Oral contraceptives and breast disease

Transcription

1 M FERTILITY AND STERILITY Copyright" 1991 The American Fertility Society Vol. 56, No.5, November 1991 Printed on acid-free paper in U.S.A. Oral contraceptives and breast disease Kathryn F. McGonigle, M.D. George R. Huggins, M.D. Department of Obstetrics and Gynecology, The Francis Scott Key Medical Center, Baltimore, Maryland EPIDEMIOLOGY OF BREAST DISEASE Breast diseases, benign and malignant, are significant public health problems in the United States and throughout the world. Benign breast disease is the most common type of breast disease and is important because the condition commonly recurs, produces discomfort, and may be confused with neoplastic disease. Fibrocystic breast changes may occur in up to 50% of premenopausal women. 1 Benign breast disease is more common in young women with a peak incidence between ages 36 and Furthermore, some types of benign breast disease are associated with an increased risk of breast cancer. Of over 500,000 breast biopsies performed each year in the United States, <10% reveal carcinoma in women< age 40 and approximately 1 in 3 are malignant in women > age 60. The remaining are benign.3 Cancer of the breast is by far the most common cancer in women, comprising almost one third of cancer cases. 4 A woman in the United States currently has a one in nine cumulative lifetime risk for developing breast cancer. 5 The American Cancer Society estimates there will be 175,000 new cases of invasive breast cancer and 44,500 breast cancer deaths in women during 1991 in the United States. 4 The incidence of breast cancer in women has been rising since the mid 1940s, but the mortality rate has increased minimally. Most of this rise has been since 1980 (Fig. 1). 6 Breast cancer incidence has increased by about 4.5% per year between 1982 and There are many theories as to why this is occurring. Reasons often cited can only partially explain this increase and include delayed child bearing, 7 less breast feeding, and increased mammographic screening. 3 6 Improved treatment modalities and earlier detection may explain the relatively stable mortality rate despite the increasing incidence. Most of the data fail to support a contribution of oral contraceptives (OCs) to this rise. However, any commonly used drug that may change the risk of benign or malignant breast diseases would have significant public health implications. Oral contraceptives have always been under great scrutiny as to what potential adverse effects on the breast they may have. Recently, because of a few studies suggesting a positive association, this scrutiny has increased. Epidemiology of OC Use Combined estrogen (E)-progestogen OCs have been in use for >30 years. As of 1988, estimates of worldwide use are over 63 million married women, 8 and in the United States approximately 13.8 million women use 0Cs. 8 Data indicate that as of 1982, 76% of American women ages 15 to 44 have used OCs. Such widespread use must be justified by a favorable risk/benefit ratio. Strong data exist supporting a protective effect of OCs on ovarian 9 and endometriap 0 cancers. However, significant controversy exists regarding the effects of OCs on the breast, especially with reference to breast cancer. The earliest OCs contained much higher dosages of E and progestogen than current formulations. Most OCs now contain 20 to 35 J.Lg of E and 0.3 to 1 mg of progestogen compared with up to 150 J.Lg and 10 mg, respectively, in the earliest formulations. These dramatic changes in OC composition in the first 10 to 15 years of their use have complicated the evaluation of their role in breast disease. Most published studies involve OC dosages that are now discontinued. It is unclear if the risk of breast disease from the current low-dose OCs differs from the more thoroughly studied high-dose preparations. Since 1970, all of the newly introduced compounds have used ethinyl estradiol (E 2) as the estrogen. 8 In the United States, the progestogens used in the low-dose and triphasic compounds are ethynodiol diacetate, norethindrone, norethindrone acetate, and norges- Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 799

2 " E 0 :t 0 0 0! " u.s Ages AgesSO+ a * a * a 0+---T-~r------r--~--~--T-~r------i Year of Diagnosis Figure 1 Breast cancer incidence in the United States with age adjusted rates for all races. (Adapted from National Cancer Institute Annual Cancer Statistics. 