Do hormones cause breast cancer?

Do Hormones Cause Breast Cancer?

DAVID 6. THOMAS, MD. DRPH

The evidence that various endogenous and exogenous sex hormones play a role in the etiology of breast cancer is reviewed. It is hypothesized that prolonged exposure to normal levels of ovarian estrogens and cyclic progesterone resulting from early menarche and late menopause, and primarily willful nulliparity and late childbearing, act at an early stage in the development of breast cancer by promoting excessive proliferation of normal epithelial stem cells. Excess endogenous or exogenous estrogens can enhance risk by stimulating proliferation of epithelial cells that have undergone partial malignant transformation. The breast, however, is much less responsive to the tumor-promoting effects of estrogens than the endometrium, and estrogens probably play a less important role in the later stages of mammary than endometrial carcinogenesis.

Cancer 53595-604, 1984.

ORMONES probably act at more than one stage in H the development of breast cancer disease. In this article, I will review the evidence for the etiologic role that various endogenous and exogenous hormones are likely to play. First, the likely pathogenesis of breast cancer is considered.

Pathogenesis

Human carcinomas probably arise from undifferentiated epithelial stem cells as a result of a series of two or more errors in normal cell division. These steps may be presumed to result in progression from normal cells, to one or more stages of intermediate cells, to fully transformed tumor cells. The errors in cell division probably result from deoxyribonucleic acid (DNA) damage caused by such initiating factors as ionizing radiation, chemicals, or viruses. Exposures to such factors are more likely to lead to the development of a carcinoma under circum- stances that increase the number of susceptible basal or intermediate cells and their rates of division, and are less likely to do so when such cells are killed or caused to differentiate rather than proliferate. This concept has been fully developed by Moolgavkar and Knudson' who pro- pose a two stage model for human carcinogenesis.

In the human breast, malignancies probably arise largely from basal cells of the ductal epithelium. Ionizing

Presented at the American Cancer Society National Conference: Breast

From the Fred Hutchinson Cancer Research Center. Supported by grant CA I5704 and contract NO I-CP-6 1059 from the

Address for reprints: David B. Thomas, MD. DrPH, Fred Hutchinson

Accepted for publication September 28, 1983.

Cancer, Boston, Massachusetts, May 19-2 I , 1983.

National Cancer Institute.

Cancer Research Center, I124 Columbia Street, Seattle, WA 98104.

radiation is the only known risk factor for breast cancer that most likely acts by causing DNA damage in these cells,2 although others must undoubtedly exist, because radiation exposure can account for only a minute proportion of all breast cancer cases. Hormones of the ovarian-pituitary axis undoubtedly play an etiologic role. These hormones are not mutagenic, and it seems to the author reasonable to assume that they most likely exert their carcinogenic effect not by causing DNA damage, but by increasing or decreasing rates of proliferation, atrophy, or differentiation of stem or intermediate cells. Risk factors that implicate these hormones in the genesis of breast cancer are shown in Table l . 3

Risk of breast cancer is approximately 100 times greater in women than men. In women, breast cancer does not occur before puberty. Thereafter, its incidence increases rapidly with age until menopause, After which time it increases more slowly with advancing years. Risk of breast cancer increases as the age at menarche decreases, and as the age at menopause increases, so that the longer a woman has normal ovarian function the greater her risk. Furthermore, premenopausal oophorectomy, without exogenous estrogen replacement therapy, reduces risk; and the degree of protection is inversely related to the age at which the ovaries are removed. Childbearing also alters risk; parous women are at lower risk than nulliparous women, and the risk in women who have had children increases with the age at which their first child is born. Having additional children may also be weakly pr~tect ive,~ particularly if at any early age.4

As mentioned above, these risk factors probably influence the risk of breast cancer through hormonally mediated alterations in mammary cell kinetics. Women ob- viously have more susceptible mammary epithelial cells

595

596 CANCER February 1 Siipplement 1984 VOl. 5 3

than men, and accordingly are at greater risk of breast cancer. Proliferation of these epithelial cells begins at puberty and is maximal between 12 and 18 years of age. This increase in susceptible stem cells can explain the rapid subsequent increase in risk with age until menopause, and the relationship of risk to age at menarche. Cessation of ovarian function is followed by involution of the breast and thus a decrease in the number of basal and intermediate cells; and this can explain the decline in the slope of the age-incidence curve after menopause, and the protective effect of early natural or artificial cessation of ovarian function.

