Endocrinology and epidemiology of breast cancer

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<ul><li><p>ENDOCRINOLOGY AND EPIDEMIOLOGY OF BREAST CANCER </p><p>BRIAN MACMAHON, MD,+ AND PHILIP COLE, M D ~ </p><p>Observations of relevance to understanding the etiology of breast cancer have been made recently both by endocrinologists and by epidemiologists. Gen- erally speaking, investigators in these 2 disciplines have worked in ignorance of the contributions of the other field. When the observations from the 2 fields are considered together, useful hypotheses, and surprising gaps in our knowl- edge, are identified. I n this paper we attempt to integrate knowledge from the 2 fields, specifically to explore 3 issues: 1. which endocrine organ is most di- rectly involved in etiology, 2. what special characteristic of that organs func- tion is associated with breast cancer risk, and 3. what are the determinants of that special characteristic. </p><p>LMOST WITHOUT EXCEPTION, WRITERS ON A the causes of breast cancer have acknowl- edged the major significance of endocrine factors. Yet there is little agreement as to which hormonal patterns, or even which en- docrine organs, are most relevant. Certainly, no findings with real preventive implications have been forthcoming. Success in uncover- ing such findings would seem most likely to come from attempts to evaluate basic endo- crinologic knowledge in the light of ob- servations on the behavior of the disease in man. </p><p>Although the descriptive epidemiology of breast cancer is as complete as that for any other cancer, and a wealth of information exists on the response of the breast to hor- mones and carcinogenic compounds, few efforts to integrate these bodies of knowl- edge have been made. I n the time available, we cannot attempt any comprehensive review along these lines. We plan only to draw to- gether epidemiologic and endocrinologic evidence on 3 basic questions: 1. which en- docrine organ is most directly involved in etiology, 2. what special characteristic of that organs function is associated with breast can- cer risk, and 3. what are the determinants of that special characteristic. </p><p>Presented at the First National Conference on Breast Cancer, Washington, D.C., May 8-10, 1969. </p><p>From the Department of Epidemiology, Harvard School of Public Health, Boston, Mass. </p><p>*Professor; t Assistant Professor. Address for reprints: Harvard School of Public </p><p>Health, 665 Huntington Ave., Boston, Mass. 021 15. Received for publication June 12, 1969. </p><p>With respect to the first question, it is superfluous to catalog the tremendous body of evidence pointing to the significance of the ovary in breast cancer. Nevertheless, we still periodically hear statements to the effect that the principal ovarian hormones, the estrogens, have never been shown to be car- cinogenic in man.16, 23, 27 T h e statement may be literally true, but its truth stems from the difficulty of demonstrating such a relationship rather than from any likelihood that the estrogens would not be found to be carcinogenic in man if the appropriate ex- periment could be performed. The indirect evidence is overwhelming; i t encompasses the demonstration of greatly reduced breast can- cer risk following oophorectomy in rodents,lg cats and dogs,s and women,g as well as the induction of cancers of the breast and other organs in laboratory animals by treatment with estrogens. Two cases have been reported of male transvestites who developed breast cancer almost certainly as a result of high doses of estrogen.30 </p><p>In recent years, considerable attention has been given to the adrenal as a potential source of unfavorable hormone patterns. It is pertinent to recall how this interest de- veloped. It stemmed from the observation that adrenalectomy has a beneficial effect in some breast cancer patients whose ovaries have been removed, and from the need to predict which women might benefit from this procedure. The discriminant based on the pattern of excretion of primarily adrenal hormones, developed by Bulbrook and Hay- </p><p>1146 </p></li><li><p>No. 6 ENDOCRINOLOGY AND EPIDEMIOLOGY OF BREAST CA * MacMahon a n d Cole 1147 ward, appears to perform this function with some, as yet unquantitated, degree of suc- cess.1p2 But i t is quite another matter to infer that patterns of adrenal steroid excre- tion are related to breast cancer risk in women with intact ovaries. Bulbrook and Hayward calculated the discriminant for 19 cases of breast cancer whose urine had been collected prior to the development of the disease: the values showed a greater variabil- ity than was evident in control women.4 The most recently reported comparison of early breast cancer cases and control women, based on larger numbers but with urines collected at the time of breast cancer diagnosis, gives no support to the view that the discriminant is atypical among women with breast can- ~ e r . 3 ~ </p><p>T h e pituitary has also been suggested as an important strand in the web of breast cancer causation, primarily because of the demonstrated role of prolactin in the experi- mental ar1ima1.