6 ) trel. 8 In Europe, norgestimate, gestodene, and desogestrel are also used. Fear of OC-related side effects, especially cancer, is a powerful deterrent to OC use. Few diseases elicit a greater emotional response by women than the fear of breast cancer. Studies have documented cumulative OC termination rates in the United Kingdom at nearly 16% after reports suggesting an adverse effect of OCs (Fig. 2)Y Subsequently, there was a rise in unwanted pregnancies and associated risks therein. A review of the theoretical concerns of the effects of OC hormones on breast tissue as well as the extensive epidemiologic data relating OC use to benign and malignant breast disease will be presented. Steroids and the Breast Theoretical Concerns The major risk factors for breast cancer, apart from age and family history, are related to a woman's menstrual and reproductive histories. Increased risk is associated with early age at menarche, late age at menopause, nulliparity, late age at first term pregnancy for parous women, history of benign breast disease, and elevated postmenopausal weight These findings suggest an etiologic role for steroid hormones in breast cancer. Furthermore, epidemiologic data suggest a relationship between E and breast cancer: (1) the condition is nearly 200 times more common in women than in men 4 ; (2) a 65% excess rate of breast cancer has been observed among women who have had endometrial cancer 15 ; (3) breast cancer risk is significantly decreased in women undergoing oophorectomy before age 50 who are not given replacement E therapy. Among women with menopause induced before age 35, the risk has been found to be only one third of the natural menopause group 16 ; and (4) breast cancer has occasionally been reported in men treated with long-term exogenous E for carcinoma of the prostate 17 and in maleto-female transsexuals receiving supplemental E. 18 A body of experimental evidence supports a role for hormones in breast diseases. Animal studies have suggested that Es and progestogens may play a role in breast cancer Breast epithelial cells contain receptors for E and progestogen. 21 Estrogens may accelerate the growth of an E-dependent carcinoma of the breast. 22 Decreasing endogenous E levels by ovariectomy, adrenalectomy, or anti-e therapy in some women with E receptor positive tumors may temporarily arrest tumor growth. Conversely, Es may inhibit cancer growth in women with an E receptor negative tumor. Thus E may promote or inhibit carcinoma. 23 Estrogens and progestogens are known to affect the risk of cancer in other hormone responsive tissues. Oral contraceptives clearly decrease the risk of ovarian and endometrial cancers, 9 10 whereas E unopposed by progestogen increases the risk of endometrial cancer Given these data, it is not surprising that there has been significant concern over whether OCs, by changing the natural level of a woman's endogenous sex steroids, may affect the risk of benign and malignant breast diseases. Percentage ' Months after events Figure 2 Oral contraception discontinuation rates as a function of time elapsed after selected news events. (From Grimes. 11 Reprinted by permission of the publisher.) 800 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

3 Breast Physiology: Endogerwus and Exogerwus Hormones There is a paucity of data on the physiology of the human breast and the effects of endogenous and exogenous hormones. If OCs exert an adverse effect on the breast for cancer, it is not clear whether it is the E or progestogen component or interactions of both that are most significant. Although the physiology of the growth and differentiation and hormonal control of the human breast are not fully understood, some information is available. The development of the female breast depends on an ideal progesterone (P) to E 2 balance in conjunction with prolactin and other endogenous hormones. 26 Before complete differentiation of breast epithelial ductal cells, they may be highly susceptible to the action of a carcinogen This full development of the mammary gland is completed only at the end of the first pregnancy Thus, there is concern that OCs may increase the risk of breast cancer with use before a first term pregnancy or with use at a very young age. The Breast and the Menstrual Cycle The menstrual cycle is regulated by a delicate balance between gonadotropins, E 2, and P. The proliferative phase or first half of the menstrual cycle is E dominant, whereas the secretory phase, or second half of the menstrual cycle, is P dominant. With ovulation, the cycle changes from the proliferative to the secretory phase. In anovulatory cycles, this fails to occur and the E dominant state is maintained. The effect of the changing levels of endogenous hormones during the menstrual cycle on proliferative activity of breast intralobular epithelium has been studied. The greatest proliferative activity occurs during the second half of the menstrual cycle, and the peak proliferative activity declines with increasing age Potten et al. 30 studied the effect of age and menstrual cycle on proliferative activity of normal human breast intralobular epithelium using tritiated thymidine. They noted that proliferative activity was highly variable and was highest on day 21.5 and lowest on day 7.5 of a 28-day menstrual cycle. Anderson et al. 31 studied proliferative activity of normal breast epithelial cells using morphological identification of mitosis. Similar