Breast cancer and hormone exposure

THE LANCET

K W Masters Manor Hospital, Moat Road, Walsall WS2 9PS, UK

70

Age range 24–34

% increase in breast cancer

findings in 12 young adults with Turner’s syndrome who had been taking either ethinyloestradiol or a low-dose oral contraceptive included three with abnormal liver function and three with raised plasma cholesterol. Until now there has not been a commercially available preparation of the natural oestrogen, 17-beta oestradiol, which can be given in low enough doses to provide the natural hormone which these prepubertal women require. This should preferably be given transdermally with progestational hormones taken orally for 12 days of the cycle after the menarche has occurred. This regimen is less likely to cause adverse effects on liver function. The pharmaceutical industry should be encouraged to develop a low-dose transdermal 17-beta oestradiol which may allow the safe induction of puberty, and care in these women changing to hormone-replacement treatment after puberty should be available free of prescription charge, as the treatment is replacing an absent hormone.

60 50

35–44 45–54 55–64

40 30 20 10 0 1962 1965

1970

1975

1980

1985

1990

Year Figure: Cumulative percentage increase from 1962 in annual registration rates for breast cancer for women in different age groups in England and Wales Data from OPCS. Note that oral contraceptive use has fluctuated following adverse publicity, notably warnings of thrombosis risk (1969) and advice that 35 year olds should stop using oral contraceptives (1975).

Breast cancer and hormone exposure SIR—The Collaborative Group on Hormonal Factors in Breast Cancer’s reanalysis of 54 epidemiological studies on breast cancer and hormonal contraceptives (June 22, p 1713)1 provides no information on menopausal hormones. Oestrogens enhance proliferation, and progesterone/ progestagens induce atrophy in endometrial glandular epithelium.2 These facts have given rise to a convention for separating contraceptive and other exogenous hormone exposures. In this combined study, most invasive breast cancers were diagnosed in women older than age 45 years, and six of ten women included had never taken contraceptive hormones How many had taken hormones for menopausal symptoms or hormone replacement therapy (HRT) and what was the effect? Among 121 700 American nurses, deaths from breast cancer increased by 45% in women currently taking postmenopausal hormones for 5 years or more. Progestagenonly takers had more risk of the disease than oestrogen users.3 Deaths from ovarian cancer were increased by 72% after 5 years of oestrogen replacement therapy in another study of 676 526 women.4 The effect of hormone replacement therapy is less likely to confuse the estimates for younger age starters. In the reanalysis, younger current contraceptive hormone users had a 56% increased risk of breast cancer. This figure increased to 95% among cases diagnosed before age 30, who were younger than 20 at first use, and had fewer than 5 years since last use. Today nearly all women are exposed to contraceptive hormones before they are 20. Many studies have found a substantial increased risk of breast cancer among younger takers but the disease incidence has increased in all age groups in England and Wales (figure). The time-course of the breast cancer epidemic in developed countries correlates uncomfortably well with changes in sex-hormone prescribing, and a causal relation is not excluded by this latest overview. Failure to consider other hormone exposures in studies of the effects of oral contraceptives greatly reduces the power of any analysis to measure the overall influence of exogenous sex hormones on breast cancer. Not all doctors are reassured by the claims of safety that have encouraged a “pro-hormone” prescribing philosophy, and this is why DASH (Doctors against abuse from steroid sex hormones) is being set up.5 General practitioners,

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obstetricians and gynaecologists, physicians, psychiatrists, surgeons, oncologists, radiologists, pathologists, and medical scientists have already expressed interest or concern that female steroid hormones are being prescribed to women without respect for their serious side-effects. Our aim is to educate doctors about the real dangers of sex hormones, backed up by scientific evidence. *Ellen C G Grant, Honor M Antony, Sarah Myhill, Elizabeth H Price, C Michael Steel *20 Coombe Ridings, Kingston-upon-Thames KT2 7JU, UK; Airedale General Hospital, Keithley, W Yorks; Upper Weston, Llangunllo, Knighton; Department of Medical Microbiology, Great Ormond St Hospital for Children NHS Trust, London WC1; and School of Biological and Medical Sciences, St Andrews University, St Andrews

1

2 3

4 5

Collaborative Group on Hormonal Factors in Breast Cancer. 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. Lancet 1996; 347: 1713–27. Grant ECG. The hormone balance of oral contraceptives. J Obstet Gynaecol Br Commonw 1967; 74: 908–18. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589–93. Rodrigues C, Callo EE, Coates RJ, et al. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995; 141: 828–35. Price EH, Little HK. Women need to be fully informed about risks of hormones replacement therapy. BMJ 1996; 312: 1301.

