CORRESPONDENCE

Re: Oral Contraceptives and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Matti A. Rookus, Richard Brohet, Flora E. van Leeuwen

Affiliation of authors: Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Correspondence to: M. A. Rookus, Ph.D., Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: m.rookus{at}nki.nl).

Narod et al. (1) recently presented results of a multicenter case–control study on the relationship between use of oral contraceptives and risk of breast cancer among BRCA1 and BRCA2 mutation carriers. Although the study is of high potential interest for the counseling of these women, it may have several methodologic limitations.

Survival bias is a major concern for this study of prevalent cases of breast cancer with a mean survival of 8.2 years, especially because, in the general population, use of oral contraceptives has been associated with lower stage disease at diagnosis (2). The authors disregard survival bias by indicating that no difference was found between women who completed the questionnaire within 5 years of their breast cancer diagnosis (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 0.98 to 1.64) and those who completed the questionnaire after 5 or more years (OR = 1.13, 95% CI = 0.93 to 1.37). At first sight, this is indeed suggestive of lack of survival bias. However, during the study period (1970 through 2000), 20%–30% of breast cancer patients in the general population died within 5 years, and prognosis for mutation carriers may have been worse (3). Thus, the difference in risk between women who completed the questionnaire within 2 years and those who completed the questionnaire after 2 or more years would have been more informative. Moreover, the higher risks associated with earlier years at diagnoses (1970–1979: OR = 1.98, 95% CI = 1.16 to 3.40; 1980–1989: OR = 1.26, 95% CI = 0.94 to 1.70; 1990–2001: OR = 1.11, 95% CI = 0.90 to 1.36) in combination with a rather small range of calendar years for data collection (cases: mean = 1999, standard deviation = 2.0) suggest that the study is not free of survival bias. Therefore, it would be helpful to see the main analyses restricted to recent cases.

A study among known BRCA mutation carriers may contain selection bias because women with cancer may seek genetic testing more frequently and for other reasons than women without cancer. For example, among women without cancer, parous women may seek genetic testing more often than nulliparous women (4). Thus, use of oral contraceptives may also differ between unaffected carriers who know their mutation status and unaffected carriers who do not.

Information on oral contraceptive use was collected by questionnaire. It is not clear whether the procedure for administering the questionnaire was similar for case patients and control subjects, especially in the centers that did not use the standard questionnaire (mainly in Europe). Part of the heterogeneity across countries (United States/Canada/Israel: OR = 1.33 to 1.38 and Europe: OR = 0.46 to 1.27) and part of the possibly country-related differences between Jewish and non-Jewish women (ORs are 1.37 and 1.11, respectively) may be associated with differences in data collection. Furthermore, it is not clear how the collected information on oral contraceptives (starting and stopping dates, duration and current use at date of interview) enabled the authors to define recent use and duration at "pseudo"-diagnosis in control subjects, when the control subjects were as old as their matched case patients at diagnosis.

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;94:1773–9.[Abstract/Free Full Text]

2 Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996;347:1713–27.[ISI][Medline]

3 Goffin JR, Chappuis PO, Begin LR, Wong N, Brunet JS, Hamel N, et al. Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer 2003;97:527–36.[CrossRef][ISI][Medline]

4 Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, Seynaeve C, Tilanus-Linthorst MM, Wagner A, et al. Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 2000;355:2015–20.[CrossRef][ISI][Medline]



             
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