to Potten et al., 30 they found a peak in proliferative activity during the second half of a 28-day menstrual cycle with a peak in mitotic index on day 25. When the authors examined the data by subgroups of age between ages 15 to 45, they found that all subgroups showed significant cyclic variation in proliferative activity throughout the menstrual cycle, but that the youngest group showed the greatest fluctuation. The differences between the age groups were not significantly different. When the authors examined their data based on parity, they found the degree of fluctuation for mitosis to be slightly greater for the nulliparous groups. The peak of proliferative activity in the breast during the second half of the menstrual cycle is opposite to what is seen in the endometrium where the peak proliferation occurs during the first half of the menstrual cycle. These studies demonstrate that peak proliferative activity in the breast occurs at a time in the menstrual cycle when endometrial proliferation is at its lowest, a time of relatively higher endogenous P levels. No difference has been found between the proliferative rates of terminal ductal cells of benign breast tissues and fibroadenomas of OC versus non-oc users. However, a recent study by Anderson et al. 34 suggested that the nulliparous breast may be more susceptible to the adverse effects of exogenous hormones. They evaluated breast epithelial proliferation using tritiated thymidine labeling of normal breast lobules. They studied the effect of natural cycles and those regulated by OCs on menstrual cycle phase and parity. Similar to previous studies, for natural cycles, proliferation was greatest in the late secretory and lowest in the late proliferative quartiles, and the variation decreased with increasing age. Natural cycles were not significantly affected by parity. There was, however, a differential effect for OCs on the parous versus the nulliparous breast for proliferative activity. For OC users, the nulliparous breast showed a significant increase of proliferative activity compared with controls and the parous breast (Fig. 3). 34 When the data were analyzed for OC type for the nulliparous breast, the progestogen-only pills showed the greatest overall activity. Increasing E dose, but not increasing progestogen dose in combination pills was associated with an increase in proliferative activity. The difference was statistically significant. These data are preliminary, and whether an increase in breast epithelial proliferative activity proceeds the development of malignancy is unknown. Progestogens and Breast Cancer Risk Most studies suggest that progestogen is protective for benign breast disease. Whether progestogens are protective to the breast for breast cancer is less clear. Because of the paucity of breast tissues studies, much of the data suggesting a protective effect of Vol. 56, No. 5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 801

4 TLI J. (adjusted I lb<cast-1 "" NATURAL J a nulliparous parous >.. ' \ '' \.. '~ \, ARTIFICIAL loci EP LP ES LS EP EP LP ES LS EP Figure 3 Influence of menstrual cycle phase on breast proliferation using thymidine labeling indices ( TLI) for natural cycles and artificial regulation by OCs. Responses for nulliparous versus parous women. EP, early proliferative; ES, early secretory; LP, late proliferative; LS, late secretory. Breast age = chronological age- age at menarche. (From Anderson et al.:w Reprinted by permission of the publisher.) progestogens on the breast have been extrapolated from endometrial data that may not be valid. In the endometrium, unopposed Es exert an adverse effect,24 25 and progestogens are protective for endometrial cancer. The studies just discussed on breast epithelial proliferative activity during the menstrual cycle suggest that endogenous hormones affect the breast differently from the endometrium. Furthermore, if exogenous progestogens are protective to the breast for cancer, preliminary studies suggest that the mechanism differs from that for the endometrium Progestogens are thought to decrease endometrial cancer by (1) down regulating E receptors37 and (2) increasing 17{3-E2 dehydrogenase (E2DH) activity, an enzyme that converts E2 to biologically less active estrone. 