CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer

Weischer M, Nordestgaard BG, Pharoah P, Bolla MK, Nevanlinna H, Van't Veer LJ, Garcia-Closas M, Hopper JL, Hall P, Andrulis IL, Devilee P, Fasching PA, Anton-Culver H, Lambrechts D, Hooning M, Cox A, Giles GG, Burwinkel B, Lindblom A, Couch FJ, Mannermaa A, Grenaker Alnaes G, John EM, Dork T, Flyger H, Dunning AM, Wang Q, Muranen TA, van Hien R, Figueroa J, Southey MC, Czene K, Knight JA, Tollenaar RA, Beckmann MW, Ziogas A, Christiaens MR, Collee JM, Reed MW, Severi G, Marme F, Margolin S, Olson JE, Kosma VM, Kristensen VN, Miron A, Bogdanova N, Shah M, Blomqvist C, Broeks A, Sherman M, Phillips KA, Li J, Liu J, Glendon G, Seynaeve C, Ekici AB, Leunen K, Kriege M, Cross SS, Baglietto L, Sohn C, Wang X, Kataja V, Borresen-Dale AL, Meyer A, Easton DF, Schmidt MK, Bojesen SE (2012) CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer. J Clin Oncol 30:4308-4316

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="">