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

Maren Weischer, Børge G Nordestgaard, Paul Pharoah, Manjeet K Bolla, Heli Nevanlinna, Laura J Van't Veer, Montserrat Garcia-Closas, John L Hopper, Per Hall, Irene L Andrulis, Peter Devilee, Peter A Fasching, Hoda Anton-Culver, Diether Lambrechts, Maartje Hooning, Angela Cox, Graham G Giles, Barbara Burwinkel, Annika Lindblom, Fergus J CouchArto Mannermaa, Grethe Grenaker Alnæs, Esther M John, Thilo Dörk, Henrik Flyger, Alison M Dunning, Qin Wang, Taru A Muranen, Richard van Hien, Jonine Figueroa, Melissa C Southey, Kamila Czene, Julia A Knight, Rob A E M Tollenaar, Matthias W Beckmann, Argyrios Ziogas, Marie-Rose Christiaens, Johanna Margriet Collée, Malcolm W R Reed, Gianluca Severi, Frederik Marme, Sara Margolin, Janet E Olson, Veli-Matti Kosma, Vessela N Kristensen, Alexander Miron, Natalia Bogdanova, Mitul Shah, Carl Blomqvist, Annegien Broeks, Mark Sherman, Kelly-Anne Phillips, Jingmei Li, Jianjun Liu, Gord Glendon, Caroline Seynaeve, Arif B Ekici, Karin Leunen, Mieke Kriege, Simon S Cross, Laura Baglietto, Christof Sohn, Xianshu Wang, Vesa Kataja, Anne-Lise Børresen-Dale, Andreas Meyer, Douglas F Easton, Marjanka K Schmidt, Stig E Bojesen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4308-16
Number of pages9
JournalJournal of Clinical Oncology
Volume30
Issue number35
DOIs
Publication statusPublished - 10 Dec 2012

Keywords

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

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