Pregnancy is accompanied initially by proliferation, but is then followed by marked differentiation of mammary epithelial cells, and there is some evidence that risk of breast cancer following radiation is initially enhanced and then reduced by a first p regnan~y.~ If the first pregnancy is interrupted during the first trimester. the risk of breast cancer may be increased,' and this could be due to the initial cell proliferation not being followed by differentiation. The earlier in life that a first pregnancy occurs, the shorter is the time when large numbers of undifferentiated susceptible stem cells are present. and thus the lower is the risk of breast cancer. Additional pregnancies could act in the same way as the first on remaining undifferentiated stem cells to further reduce risk. These concepts have been developed and incorporated into an elegant mathematical model for the genesis of breast cancer by Moolgavkar and associates.'

The hormones most likely involved in these pathogenic cellular changes are estrogens and progesterone, but androgens and prolactin may also play a role. Estrogens cause proliferation of human breast tissue, and would therefore be expected to increase risk of breast cancer by stimulating the growth of stem and intermediate cells. Progesterone, which is largely produced during the luteal phase of the menstrual cycle, causes alveolar cell growth in the estrogen primed breast, but also differentiation, so it is unclear whether its net effect would be to increase or decrease the risk of breast cancer. Androgens depress mammary cell growth, and would be expected to be protective against breast cancer. Prolactin acts on the estrogen-primed breast to stimulate and maintain lactation; and since it is associated with the functioning of differentiated cells, rather than the stimulation of cell growth, it would be expected, if anything, to decrease risk. The evidence that these hormones alter the risk of breast cancer is summarized in the remaining portions of this report.

Prolonged Estrogen and Cyclic Progesterone Stimulation

Menarche, menopause, and childbearing are normal events, and an important question to be answered is

TAN F I . Factors Implicating Endogenous Hormones in the Genesis of Breast Cancer

Factor Influence on risk

Female sex

Age at menarche Age at menopause Oophorectom y

Nulliparity Age at first birth Paritv

Age Increases risk Increases risk Inversely related to risk Directly related to risk Protection inversely related to age at

Increases risk Directly related to risk Additional children weaklv Drotective

oophorectom y

whether risk is altered solely by the timing of these events, or altered because the endocrinologic changes associated with them vary with age. If merely the timing of these normal events plays an etiologic role, then risk of breast cancer is most likely enhanced by prolonged exposure to normal endogenous estrogens and cyclic progesterone resulting from an early menarche and a late menopause, and from few and late interruptions in these exposures by pregnancies. On the other hand, if variations with age in the hormonal changes associated with these events play a role, then risk of breast cancer may be due to aberrations in the internal hormonal milieu.

Evidence for hormonal aberrations playing a role is not strong. In 19110, Korenmad hypothesized that anovulatory cycles would occur more frequently in women with an early menarche and a late menopause and that these periods of estrogen stimulation without cyclic progesterone were windows of susceptibility. However, there is now evidence from two studies that women with an early menarche are not more likely to have anovulatory cycles than women with a later menarche.'.'' On the other hand, one of these studies has shown levels of all three major urinary estrogens to be higher in women with an early rather than late menarche." This observation, if confirmed by others, would suggest that excess estrogen stimulation associated with an early menarche may play an etiologic role iin the genesis of breast cancer, even though anovulatory cycles early in life do not.

It has been suggested that the relationship of late age at first birth to breast cancer is due to relative infertility (and anovulatory cycles) in women with a delayed birth. However, this is an unlikely explanation. In one study: cycle length and variability prior to mamage was found to be unrelated to subsequent pregnancy rate; and in another investigation" the protective effect of a first birth was observed in women who first gave birth within two years of mamage, as well as in women who gave birth only after being married for a longer period of time.