~5 However, there is no con- sensus that prolactin even exists in the hu- man.3 Most authors believe that prolactin activity in the human is associated with growth hormone-but growth hormone is not known to have the luteotropic effects in the human which prolactin has in the mouse- and it is presumably this luteotropic activity with which carcinogenesis is associated in the mouse.26 </p><p>Relationships between the various endo- crine systems are enormously complex, and organs other than the ovary may well be in- volved in breast carcinogenesis. However, in the absence of collateral evidence implicating the adrenal or the pituitary in the human, the information now available clearly identi- fies the ovary as the prime target for etiologic investigations. </p><p>Turning to the second question posed, we must ask which specific aspect of ovarian function seems likely to be associated with breast cancer risk. In approaching this matter, the epidemiologic observation that pregnancy decreases life-long breast cancer risk in women is particularly intriguing, for if ova- rian hormones were carcinogenic one would expect pregnancy to be associated with in- creased, rather than decreased, risk. A num- ber of hypotheses have been offered to re- solve this paradox. </p><p>T h e oldest and most widely credited is that lactation protects against the development of breast cancer.IS The protective mechanism </p><p>might be through anatomical or physiological changes in the breast itself or through asso- ciated hormonal changes. This hypothesis has been particularly attractive because it would also explain other epidemiologic features of the disease-notably the very low rates seen in some parts of the world, and the increasing breast cancer rates experienced by American women born since 1900.20 Evidence has now accumulated to the point where the lactation hypothesis must be discarded. Several studies in the United States during the last decade have shown that breast cancer patients do not differ from unaffected women with respect to lactation history if account is taken of the fact that breast cancer patients tend to be of low parity.", 28, 34 These studies have recently been reinforced by an international collabora- tive study which has demonstrated that the same is also true in areas of the world where lactation is prolonged.31- 36 </p><p>A second hypothesis suggests that it is not the absolute level of estrogen activity that determines breast cancer risk but rather its cyclic fluctuation.1s3 35 Thus, factors which interrupt the monthly cycle-oophorectomy, pregnancy, lactation-would reduce breast cancer risk. However, it has been shown in mice that equivalent doses of estrogens when given intermittently are considerably less car- cinogenic than when given at a constant rate.24 With respect to man, this hypothesis is discredited by the demonstration that nurs- ing confers no protection. Even in areas of the world where lactation is responsible for an interruption of the menstrual cycle as long as that which occurs during pregnancy, lactation is not protective, although preg- nancy is.36 </p><p>A third hypothesis is that the high estrogen production of pregnancy is counteracted by correspondingly high levels of other hor- mones. Progesterone is one possibility,lO since progesterone opposes certain actions of the estrogens. However, progesterone also aug- ments some estrogen effects. This is partic- ularly so in regard to the breast, where both hormones act in concert to bring about maturity and functional competence. In addi- tion, progesterone itself has a well-established action as a promoter of chemical carcino- gens,lz. 13 of estrogens,26 and of combinations of chemical carcinogens and e~tr0gens. l~ Thus, it may well be that progesterone conveys in- creased, rather than decreased, risk of breast cancer. The former action is more in keeping </p></li><li><p>1148 CANCER December 1969 Vol. 24 </p><p>with the fact that both progesterone levels and breast cancer risk fall after oophorectomy. </p><p>The most attractive explanation of the pregnancy paradox has been offered by Wotiz et a1.33 These authors suggest that the factor which inhibits the carcinogenic activity of estrogens during pregnancy is itself an estro- gen-estriol. Three estrogens are produced by women in large amounts; two, estrone and estradiol, have been shown to be car- cinogenic; the third, estriol, has not.29 In experimental studies of the capability of estrogens to promote uterine growth, it has been shown that estriol inhibits the action of the other estrogens, probably by competi- tion for molecular-binding sites.33 During pregnancy, production of estriol increases much more than does that of the carcino- genic estrogens. The overall effect may there- fore be a reduction in the estrogen carcino- genicity to which the woman is subject.17 </p><p>Whatever hypothesis is ultimately found to provide the correct explanation for the protective effect of pregnancy, it will require some modification-or at least further spe- cification-to accommodate the conclusions of a recent reevaluation of the association between parity and breast cancer risk.21 I t appears that total parity is not so directly related to breast cancer risk as is the age at which a woman has her first child. The asso- ciation between breast cancer risk and total parity results primarily from the fact that women who have their first child at a young age tend to achieve a high total parity. The effect on breast cancer risk of the age at which a woman has her first child is marked- when this occurs under the age of 20 the reduction in risk is about the same as that observed in women who undergo total oopho- rectomy prior to 40 years of age. Subsequent pregnancies have much less effect than the first. These findings strongly au,ment certain other epidemiologic observations which point to the importance of events during the dec- ade or so after puberty in determining breast cancer risk. </p><p>There are at least 3 ways in which the apparent protcctive effect of early first preg- nancy may be accounted for: 1. the protective capability of pregnancy, e.g., the excretion of estriol, may decrease with age; 2. the endo- crine status of nonpregnant women, e.g., the ratio of carcinogenic estrogens to estriol, may be most unfavorable in the years immediately after puberty and become more favorable </p><p>with age-an early pregnancy would then be exerting its protective effect during a period of otherwise particularly high risk-or 3. the first pregnancy may be a tyigger that term- inates, or virtually terminates, a period of high risk of tumor induction. Thus, the earlier the pregnancy occurs the shorter will be the period of high risk. In the context of the role of the estrogens, it is, of course, tempting to think that this period of high risk coincides with the onset of puberty. This possibility has not yet been adequately tested by epidemiologic analyses, since the time of puberty is impossible to determine, and even that of menarche difficult to assess with any reliability in middle-aged and elderly women. However, there is some evidence to the effect that breast cancer patients report earlier menarche than controls.31, 36 </p><p>There are several considerations which add credibility to the concept that most breast tumors are induced in the decade or so after puberty. It is well known that de- veloping tissues are much more susceptible to tumor induction, and this is a time when the breasts are undergoing active develop- ment; Dao has shown convincingly that estro- gens are critical in the induction, and not merely in the maintenance, of breast cancer.6 In the context of the estrogen fraction hypo- thesis, high risk in the period after puberty might be predicted from the high proportion of menstrual cycles that are anovulatory dur- ing these years. Such cycles have no luteal phase and, therefore, lack the relatively high estriol levels produced by the corpus lu- teum. Grattarola has indeed shown that pre- menopausal breast cancer patients have a significantly higher frequency of anovulatory cycles than do control women of comparable age.1" </p><p>We have previously reviewed the evidence suggesting an etiologic role for the estrogen fractions during the decade or so after pu- b e r t ~ . ~ The hypothesis has important impli- cations for the understanding of the etiology of breast cancer, the identification of groups of women at high risk, the possibility of in- stituting preventive measurcs in such women, and the recognition of the potential effects of the oral contraceptives. Information on the variation in excretion of the several estro- gen fractions by age, parity, nationality, and other demographic variables would allow simple, albeit indirect, tests of the concept. Regretfully, in spite of the many thousands </p></li><li><p>No. 6 ENDOCRINOLOGY AND EPIDEMIOLOGY OF BREAST CA - MacMahon and Cole 1149 of estrogen fraction determinations that have been done in the last few years, such data are not available. There has been little interest among endocrinologists in the estrogen pro- files of girls of this age, and, in addition, endocrinologic work in general has proceeded without regard for the considerations of samp- ling that are needed to provide information on the normal population. </p><p>The third area in which a combination of endocrinologic and epidemiologic observa- tions may be fruitful is the identification of the causal determinants of whatever hor- mone pattern is ultimately found to be re- lated to breast cancer risk. Here, the inter- national differences in breast cancer rates seem to be most provocative,7 or it is now evident that none of the variables so far identified-including age at first pregnancy -account for more than a small part of the observed international differences. Studies </p><p>of Japanese migrants to the United States indicate that their breast cancer rates, and those of their daughters, have changed much more slowly than do rates of most other can- cers.ll This observation suggests that ge...</p></li></ul>