38 Neither of these mechanisms occurs in preliminary studies of breast cancer tissues Shinzaburo et al. 35 evaluated the effect of highdose oral medroxyprogesterone acetate (MPA) on E and progestogen receptors in breast cancer tissues. Twenty postmenopausal patients with E receptor and progestogen receptor positive breast cancers were evaluated. Ten patients received 1,200 mg/d MP A for 7 days after drill biopsy and before mastectomy, and 10 patients served as controls. Progestogen but not E receptors were reduced. Furthermore, Teulings et al.36 evaluated 6 patients with progressive metastatic breast cancer. Activity of E2DH was measured at baseline and after megace treatment. Four of the 6 patients had measurable enzyme in breast cancer tissue. No increase in ~DH activity after treatment with megestrol acetate was seen. However, three of the four women with measurable enzyme activity had a partial response after megestrol acetate treatment as demonstrated by tumor regression. Thus, it appears that the mechanisms by which progestogens affect breast cancer vary substantially from those on endometrial cancer and benign endometrial tissues. Although progestogens down regulate E receptors and increase E2DH activity in endometrial cancer and benign endometrial tissues, these preliminary data suggest that they fail to do so in breast cancer tissue. The effects in benign breast tissues are unknown. Accordingly, endometrial data should not be extrapolated to the breast. If progestogens are protective to the breast for breast cancer it may be because of other indirect mechanisms, such as by decreasing gonadotropins and adrenocorticotropic hormone and indirectly decreasing E synthesis from the ovaries and the adrenals.35 Preliminary data do not suggest an adverse effect of progestogen on the risk of developing breast cancer There are a small number of studies that suggest that a decreased lifetime exposure to progestogen in the form of an inadequate luteal phase or menstrual irregularities may increase the risk of developing breast cancer Furthermore, data do not suggest that progestogen exposure worsens breast cancer, but this may be dose related. High doses of progestogens have been demonstrated to be efficacious in treatment of some cases of advanced breast cancer Preliminary cellular studies suggest a protective role for progestogen in breast cancer tissue. Progestogen has been shown to prevent the stimulation of cancer cell growth and protein synthesis by E in culture. 44 In contrast, a study by Longman and Buehring'5 suggested that the effects of progestogens on the breast may differ for benign versus cancer tissues. They evaluated the in vitro effect of contraceptive steroids on human mammary cell growth, evaluating normal breast tissues, nonmalignant atypical, and malignant breast tissues. Growth of most cultures was stimulated by Es. However, 75% of the malignant specimens were stimulated by one or more progestogen and none of the nonmalignant cells were. Paradoxically, others have suggested that regular cycles and increased lifetime exposure to progestogen may increase the risk of breast cancer. Henderson et al. 46 studied daughters of women with breast cancer, who have at least twice the cancer risk of the general population. These women had higher levels of circulating P on day 22 of the menstrual cycle than controls. The authors suggest that regular ovulation may increase the risk of breast cancer. This result was later confirmed by Trichopoulos et al.'7 Some epidemiological evidence suggests that breast cancer risk increases with increasing cumu- 802 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

5 lative number of regular ovulatory cycles. Women establishing regular menstrual cycles within 1 year of the first menses had more than double the risk of breast cancer compared with women taking >5 years to establish regular cycles. 48 Similarly, LaVecchia et al. 49 found a negative association between breast cancer risk and a history of irregular menstrual bleeding (lower endogenous progestogen levels). Clearly, more basic breast tissue studies are needed to elucidate the effects of endogenous and exogenous hormones on benign and malignant breast tissues. Difficulties in Study Design The investigation of OCs and their role in the development of breast neoplasia is complicated by several problems: (1) There is no suitable animal model; although each steroid formulation used for contraception undergoes extensive testing in several animal species before human investigative use, neither positive nor negative results with animal exposure to suspected carcinogens can be applied to humans with any degree of certainty. 20 (2) There is generally a long lag time from exposure to a carcinogen to the development of a frank malignant disease. Theoretically, OCs could act as an initiator, transforming a normal cell into a malignant cell or as a promoter, promoting the growth of already transformed, but latent breast cancer cells. Tumor initiation might require 30 years between exposure and clinical expression, whereas promotion might be evident in a much shorter period of time past exposure. Most investigators believe that steroid hormones promote rather than initiate tumor growth Because of a potentially long lag time, evaluation is more difficult. (3) An increase in the relative risk of a rare disease, such as breast cancer in young women, is difficult to document because of the large numbers of women who must be studied. There is a low incidence of breast cancer in young women. At age 25, incidence is estimated to be 3 per 100,000 women and at age 35, 75 cases per 100,000 women occur annually in the United States. 