The hormonal changes associated with a first pregnancy have not been sufficiently studied to determine whether they vary with age in such a manner and magnitude as to alter the risk of breast cancer. One study, however,

No. 3 HORMONES AND BREAST CANCER - Thomas 597

TABLE 2. Risk Factors for Endometrial Cancer and Their RelationshiD to Breast Cancer

Risk factor

Probable mechanism in the genesis of endometrial cancer Relative strength of association

with cancers of No cyclic

Excess estrogen progesterone Endometrium Breast

Late menopause Estrogen secreting tumors Polycystic ovary/anovulatory cycles Obesity Nulliparity Low parity Menstrual irregularity Exogenous estrogens

+ ++ ++ + + + + ++

++: definite risk factor, association strong; +: definite risk factor, association moderate; +: probably a risk factor: -: not a risk factor,

showed the estriol excretion ratio to be higher in young parous women than in young nulliparous women,13 suggesting changes in estrogen metabolism and excretion following an early first birth.

On balance, however, the available evidence suggests that it is largely the timing of the early events of menarche and birth of first child that alter risk, rather than associated anovulatory cycles and estrogen stimulation without cyclic progesterone, or other aberrations resulting in excess estrogens. This conclusion is supported by an additional argument. As discussed subsequently, the endometrium is undoubtedly more sensitive to the carcinogenic effects of estrogens than is the breast, and if excess estrogen stimulation were the mechanism by which ages of menarche and first birth altered risk, then risk of endometrial cancer should also be related to these events, and it is not.

Additional studies should be conducted to identify hormonal difference in women with different ages at menarche and first birth. It is hypothesized that the results will be largely negative; and if they are, then this will be additional evidence that risk of breast cancer is enhanced early in reproductive life, not by exposure to unopposed estrogens, but by prolonged exposure to normal levels of estrogens and cyclic progesterone. There is, however, evidence that excess estrogen stimulation, particularly later in life, can also alter a woman’s risk of breast cancer.

Excess Estrogen Stimulation: Lessons from the Study of Endometrial Cancer

The major known risk factors for endometrial cancer are shown in Table 2.14 All represent conditions associated with either excess estrogens or a lack of cyclic progesterone, or both. Women with a later natural menopause are not only exposed to normal endogenous estrogens and cyclic progesterone for a longer period of time than women with an earlier menopause, but are also probably more likely to be exposed to anovulatory cycles. One study

adequately studied; 0: not observed to be a risk factor. not adequately studied.

showed women with a late menopause to have longer menstrual cycles and greater variability in cycle length than women with an earlier menopause.’ Women with estrogen-secreting tumors and polycystic ovaries produce an excess of ovarian estrogens, and in obese women there is an excess conversion of androstenedione (of adrenal origin) to estronel5.I6; and blood estrogen levels are elevated in all of these conditions. Women with polycystic ovary syndrome, and other conditions known to be characterized by anovulatory cycles, also lack cyclic exposure to progesterone; and nulliparity, low parity, and menstrual irregularity also distinguish women with a tendency to have anovulatory cycles. Finally, estrogen levels are enhanced by the administration of exogenous estrogens of various types.

The last column of Table 2 summarizes the relationship of these endometrial cancer risk factors to risk of breast cancer. The three premenopausal factors thought to be related to endometrial cancer because of their association with anovulatory cycles are nulliparity, low parity, and menstrual irregularity. The latter is not a risk factor for breast cancer, and evidence has been presented previously that the childbearing factors are not explainable on the basis of anovulatory cycles. Anovulatory cycles associated with a late menopause have been mentioned and may play an etiologic role in breast cancer (although prolonged exposure to normal ovarian estrogens and cyclic progestogen may also be operative).

The remaining four risk factors in Table 2 are associated with an estrogen excess. All but estrogen-secreting ovarian tumors have been related to risk of breast cancer, and the possible relationship of breast cancer to such ovarian tumors has not been adequately studied because of their rarity.

Two studies have now shown an increased risk of breast cancer in women with anovulatory cycles. A follow-up study at Johns Hopkins Hospital showed risk of premenopausal breast cancer to be 5.4 times higher in infertile

598 CANCER February I Supplement 1984 Vol. 53

TABI.F 3. Relationship of Weight to Breast Cancer

Menopausal status

Reference Pre Post All

Valaoras cr a/.” M i m 6’1 ul.” Ravnihar er Lin (’I ul.’5 De Waard er d2‘ ’’ Soini”’ Adami 1’1 a/.” Stasrewski” Cc’ynder rt ul 2 2

Choi ei ul.” H irayama’” De Waard and Baanders-van

lkiiewijn” Harris er d3’ Brinton er ul.”

