Affiliations of authors: J. L. Hopper, The University of Melbourne, Centre for Genetic Epidemiology, Carlton, Victoria, Australia; J. A. Baron, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
Correspondence to: John A. Baron, M.D., Dartmouth Medical School, Section of Biostatistics and Epidemiology, Evergreen Center, 46 Centerra Pkwy., Ste. 300, Lebanon, NH 03766 (e-mail: john.a.baron{at}dartmouth.edu).
In a recent issue of the Journal, Narod et al. (1) reported findings from a large sample of 2611 BRCA1 and BRCA2 germline mutation carriers regarding the association of oral contraceptive use with the risk of breast cancer. An interesting feature of this reportnot commented on by the authorsis data regarding cigarette smoking. The proportion of breast cancer case subjects who ever smoked was 39%, and the proportion among control subjects was 41%. These data clearly suggest no material association between cigarette smoking and breast cancer risk, a finding in agreement with a recent pooled analysis of major breast cancer studies (2).
In 1998, Narod et al. published in the Journal an earlier report from the same study (3). By contrast with the current data, that analysis, based on only 372 subjects, suggested that smoking reduced the risk of breast cancer in women known to carry a germline mutation in BRCA1 or BRCA2. In that analysis, the proportion of case subjects who had ever smoked was 39% (as in the current report), whereas the proportion among control subjects was 52% (higher than in the current, larger report). With a higher smoking prevalence among the control subjects, an adjusted odds ratio of 0.54 (P = .007) was found.
It is not clear what might explain the difference in findings between the two analyses. Certainly the use of clinic-based data introduces potential problems in design and interpretation (4,5). Indeed, the two different prevalences of smoking among the control samples could be the result of seemingly subtle differences in participation in genetic counseling clinics and the studies conducted there. The differences in the smoking findings may also illustrate a possible pitfall of studies with continuing enrollment. Premature or repeated analyses of evolving data may lead to a decision to publish apparently "significant" findings that have actually emerged by chance.
It is also possible that the statistics generated from the matched analyses do not appropriately reflect the association in the whole study sample. The methodology used by Narod et al. (1)matching on mutated gene, age, and country of residencereduces the potential for bias. However, this approach does not optimize the use of the data because a large proportion of carriers with and without breast cancer are not included. It would be interesting to see analyses that are based on less stringent matching criteria, greater control-to-case matching ratios, and/or modeling of possible confounding effects.
REFERENCES
1 Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:17739.
2 Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al. Alcohol, tobacco and breast cancercollaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002;87:123445.[CrossRef][ISI][Medline]
3 Brunet JS, Ghadirian P, Rebbeck TR, Lerman C, Garber JE, Tonin PN, et al. Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 1998;90:7616.
4 Hopper JL. Genetic epidemiology of female breast cancer. Semin Cancer Biol 2001;11:36774.[CrossRef][ISI][Medline]
5 Baron JA, Haile RW. Protective effect of cigarette smoking on breast cancer risk in women with BRCA1 or BRCA2 mutations? J Natl Cancer Inst 1998;90:7267.
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