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. 2012 Dec 10;30(35):4308-16. doi: 10.1200/JCO.2012.42.7336. Epub 2012 Oct 29.

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.

MeSH terms

  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Checkpoint Kinase 2
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Middle Aged
  • Neoplasms, Second Primary / enzymology*
  • Neoplasms, Second Primary / genetics*
  • Prognosis
  • Prospective Studies
  • Protein-Serine-Threonine Kinases / genetics*

Substances

  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases