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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3093-3094 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.1009
In ReplyDepartment of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark
Department of Clinical Biochemistry, Rigshospitalat, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark We thank Drs Iniesta and Merajver for their correspondence, in which they raise concern about our decision to exclude studies of individuals of ethnicities other than those of Northern and Eastern European descent, male breast cancer patients, and bilateral breast cancer patients in our recent meta-analysis on CHEK2*1100delC and risk of breast cancer.1 We agree that ethnicity is important when advising on genetic testing, as we stated in our answer to the parallel letter by Lee and Ang.2 Male breast cancer and CHEK2*1100delC has been estimated in six case-control studies.3-8 Participants in these studies had heterogeneous ethnic backgrounds, the majority were proven BRCA1- and BRCA2-mutation–negative individuals, and they had various familial histories of breast cancer. These studies only detected four heterozygous patients and have a pooled odds ratio of 1.1 (95% CI, 0.4 to 3.0) for male breast cancer for CHEK2*1100delC heterozygotes versus noncarriers (Fig 1).
Bilateral breast cancer and CHEK2*1100delC heterozygosity has been examined in three case-control studies.5,9,10 Participants in these studies had heterogeneous ethnic backgrounds, unknown BRCA1 and BRCA2 carrier status, and various familial histories of breast cancer. These studies only detected 13 heterozygous patients and have a pooled odds ratio for bilateral breast cancer for CHEK2*1100delC heterozygotes versus noncarriers of 6.8 (95% CI, 3.5 to 13.0; Fig 1). A Russian study11 on bilateral breast cancer was excluded due to partial overlap with a previous publication.9 Finally, Drs Iniesta and Merajver mention the article by Broeks et al,12 finding a 6.5-fold risk of bilateral versus unilateral breast cancer for CHEK2*1100delC heterozygotes versus noncarriers; however, due to its case-only design, this study could not be included in our meta-analysis of case-control studies. Iniesta and Merajver expressed doubts regarding the uniformity of the selection of familial breast cancer studies included in our meta-analysis.1 We agree that the definition of familial breast cancer varies among countries, and that this problem is a limitation to all studies of familial breast cancer. In this aspect, there is no difference among the present CHEK2*1100delC meta-analysis and many studies of BRCA1 and BRCA2 mutations. Nevertheless, screening for BRCA1 and BRCA2 mutations in individuals with a familial history of breast cancer is widely accepted. We would also like to emphasize that CHEK2*1100delC heterozygosity has been associated with an increased risk of developing a second breast cancer and adverse prognosis among female breast cancer patients of Northern European descent.13 In our view, CHEK2*1100delC genotyping should therefore be offered to these patients with or without familial predisposition to intensify surveillance of heterozygous patients for early signs of a new breast cancer or relapse. The risk estimation of breast cancer among healthy female first-degree relatives of CHEK2*1100delC heterozygous breast cancer patients will be more precise when their CHEK2*1100delC status is known. Finally, if genetic testing is also offered to women in the general population, absolute 10-year risk of breast cancer as a function of CHEK2*1100delC heterozygosity, age, body mass index, and hormone replacement therapy should be discussed with the woman tested for CHEK2*1100delC (Fig 214).
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Weischer M, Bojesen SE, Ellervik C, et al: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: Meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26:542-548, 2008 2. Lee ASG, Ang P: CHEK2*1100delC Screening of Asian Women With a Family History of Breast Cancer Is Unwarranted. J Clin Oncol 26:2419, 2008 3. Falchetti M, Lupi R, Rizzolo P, et al: BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat, 10.1007/s10549-007-9689-2 [epub ahead of print on 28 July 2007] 4. Neuhausen S, Dunning A, Steele L, et al: Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108:477-478, 2004[CrossRef][Medline] 5. Offit K, Pierce H, Kirchhoff T, et al: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4:1-1, 2003[Medline] 6. Ohayon T, Gal I, Baruch RG, et al: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108:479-480, 2004[CrossRef][Medline] 7. Syrjäkoski K, Kuukasjarvi T, Auvinen A, et al: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108:475-476, 2004[CrossRef][Medline] 8. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al: The CHEK2 Breast Cancer Consortium: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55-59, 2002[CrossRef][Medline] 9. Chekmariova EV, Sokolenko AP, Buslov KG, et al: CHEK2 1100delC mutation is frequent among Russian breast cancer patients. Breast Cancer Res Treat 100:99-102, 2006[CrossRef][Medline] 10. Vahteristo P, Bartkova J, Eerola H, et al: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432-438, 2002[CrossRef][Medline] 11. Sokolenko AP, Rozanov ME, Mitiushkina NV, et al: Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia. Fam Cancer 6:281-286, 2007[CrossRef][Medline] 12. Broeks A, de Witte L, Nooijen A, et al: Excess risk for contralateral breast cancer in CHEK2*1100delC germline mutation carriers. Breast Cancer Res Treat 83:91-93, 2004[CrossRef][Medline] 13. Schmidt MK, Tollenaar RA, de Kemp SR, et al: Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25:64-69, 2007 14. Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25:57-63, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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