0

t + 0 0 0 _ _ +

+

0 ++ i~ t tt i~ +

+

0 0

++ 0 0 i- + t t

+t

++ 0: no association; t: increased risk, magnitude small or not statistically

significant: t +: increased risk, magnitude large or statistically significant: --: decreased risk, magnitude large or statistically significant.

women with anovulatory cycles than in infertile women with normal cycles.” The risk of postmenopausal breast cancer was not altered significantly, but the numbers of older women studied were small. In a follow-up study at the Mayo Clinic, risk of breast cancer was found to be 1.45 times higher than expected in a cohort of women with evidence of estrogen production and either clinical evidence of anovulation, or gross or histologic evidence of polycystic ovarian disease.” In this study, risk was greatest in women over age 55 (3.6-fold increase). The observed increments in risk are not as large as for endometrial cancer. The results of these two studies do not contradict the observations made previously that the re- lationships of nulliparity and age at first birth to risk of breast cancer are not explainable on the basis of anovulatory cycles. These two studies are of highly selected

women treated for infertility, and such women constitute too small a proportion of the population to be included in sufficient numbers in general studies of breast cancer to influence the results of such studies. In other words, anovulatory cycles can explain only a small proportion of all breast cancers that occur in the general population. The studies of infertile women are nonetheless of con- siderable value in showing that excess estrogens can increase the risk of hreast cancer.

Although some studies have not shown an association between body weight and breast cancer,’”-” most reports in which information is presented separately by menstrual status show an increased risk in postmenopausal women23-33 (Table 3). Again, the association is not as strong, or as consistently observed, as for endometrial cancer.

The influence of noncontraceptive exogenous estrogens on risk of breast cancer has been thc subject of a recent review,34 from which Tables 4, 5 and 6 are adapted. Table 4 summarizes results from 10 case-control studies of breast cancer in relation to menopausal estrogens that have been conducted since 1974.35-44 Only four of the 10 yielded estimates of the relative risk in ever-users that are greater than unity; two of these were of borderline statistical significance (95% confidence limit of the relative risk = 1 .O). One prosptxtive of 189 1 women treated with conjugated estrogens for an average of 12 years re- vealed a comparable relative risk of I .3 that was also of borderline statistical significance (P = 0.06). Another prospective s t~dy ,““~’ showed a statistically significant fourfold increase in risk in estrogen users, but this result is probably an artifact of improper study design and anal- y ~ i s . ~ ~ By way of contrast, 15 of 16 studies of endometrial cancer summarized by WeissI4 provided estimates of the relative risk in ever-users that were significantly greater than one; and these 15 estimates ranged from 1.4 to 1 1.3, and averaged about 5.

T A H L t 4. Estimates from Ten Case-Control Studies of Relative Risk of Breast Cancer in Women Who Ever Used MenoDausal Estroaens

Source of Type of No. of Relative Statistical Reference Year cases controls cases risk* significance

BCDSP‘’ I974 Hospital Hospital 5 I 0.96t

Casagrande 1’1 a/.’’ 1976 Population(?) Doctor’s otfice ti0 0.75

SanweII P I a/.’* 1977 Hospital Hospital 2114 0.82 RaLnihar rt ul l9 1979 Hospital Hospital 177 0.73t Jick (’I a/.“ I980 Hospital Hospital 0 7 0.97t.$

Brinton er ul 1981 Screenees Screenees 811 1 I .24 Hoover 6’1 a/.‘” 1981 Population Population 345 1.4

Craig PI a/ ” I974 Population Population 34 I . O t

Neighborhood 3 3 3. I

Ross P/ ul.“ 1980 Community Community 1.11 1 . 1

Kelsey e r a1 ‘‘ 1981 Hospital Hospital 3.12 0.9

NS: not significant ( P > .05 or 95% confidence limits include 1.0):

* Risk in ever-users relative to neber-users of menopausal estrogens.

t Calculated from published data on cases and controls. $ Risk in current and past users relative to nonusers. B: borderline significance (lower 9 5 4 confidence limit equals 1 .0).