52 (4) Increasing age is the major risk factor for breast cancer (Fig. 4) 6 with women age 70 having a 13-fold increased risk compared with women age Because women over age 60 today were rarely exposed to OCs, present studies have primarily evaluated the effect of OCs on breast cancer in young women and fail to evaluate the risk of breast cancer in older women who have the highest underlying risk. (5) Evaluation is complicated by many other etiologic influences such as genetic, cultural, geographic, and environmental exposure to carcinogens. c: E 0 31: 80 ~... li 1i "' u c: :!! u.e < Age In Y r Figure 4 Breast cancer incidence by age and average annual incidence rates in the United States from 1982 to 86. (Adapted from National Cancer Institute Annual Cancer Statistics. 6 ) Epidemiology Data on OC use and breast disease have been accumulated mainly through large retrospective casecontrol studies and more recently through prospective cohort studies. For case-control studies, the risk is calculated as an "odds ratio" and is an estimated relative risk. For the purpose of this article, all risk ratios will be referred to as relative risks (RR). An RR > 1.0 suggests an increased risk. An RR equal to 1.0 suggests no change in risk and <1.0 suggests that the risk is decreased. The data from these studies must be interpreted with caution. For case-control studies, because the baseline incidence is not clearly delineated, the potential exists for overestimating the absolute risk to the patient. An increase in the RR of a rare disease, such as breast cancer in young women, has less public health implications than a more common disease. For example, a five times increased RR of a disease with a baseline incidence of 5/1,000 has more implications than a five times increased RR of a disease with a baseline incidence of 5/1,000,000. Furthermore, for case-control studies the contraceptive history is obtained in a retrospective manner, and there may be failure to match controls for all variables. In addition, earlier detection of breast cancer in OC users may occur because OC users undergo more breast exams that non -OC users. All of these may lead to inaccuracies in the data. The largest case-control study in the world evaluating the subject of OCs and breast disease is the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. 53 Over 4, 700 Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 803

6 women with breast cancer diagnosed between ages 20 and 54 from eight geographic areas within the United States were identified between 1980 and Numerous other case-control analyses have been published. Most of these include much smaller numbers of women, usually <1,000 cases of breast cancer. Prospective cohort studies of breast cancer in young women require that large numbers of patients be followed over long periods of time because of the low incidence of disease in this group. The cost and logistic problems involved in conducting such studies has limited their numbers. Ongoing cohort studies in Great Britain, each begun in 1968, include the Royal College of General Practitioners' Studyli 4 and the Oxford Family Planning Association Study. 55 In the United States, the Nurses Cohort Study, 56 begun in 1976 with a cohort of 118,273 women, is the largest in the world evaluating this subject. In its most recent publication, 56 1, 799 cases of breast cancer were identified in 10 years of follow-up. The Walnut Creek Study 57 is no longer ongoing. High dropout rates are a problem with cohort studies. In the most recent publication from the Royal College of General Practitioners' Study, 54 only 18,000 of 47,000 women in the original cohort remained. Furthermore, in evaluating data from cohort studies, one must remember that RRs may be calculated on a relatively small number of cases. Only 239 total cases of breast cancer were identified in the cohort of the Royal College of General Practitioners' Study. 54 When these numbers are further divided into subgroups, they become even smaller, diminishing the power of the study. BENIGN BREAST DISEASE AND OC USE Benign breast disease is associated with an increased risk of subsequent breast cancer. 5 s-oo The nature of the relationship between benign and malignant breast diseases is uncertain. Because the mean age of women with benign breast disease is 15 to 20 years younger than that of women with breast carcinoma, 2 61 some investigators postulate that benign breast lesions are actually premalignant. Conversely, benign and malignant breast lesions could develop independently but have overlapping etiologies that share some of the same risk factors Benign breast disease is not a single well-defined disease, making this hypothesis difficult to evaluate. The histologic diagnoses are sometimes confusing and inconsistent. Fibrosis, fibrocystic disease, fibroadenoma, cystic mastitis, adenosis, hypermetaplastic disease, and intraductal papillomas are terms used in discussion of benign breast disease. 