SIR—The Collaborative Group on Hormonal Factors in Breast Cancer1 presents an interesting new finding, in that cancers diagnosed in both current and ex-users of oral contraceptives are less clinically advanced than those found in never users. The investigators have not explained why this finding is true even of ex-users. However, surveillance bias could provide an explanation not only in current users (as they mention) but also in ex-users. Women who take the pill are regularly seen by doctors and nurses, who are likely to suggest breast checks and teach breast awareness: this is certainly the policy at the Margaret Pyke Centre and other clinics known to us. Thus, any cancers are likely to be detected at an earlier stage in pill takers relative to never users. Most women start taking oral contraceptives when they are reasonably young (the study found that only 17% of women

Vol 348 • September 7, 1996

THE LANCET

started after the age of 35). Thus, when they stop, they will have been taught that breast examinations are important and are therefore likely to request them, or to perform selfexamination for many years, perhaps the rest of their lives. Certainly, this is a pattern of behaviour that we have observed over the years. Meanwhile, never users are less likely to be exposed to such health education advice. This difference could possibly account for the surprising finding that cancers in ex-users as well as in current users are likely to be less advanced compared with never users. *Anne Szarewski, John Guillebaud Margaret Pyke Family Planning Centre, 73 Charlotte Street, London W1P 1LB, UK

1

Collaborative Group on Hormonal Factors in Breast Cancer. 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. Lancet 1996; 347: 1713–27.

Authors’ reply SIR—Our report provided a summary of the main findings from a comprehensive analysis of data on 53 000 women with breast cancer and 100 000 controls from 54 studies. Over 100 additional tables, figures, and appendices giving further detailed results are being published elsewhere:1 those results do not, however, alter the main conclusions summarised in The Lancet paper—ie, that there is a small increase in the risk of having breast cancer diagnosed while women are taking oral contraceptives and in the few years after stopping; that there is no increase in the risk of having breast cancer diagnosed 10 or more years after stopping use; and that the cancers diagnosed in women who have used oral contraceptives are less advanced clinically than the cancers diagnosed in never users. Many of the questions raised by your correspondents are answered in our other report.1 For example, the additional data show that the main findings for oral contraceptive use are not materially modified by other factors that were considered, including the use of hormone replacement therapy. Overall, 944 women with breast cancer and 3006 controls who had used combined oral contraceptives had also used postmenopausal hormone replacement therapy, and there were no significant differences in the main results for oral contraceptive use according to whether or not women had ever used hormone replacement therapy. 1·4 Cancer localised to the breast Cancer spread beyond the breast

Relative risk

1·3 1·2 1·1 1·0 0·9 0·8 <5

5–9

10+

Never use

Years since last use of oral contraceptives Figure: Relative risk of breast cancer according to time since last use of oral contraceptives and extent of tumour spread Relative risk (given with 95% CI) relative to never users, stratified by study, age at diagnosis, parity, age at first birth, and age at which risk of conception ceased.

Vol 348 • September 7, 1996

That the cancers diagnosed in women who had ever used combined oral contraceptives were less advanced clinically than the cancers diagnosed in women who had never used oral contraceptives was seen consistently at each level of time since last use (figure). It is not possible to infer from the evidence whether the pattern of risk illustrated in the figure is due to the earlier detection of breast cancer in women who have used oral contraceptives, to the biological effect of hormonal contraceptives, or to other reasons. Future research may clarify why such a curious pattern of breast cancer is associated with oral contraceptive use and what its implications are in terms of the long-term risk of dying from breast cancer. Women whose cancers are localised to the breast have a better outlook than do those whose cancers have spread beyond the breast, and so women who have used oral contraceptives may well not be at an increased risk of death from breast cancer. The Collaborative Group on Hormonal Factors in Breast Cancer has reported on the incidence of breast cancer in relation to hormonal contraceptive use. It is now important to examine the evidence for mortality from breast cancer. *Valerie Beral, Gillian Reeves, Diana Bull, Richard Peto, on behalf of the Collaborative Group on Hormonal Factors in Breast Cancer Imperial Cancer Research Fund, Cancer Epidemiology Unit, University of Ox ford, Radcliffe Infirmary, Ox ford OX 2 6HE, UK

1

Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception 1996: 54 (3s): 1s–106s.

Evidence for diverse mutagens in breast cancer SIR—Analysis of the pattern of P53 gene mutations can serve as a “mutagen test”1 since P53 gene mutations occur with high frequency in most neoplasms and mutagens leave molecular fingerprints.2 Hopefully, patterns of mutation in the P53 gene (and possibly other tumour suppressor genes) may implicate specific mutagens in cancers for which classical epidemiological studies have been equivocal. We have analysed the patterns of described P53 mutations in breast cancer and, for comparison, in lung cancer. Pairwise analyses of mutational patterns in the P53 gene in breast cancers from 15 geographically and/or ethnically diverse populations reveal differences among the populations (table). Many differences were large since statistical significance was observed with studies that often contained only 13–18 mutations divided among eight mutational categories. The differences are unlikely to be secondary to methodological differences because four populations analysed by our laboratory by identical methods were different. The differences are also unlikely to represent varying mixtures of two or three mutagens in diverse populations, because sub-analyses by Fisher’s exact test show highly distinct patterns of mutations–eg, excess microdeletions/insertions occur in midwest, predominantly rural, US whites, and excess A:T→G:C transitions occur in Afro-American Detroit women. In contrast, the number of pairwise differences found in P53 gene mutational patterns in lung cancer among smokers is similar to chance expectation (table) and the pattern in smokers differs markedly from the pattern observed in lung cancers from non-smokers.3 Thus, diverse ethnic groups respond similarly to mutagens in cigarette smoke or the potent mutagen(s) in cigarette smoke override genetic differences between populations. In addition, detailed

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