NS NS NS NS NS NS NS NS B B

NS

No. 3 HORMONES A N D BREAST CANCER - Thomas 599

However, somewhat more consistent findings among studies of breast cancer are evident when doses of estrogens received are considered. This was done in five case-control studies and one prospective study, the results of which are summarized in Table 5 . Ross and associates4' found a relative risk of 1.8 in users of more than 7-years duration; Brinton and coworkers4* found a weak, but statistically significant, increase in risk with duration of use; Hoover and associates43 observed an increase in relative risk with number of prescriptions for estrogens on record in a pre- paid health plan; Hoover and associate^,"^ Brinton and associate^,^^ and Hoover and associates4' all found the relative risk to increase with the daily dose of estrogens taken; and Ross and coworkers4' observed the relative risk to increase with the total cumulative amount of estrogens received. Only the studies by Kelsey and asso- c i a t e ~ ~ ~ and Ravnihar and coworkers39 failed to show some indication of an increased risk in relatively heavy users of estrogens, and in the latter study this may be explained by there being too few long-term users in the group that used estrogens for more than 2 years.

The menopausal estrogens used by women in all of the studies cited above were predominantly conjugated estrogens, and the findings presented thus largely reflect the influences of these preparations on risk of breast cancer. Additional evidence for a dose-response comes from three studies of women treated with diethylstilbestrol (DES) during pregnancy for threatened abort i0n,4~-~~ and two case-control studies of DES used for menopausal the rap^.^^,^^ As shown in Table 6, excess risk was greatest in the study in which the mean total dose of DES during pregnancy was 16.3 g;48 a small excess was found in the study in which the mean dose was 1 1 g;49 and no excess risk was observed in the study in which women received an average of 1.5 g." The total doses received by users of DES included in the two case-control s t ~ d i e s ~ ~ , ~ ~ are unknown, but the usual daily dose for menopausal symptoms is 0.2 to 0.5 mg. At the higher level of use, a woman would receive a total of 1 g after about 5.5 years of con- tinuous therapy. This amount is of the same order of magnitude as that received by the women in the prospective study of Brian," and the observed relative risks of 1 .O, 1.1, and 0.9 are all comparable.

TABLE 5 . Relative Risk of Breast Cancer in Relation to Various Doses of Menopausal Estrogens

Measurement Relative of dose Reference Dose category risk

Duration of use Ravnihar et

Ross et d4'

Brinton et

Number of Hoover et u I . ~ ~ prescriptions

Daily dose Hoover et aL4'

Brinton et

Hoover et U I . ~ ~

Cumulative dose Ross el aL4'

Kelsey el al."

<2 yr 2 2 yr

2 7 yr

<5 yr 5-9 yr 10+ yr

I 2-4 5-9 2 10

< I .25 mg 21.25 mg

0.3 mg 0.6 mg 1.25 mg 2.5 mg

0.3 mg 0.625 mg >0.625 mg

I - I499 mg/life >I500 mg/life

1-49 mg-mo 2 5 0 m w n o

0.73 0.74

I .8

1.19 I .29 1.21

I .o I .3 I .5 1.7

1 . 1 1.5

0.79 1.34 1.18 1.70

I .2 1 . 1 I .9

0.8 I .9

0.84 0.65 -

Additional evidence that high doses of estrogens can cause breast cancer comes from a report of two transvestite men who received massive doses of estrogens to induce breast development, and who subsequently developed breast cancer."

The risk of endometrial cancer increases within a few years of use of exogenous estrogens, and declines within 1 or 2 years after administration is stopped. These observations indicate that estrogens act by promoting the growth of cells in a late stage in the process of neoplastic transformation. Indirect evidence suggests that this may also be true for breast cancer. Women with benign breast lesions characterized by proliferation of the ductal epithelium are at increased risk of breast ~ a n c e r , ~ ~ . ~ ~ perhaps because such lesions represent cells in an intermediate stage between normal and cancerous; and one has shown exogenous estrogens to particularly enhance

TABLE 6. Estimates from Five Studies of Relative Risk of Breast Cancer in Users of DES

Average cumulative Relative Reference Type of study Reason for DES treatment dose (gms) risk

Beral and Colwel14" Randomized trial Prevent fetal loss* 16.3 3.4

Brian el a/."' Prospective Prevent fetal loss I .5 I .O Kelsey et al.44 Case-control Menopausal symptoms unknown? l . l $

Bibbo el U I . ~ ~ Randomized trial Prevent fetal loss 11.0 I .5

Hoover d d4' Case-control Menopausal symptoms unknown? 0.96

* DES given simultaneously with ethisterone (average cumulative dose:

t See text. unknown.