64 Because there is no standard terminology for benign proliferative breast disorders, direct comparisons between various studies are difficult. Despite this confusion, an attempt to analyze benign breast disorders as to risk of subsequent development of breast cancer has been made Many studies have demonstrated that proliferative epithelial lesions affecting the small ducts and terminal ductal lobular unit confer an excess risk for breast cancer A consensus conference jointly sponsored by the College of American Pathologists and the American Cancer Society convened in 1985 to determine the risk relationship between benign lesions and breast cancer. 69 Risks were determined and categorized by pathological examination. The most common symptomatic benign breast conditions are lobular hyperplasia, cystic duct dilation, fibroadenoma, and sclerosing adenosis. These were associated with no increased risk of breast cancer. Only those patients with significant hyperplasia showed an increased risk of breast cancer (1.5 to 5 times). 69 Epidemiology Studies A number of studies have demonstrated that OC use is associated with a significantly decreased risk of benign breast disease Relative risks have generally been found to be 0.3 to 0.7 that of non OC users. Most studies do not include women with biopsy proven benign breast disease, making the data less clear-cut. A few studies have failed to support such an association Overall, most investigators agree that the high-dose progestogen OCs used in the 1970s exert a protective effect against benign breast disease. However, the low-dose progestogen OCs may not confer this same protective effect. Temporal Relationship of OC Use to Benign Breast Disease Both increasing duration and recentness of OC use appear to be important factors in the decreased risk of benign breast disease seen with OC use. Most studies indicate that the association of benign breast disease with increasing length of OC use begins to appear after only 2 to 5 years of use B- 81 Several studies have found that the protective effect is lost within a few months to 1 year of stopping 0Cs. 7 B- 80 However, other studies have reported that the protective association with fibrocystic disease persisted after cessation of OC use for 24 months or more Brinton et al. 76 found a decreased risk 804 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

7 of benign breast disease with increasing length of OC use for all types of benign breast disease but found that for cystic disease, use over 2 years was necessary to see the effect, whereas for fibroadenoma, risk reduction was seen for short-term use ( <2 years). Other studies have failed to find a reduction in risk for fibroadenoma with such shortterm use. Association With Type of Benign Breast Disease The protective effect of long-term OC use has been reported for both fibrocystic disease and fibroadenoma Hislop and Threlfalf3 studied the effect of OCs on both clinical benign breast disease (without biopsy) and biopsied benign breast disease and found a significantly decreased risk of biopsied benign breast disease and a nonsignificantly decreased risk of clinical benign breast disease with long-term OC use. A few studies have found a decreased risk of both biopsied and nonbiopsied breast disease LiVolsi et al. 85 and Pastides et al.75 studied the effect of OC use on fibrocystic disease with reference to its histopathology. Each based the grading of epithelial atypia on the Black and Chabon66 and Haagensen67 classification systems. LiVolsi et al. 86 found that OCs decreased the frequency of fibrocystic disease only in those with minimal or absent atypia. Similarly, Pastides et al.75 found that those with no or low and intermediate atypia had less OC use than controls, whereas those with marked atypia had similar patterns of OC use as controls, suggesting that OCs protect only against the less atypical breast lesions. In contrast, Hsieh et al., 86 using the Black and Chabon66 classification system, found the protection from fibrocystic breast disease with OC use to be greater in those women with a higher atypia score. Association With E and Progestogen Several studies have evaluated the effect of type or dose of hormone content in OCs in relation to benign breast disease. Kelsey et al.87 failed to find an association between the use of combination OCs and benign breast disease but found a decreased risk for the use of sequential OCs. Brinton et al. 76 and the Royal College of General Practitioners' Study70 found no association with E dose, type of E, or type of progestogen. They found, however, the lowest risk of confirmed cystic disease in users of OCs containing the highest progestogen dose. In both studies, analysis was made of women taking OCs with the same dose of ethinyl E2 (50 JLg) and with varying dosages of norethisterone