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
Calle EE., Heath CW., Miracle-McMahill HL., Coates RJ., Liff JM., Franceschi S., Talamini R., Chantarakul N., Koetsawang S., RachawatRachawat D., Morabia A., Schuman L., Stewart W., Szklo M., Bain C., Schofield F., Siskind V., Band P., Coldman AJ., Gallagher RP., Hislop TG., Yang P., Duffy SW., Kolonel LM., Nomura AMY., Oberle MW., Ory HW., Peterson HB., Wilson HG., Wingo PA., Ebeling K., Kunde D., Nishan P., Colditz G., Martin N., Pardthaisong T., Silpisornkosol S., Theetranont C., Boosiri B., Chutivongse S., Jimakorn P., Virutamasen P., Wongsrichanalai C., McMichael AJ., Rohan T., Ewertz M., Paul C., Skegg DCG., Boyle P., Evstifeeva M., Daling JR., Malone K., Noonan EA., Stanford JL., Thomas DB., Weiss NS., White E., Andrieu N., Brêmond A., Clavel F., Gairard B., Lansac J., Piana L., Renaud R., Fine SRP., Cuevas HR., Ontiveros P., Palet A., Salazar SB., Aristizabel N., Cuadros A., Bachelot A., Lê MG., Deacon J., Peto J., Taylor CN., Alfandary E., Modan B., Ron E., Friedman GD., Hiatt RA., Bishop T., Kosmelj J., Primic-Zakelj M., Ravnihar B., Stare J., Beeson WL., Fraser G., Allen DS., Bulbrook RD., Cuzick J., Fentiman IS., Hayward JL., Wang DY., Hanson RL., Leske MC., Mahoney MC., Nasca PC., Varma AO., Weinstein AL.
Background: The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. Methods: Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. Findings: The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95% Cl] in current users 1·24 [1·15-1·33], 2p<0·00001; 1-4 years after stopping 1·6 [1·08-1·23], 2p=0·00001; 5-9 years after stopping 1·07 [1·02-1·13], 2p=0·009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1·01 [0·96-1·05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives: for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0·88 (0·81-0·95; 2p=0·002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90% of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0·5 (95% Cl 0·3-0·7), 1·5 (0·7-2·3), and 4·7 (2·7-6·7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons. Interpretation: Women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed, although the additional cancers diagnosed tend to be localised to the breast. There is no evidence of an increase in the risk of having breast cancer diagnosed 10 or more years after cessation of use, and the cancers diagnosed then are less advanced clinically than the cancers diagnosed in never-users.