Based on observations of women with intact ovaries. 13.8 gm). Q Limited to women with more than one prescription; ovarian status

600 CANCER February 1 Supplement 1984 Vol. 53

TABLE 7. Relative Risks of Breast Cancer in Ever-Users of Oral Contraceptives

Source of Years cases Relative Reference subjects No. of cases Age of cases diagnosed risk

BCDSP” Paffenbarger el a/.J6 Sartwell el a/.’* Henderson ei aL5’ Kelsey ei al.” Ravnihar el al.” Pike ei a!.‘ Hams ei aL3’ Kelsey ei a/.44 Vessey el a1.6’ CASHJ9 Brinton ei a/.60

Hospital Hospital Hospital Office Hospital Hospital Population Population Hospital Hospital Population Screenees

23 452 284 308 99

I90 I63 I12 332

1176 689 963

20-75 - 4 0

20-73 40-64 20-44 20-49 s 3 2

35-54 45-74 16-50 20-54

All

I972 1970- I972 1969- I972 I97 I - 1973 197 1-1973 1972- I974 1972-1978

1977-1979

1980- 198 1

1977-1978

1968- 1980

1973-1977

0.60 1 . 1 0.86 0.74 1.35 0.9 I 1.15 1 .o 0.9 0.98 0.9 1 . 1

Estimated from 12 case-control studies.

the risk of breast cancer in women with such lesions. Another study33 showed oophorectomy to be protective against women with invasive breast cancer, but not against in situ disease, and also body weight to be more strongly related to invasive than in situ tumors, suggesting that endogenous estrogens may be specifically involved in the late stage of progression from in situ to invasive breast cancer.

Combined oral contraceptives are a mixture of an estrogen and a progestogen, but have a net progestational effect. The influence of these preparations on risk of breast cancer has been studied intensively. Results from 12 case- control studies6,32.38,39,44,55-61 and 3 prospective studies6’* are summarized in Tables 7 and 8, respectively. None of these show a significant alteration in risk. Risk has also not consistently been observed to be altered in long-term users (Table 9), or after an appreciable latent period (Table 10). These findings are in contrast to those for endometrial

which show risk of these conditions to be substantially reduced by use of combined oral contraceptives.

In summary, it appears that high doses of exogenous estrogens increase the risk of breast cancer, but that smaller amounts, which have been shown to increase the risk of endometrial cancer, do not. Also, risk factors that are indicative of an absolute excess of endogenous estrogens, or a relative excess at menopause due to a lack of cyclic progesterone, tend to distinguish women at increased risk

and benign breast

of breast cancer, hut are not as strongly associated with this neoplasm as with endometrial cancer. Thus, the breast appears to be less susceptible to the tumor promoting effects of estrogens that the endometrium, and larger amounts of estrogens are required to achieve an observable alteration in risk of malignancy. This conclusion has two implications for our understanding of the etiology of breast cancer:

1. Since incidence rates of breast cancer are generally much higher than those of endometrial cancer (particularly in populations where exogenous estrogens are not used), absolute or relative excesses of endogenous estrogens play less of ;I role in the genesis of breast cancer than endometrial cancer, and probably only a minor one. The same is true for exogenous estrogens. Incidence rates of endometrial cancer increased rapidly in the United States following a rise in use of menopausal estrogens, and declined soon after the frequency of use was reduced,I4 but there was no (comparable temporal change in rates of breast cancer.