acetate. The Royal College of General Practitioners' Study group reported the lowest risk for benign breast disease in the highest or 4.0 mg progestogen pills (RR = 0.27), intermediate risk for the 2.5 to 3.0 mg pills (RR = 0.5), and virtually no decrease in risk for the lowest dose or 1.0 mg pills. In a recent analysis by Berkowitz et al., 84 no decreased risk of benign breast disease was found in women with a history of OC use. For those women using compounds more commonly used today, i.e., 20 to 50 JLg E and 1 to 2.5 mg progestogen, the RRs were close to 1 or greater. It is possible that the protective effect of OCs on benign breast disease is present only with higher dosages of progestogens than those used in current OC formulations. If so, the protective effect on benign breast disease seen in previous studies may no longer be present in women using current OC formulations. Further studies are necessary to evaluate this issue. Histology of the Breast in OC Users Studies of benign breast lesions have demonstrated no differences in the histologic appearance of fibroadenomas or fibrocystic disease89 90 in women using OCs as compared with controls. Epithelial hyperplasia in fibroadenomas was related to use of OCs in two studies However, both these studies have been criticized because they were uncontrolled.93 Mammography and OCs In 1976 W olfe94 published a classification scheme for the appearance of breast parenchyma by mammography based on risk for developing breast cancer. N1 represented normal tissue, P1 prominent ducts but limited in extent, P2 extensive prominent ducts, and DY dysplasia. Risk increased from N1 to DY in which DY had a 22-fold increased risk relative to N1 of developing breast cancer in a follow-up of approximately 2.5 years. In a recent study, destavola et al.95 evaluated the relationship of Wolfe's classification of mammographic parenchymal patterns to breast cancer risk. They found that although the high-risk patterns were associated with an increased risk of breast cancer, the degree of discrimination was not as marked as suggested by Wolfe. For both premenopausal and postmenopausal women, P2 or DY Wolfe grades were found to have a nonstatistically approximately twofold increased risk of breast cancer compared with women with P1 or N1 (low risk) patterns. Premenopausal women who had used OCs were found to have an increased incidence of N1 (low-risk pattern) and decreased incidence of Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 805

8 other higher risk patterns (P1 to DY). The difference was statistically significant. For postmenopausal women, the effect was somewhat different. An increase in N1 (low risk) and P2 and DY (high risk) patterns was found and a decrease in P1 (medium risk). Leinster and Whitehouse 96 and Gravelle et al. 97 also studied the relationship of OC use to breast parenchymal patterns according to Wolfe's scheme. For women with a history of OC use, an increase in low-risk radiographic patterns and a decrease in high-risk patterns was found. It is not known if the radiological appearances of high-risk patterns are associated with similar changes in the histology of the breast. If so, a shift from the DY or P2 patterns to the N1 patterns suggests a decreased risk of breast cancer. Leinster and Whitehouse, 98 furthermore, examined factors that influence the occurrence of breast arterial calcification on mammography. In general, it occurs more commonly with advancing age, especially after menopause. Oral contraceptive use was found to be associated with a lower incidence of calcification before but not after menopause. Clinical Implications There are excellent data to support the hypothesis that the high-dose progestogen OCs used before the mid 1970s protected against most forms of benign breast disease. However, the data are unclear whether OCs protect against those forms of benign breast disease associated with a decreased or increased risk of subsequent breast cancer based on histologic or mammographic studies. Furthermore, it is unclear whether current low-dose progestogen OCs will confer the same protection. Ory et al. 99 calculated from pre-1979 study estimates that the protective effect of OCs on benign breast disease resulted in 23,490 fewer breast biopsies per year among 0.1 L.J _L..JL..l.~ J..._L...l,-J-_L...I..._J_JL...J. J J Wn~~MffiffiV~ Total years of OC use Figure 5 Breast cancer in women younger than 60 years of age: RR by total years of OC use in 17 studies. (From Schlesselman.100 Modified and published in Schlesselman.101 Reprinted by permission of the publishers.) 0.1 LL--l--1---'--l'--I--1.