumor size, lymph node status, progesterone receptor status, and human epidermal growth factor receptor 2.

Fig 2.

Cumulative incidence of breast cancer–specific death according to CHEK2*1100delC carrier status for all participants, separated by estrogen receptor status: (A) all patients; (B) estrogen receptor–positive patients; (C) estrogen receptor–negative patients. Patients were included at time of blood sampling following a first breast cancer and were observed until death or end of follow-up, whichever came first. Other causes of death were considered as a competing event. Multifactorially adjusted hazard ratio (HR) for breast cancer–specific death in heterozygotes versus noncarriers stratified by study and adjusted for age at diagnosis, year of diagnosis, body mass index, menopausal status, tumor size, lymph node status, progesterone receptor status, and human epidermal growth factor receptor 2.

Fig 3.

Cumulative incidence of second breast cancer according to CHEK2*1100delC carrier status for all participants, separated by estrogen receptor status: (A) all patients; (B) estrogen receptor–positive patients; (C) estrogen receptor–negative patients. Patients were included at time of blood sampling following a first breast cancer and were observed until death, diagnosis of a second breast cancer, or end of follow-up, whichever came first. Any death was considered as a competing event. Multifactorially adjusted hazard ratio (HR) for second breast cancer in heterozygotes versus noncarriers stratified by study was adjusted for age at diagnosis of the first breast cancer, study, year of diagnosis of the first breast cancer, and family history. Because we observed no second breast cancers among the 41 CHEK2*1100delC heterozygous women with estrogen receptor–negative first breast cancer, an HR could not be calculated in these women. N/A, not applicable.

Fig 4.

Risk of a first breast cancer by CHEK2*1100delC carrier status in individual studies ranked by statistical power for all studies combined, separated by estrogen receptor status. The combined odds ratios were adjusted for age at diagnosis (cases) or ascertainment (controls). The combined studies odds ratio included participants from all 22 studies, including Australian Breast Cancer Family Study (ABCFS) and Leiden University Medical Centre Breast Cancer Study (ORIGO), which are not shown individually. These two studies had no heterozygous controls, and therefore odds ratios could not be calculated for these individual studies. Odds ratio was not calculated for Hannover Breast Cancer Study (HABCS) because their case series with follow-up data was strongly biased toward CHEK2 mutation carriers. ABCS, Amsterdam Breast Cancer Study; BBCC, Bavarian Breast Cancer Cases and Controls; BSUCH, Breast Cancer Study of the University Clinic of Heidelberg; CGPS, Copenhagen General Population Study; HEBCS, Helsinki Breast Cancer Study; KARBAC, Karolinska Breast Cancer Study; KBCP, Kuopio Breast Cancer Project; LMBC, Leuven Multidisciplinary Breast Centre; MCBCS, Mayo Clinic Breast Cancer Study; MCCS, Melbourne Collaborative Cohort Study; NBCS, Norwegian Breast Cancer Study; NC-BCFR, Northern California Breast Cancer Family Registry; OFBCR, Ontario Familial Breast Cancer Registry; PBCS, National Cancer Institute Polish Breast Cancer Study; RBCS, Rotterdam Breast Cancer Study; SASBAC, Singapore and Sweden Breast Cancer Study; SBCS, Sheffield Breast Cancer Study; SEARCH, Study of Epidemiology and Risk Factors in Cancer Heredity; UCIBCS, University of California at Irvine Breast Cancer Study.

Fig A1.

Pre-study schema.