2. Those risk factors for breast cancer that are not also risk factors for endometrial cancer must be mediated by some means other than simply increased levels of endogenous estrogens or lack of cyclic progesterone, for if either of these were their mechanism of action, they would also be associated with endometrial cancer. These other risk factors include age at menarche and age of birth of

TABLE 8. Prospective Studies of the Relationship of Oral Contraceptives to the Risk of Breast Cancer

Incidence per lo00 woman-years (no. of cases) Relative risk

Reference Age Nonusers Past user Current user Past user Current user

Vessey” All 0.52 (33) 0.45 (18) 0.54 (21) 0.86 I .04 <35 0.28 (6) 0.15 (3) 0.18 (5) 0.53 0.64

RCGP) All 0.39 (58) 0.45 (39) 0.50 (36) 1.14 I .26 -.- (0.7-1.9) (0.7-2.2)

Trapidob4 All 1 . 1 (370) 0.93 (85) 0.84 (0.7-1.2)

No. 3 HORMONES A N D BREAST CANCER * Thomas 60 1

TABLE 9. Relative Risks of Breast Cancer in Young Women with Long-Term Use of Oral Contraceptives

Source of No. of Age of Years cases Relative risk in Minimum Reference subjects cases cases diagnosed long-term users years of use

Paffenbarger ei Hospital 452 4 0 1970-1 972 1.7 8 Kelsey er Hospital 99 20-44 1971-1973 I .7 5 Ravnihar et ~ 1 . ' ~ Hospital I90 20-49 1972- I974 0.95 2 Brinton ei al." Screenees 458 Premenop 1973- I977 1 . 1 10 Pike et Population 163 532 1972-1978 I .56 4 Hams er al." Population 112 35-54 1977- I978 0.8 5

CASHs9 Population 689 20-54 1980- I98 I 0.9 1 1 Vessey et a/.'' Hospital 1 I76 16-50 1968- I980 0.99 8

Premenop: premenopausal.

first child, which have already been considered. They also include a family history of breast cancer and prior benign breast lesions, which, along with nutritional and geographic factors, are considered in the next section.

Other Possible Hormonal Factors

The geographic variation in incidence rates of breast cancer is c~nsiderable.~~ This variation is largely due to environmental and not genetic factors, because migrants from low-to-high risk countries, or their children, tend to develop breast cancer at rates closer to those of the native population of their country of adoption than of their country of origin.3 The international differences in rates are not due to differences in menstrual or childbearing factors, because these differences are just as large for men7' and single women7* as for married women. Large increases in rates over time in Iceland,73 and more recently in Japan," are similarly not explainable by changes in patterns of childbearing (although smaller temporal trends in the United States and Britain may be3). In Iceland and Japan, increases in rates are observable in succeeding birth cohorts; and rates are greater in the children of migrants to high risk countries than in the migrants themselves. These observations indicate that the environmental factors responsible for the spatial and temporal variation in rates are operative early in life. These factors are probably nutritional. National rates of

breast cancer have been correlated with national fat and meat cons~mption,'"~~ and case-control s t ~ d i e s ~ ~ - ' ~ have shown risk to be related to total fat and meat consumption.

One hormonally mediated mechanism by which a diet rich in animal products could increase risk is the production of obesity which, as discussed previously, is associated with enhanced production of estrone from androstenedione.

Another hormonally related mechanism is the production of steroid hormone-like substances by the action of intestinal bacteria on bile salts. In one recent study" women with breast cancer were found to have higher excretion of fecal steroids than controls. In another," postmenopausal vegetarian women were found to excrete slightly less estrogens in their urine than meat-eating women, and to have higher sex hormone-binding globulin, indicating that less unbound estrogen is available in the vegetarians. However, vegetarians and nonvegetarians differ little in their rates of breast cancer,77 and this mechanism is therefore unlikely to explain the large international differences in rates.

A third mechanism for a dietary influence on risk is that a high fat and meat diet, or other nutritional factors with which they are correlated, are related to early menarche and late menopause. However, as mentioned above, variation in these menstrual factors among countries can- not explain the international differences in rates of breast cancer.

TABLE 10. Relative Risks of Breast Cancer by Years Since Initial Use of Oral Contraceptives

Minimum years Relative Reference Type of study Subgroup of women since initial use risk

Paffenbarger et dSh Case-con trol All women Brinton ei a/."' Case-control Premenopausal

Postnatural menopause All women

C A S H ~ O Case-control All women Hams el a/." Case-control All women Vessey et d6' Case-control All women Vessey ei a/.62 Prospective All women Traoido et dh4 Proswctive All women

6 13 13 13 16 15 12 12 10

1 . 1 0.78 0.88 0.8 I 0.9 I .4 0.73 1.58 I .02

602 CANCER February 1 Supplement 1984 Vol. 53

First and second degree relatives of women with breast cancer have roughly a twofold increase in risk of devel- oping the disease themselves.’ Hormonal studies of such women have yielded inconsistent results. Some have shown relatives of patients to have excess ~ r i n a r y ~ ~ * * ~ or plasmax4 levels of estrogens and elevated concentrations of plasma p r ~ l a c t i n , ~ ~ but others have not confirmed the latter findings.82 Low levels of plasma androgens have been reported in sisters of breast cancer patientsx5 Daughters of patients have been reported to have increased levels of plasma progesteronex4 and urinary pregnane- d i 0 1 , ~ ’ ~ ~ ~ but not members of selected high risk families.82 The inconsistency and paucity of these findings make them difficult to interpret, but in the aggregate these results suggest that some familial clustering of cases may be mediated by hormonal aberrations. Such aberrations could result from either genetic or environmental influences on hormone production or metabolism. However, in view of the inconsistency of the results and the generally small differences reported, it is likely that mechanisms unrelated to hormones play a more major role in the familial aggregation of this disease. This conclusion is consistent with the hypothesis of Moolgavkar and Knudson’ that familial aggregation results from high-risk individuals being born with the basal cells of their mammary epithelium already genetically transformed into intermediate cells.

Women with benign breast lesions characterized by ductal epithelial hyperplasia are at increased risk of breast ~ a n c e r . ~ ~ . ~ ~ There is little evidence that their excess risk is hormonally mediated,86.87 and they are probably at increased risk because their lesions represent cells in an intermediate stage of carcinogenic transformati~n.~,’

A large prospective study on the Isle of Guernsey has shown that women who excrete low levels of the androgen metabolites etiocholanolone and androsterone have elevated risks of subsequent breast cancer.88 This is consistent with the effect of androgens to retard the growth of mammary epithelial cells. Of particular interest is the observation that low urinary .androgen metabolites, age at menarche, family history of breast cancer, and age at birth of first child, independently influenced the risk of breast cancer (on a logistic scalex9). This indicates that low estrogen levels are not the mechanism by which the other three risk factors considered influence the risk of breast cancer. The determinants of low urinary androgen metabolite excretion are unknown.

Finally, it has been proposed” that a combination of elevated prolactin and estrogens is a hormonal mechanism that enhances risk of breast cancer. However, since breast feeding is not a risk factor for breast cancer’ and high levels of prolactin occur during lactation, this hypothesis seems untenable.

Hypothesized Role of Endogenous Hormones

In summary, I offer the following hypothesis for the mechanisms by which hormones alter the risk of breast cancer. Hormones most likely influence risk not by causing damage to cellular DNA as ionizing radiation probably does, but by altering the kinetics of susceptible stem cells of the mammary epithelium or stem cells that have undergone some degree of malignant transformation. Early in adult life, risk of an initial transformation is enhanced as a result of excessive proliferation of normal stem cells, largely in response to prolonged exposure to normal levels of ovarian estrogens and cyclic progesterone. This prolonged exposure results from early menarche, and late menopause, which may be caused by nutritional factors, and primarily willful nulliparity or late childbearing. The more stem cell proliferation that takes place, especially between menarche and the birth of the first child, the greater is the chance that some stem cell will be transformed into an intermediate cell (by mechanisms that are not known). Intraductal carcinomas, and benign breast disease characterized by ductal epithelial cell proliferation, may be lesions representing such intermediate cells. In- termediate cells can in turn be stimulated to proliferate by a lack of cycli’c progesterone at menopause, or by excess estrogen levels, and such proliferation enhances the risk of an inteimediate cell undergoing a malignant transformation into a tumor cell. However, it takes larger amounts of endogenous estrogens to alter the risk of breast cancer than endometrial cancer; and, since breast cancer occurs with the greater frequency, either other hormonal aberrations, perhaps involving reduced levels of androgens, play a role in its genesis, or the later stages of breast cancer development are not highly dependent on hormonal factors.

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Do hormones cause breast cancer?