-J.._..._...l..._...l..._...L.._ L~~,-L-l o s s 7 a e ro ~ ~ ~ M ffi re v ~ Total years of OC use Figure 6 Breast cancer in women younger than 45 years of age: RR by total years of OC use in nine studies. (From Schlesselmen.101 Reprinted by permission of the publisher.) the 8 million women in the United States taking OCs at that time. Should the conclusions of studies by Berkowitz et al., 84 Brinton et al., 76 and the Royal College of General Practitioners' Study 70 be confirmed, the decreased progestogen doses in current OC formulations may fail to provide protection against benign breast disease. Accordingly, the beneficial effects of OCs on benign breast disease may be much less than the estimates of Ory et al. 99 Further studies will be necessary to clarify this issue. BREAST CANCER AND OC USE Epidemiology Studies An immense amount of data has been published concerning the relationship between OC use and the risk of breast cancer in women. Studies that have shown a protective effect of OCs against benign breast disease have failed to show the same protection against breast cancer. Figure 5 summarizes the results of 17 case-control studies published during the 1980s These studies evaluated the risk for the cohort of women under age 60 and overall failed to show an association between breast cancer and increasing duration of OC use However, as data accumulated in the 1980s, several studies suggested that OCs may increase the risk of breast cancer before age 45. Figure summarizes the results of nine case-control studies for the development of breast cancer before age 45 based on years of OC use. Overall, there appears to be an increase in risk with increased duration of OC use. Furthermore, some studies suggest that use before a first term pregnancy may be a significant risk factor for this cohort. Figure summarizes the results of nine case-control studies based on OC use before a first full term pregnancy for the development of breast cancer before age 45. Again there appears to be a subtle increase in risk with increased duration 806 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

9 ~ 11:---<o----~..., _ a; a: 0.1 L..L-l..-l '---'...-JL--L-J..._.J..._.J.._...J._...J_-'--L...L.-l..-l..--' o s s 1 a 9 m n ~ ~ M m m u m Total years of OC use before FTP Figure 7 Breast cancer in women younger than 45 years of age: RR by total years of OC use before first term pregnancy (FTP) in nine studies. (From Schlesselman. 101 Reprinted by permission of the publisher.) of OC use. Because of these preliminary data, most recent studies have separately analyzed a cohort of women for development of breast cancer at a young age and have also evaluated other subgroups. Investigators have focused on those subgroups of patients who are independently at an increased risk of breast cancer. Several of these recent studies have identified a possible increased risk of early occurring breast cancer and long-term use of high-dose combination OCs used in the 1960s and 1970s, sometimes only in a particular subgroup. Association With Age For the cohort of women developing breast cancer under age 60, almost all studies published in the last 10 years have failed to identify a positive association between OCs and breast cancer During this time period, data from two studies, Ravnihar et al. 119 and the World Health Organization (WHO) collaborative study/ 20 suggested an increased risk with increased duration of use for this group. Ravnihar et al. 119 found the risk for OC users of developing breast cancer between the ages of 24 and 54 was about 1.6-fold that of never users. The risk increased with increasing duration of OC use. The highest risk was in those who used OCs for > 7 years, with a statistically significant test for trend with increased duration. The WHO Collaborative study/ 20 a hospital-based case-control analysis from 10 countries, found an increased risk (RR = 1.15) for breast cancer in women < age 60 who had ever used OCs. The risk was of borderline statistical significance. A statistically significant trend of increasing risk with years of use was found. For >8 years of use the RR was On the contrary, Harris et al. 111 in a recent casecontrol analysis, found a significantly decreased risk of breast cancer in women < age 50 after 5 or more years' duration of use (RR = 0.4). Furthermore, the test for a decreasing trend with increased use was statistically significant. Overall, most studies suggest that long-term use does not appear to confer an elevated risk for the cohort of women under age 60, although a few have suggested an increased risk. Furthermore, prolonged OC use before a first term pregnancy does not increase risk for this group. When the cohort is limited to women developing breast cancer before age 45, a positive association emerges in many studies Several of these have noted this increase only in certain subgroups of this cohort. The WHO Collaborative study 120 found no significant difference overall in evaluating risks for women under age 35 versus over age 35. Relative risks for both groups were nonstatistically increased (1.26 and 1.12, respectively). In contrast, Wingo et al. 106 in the Centers for Disease Control analysis of the Cancer and Steroid Hormone Study data found a differential effect for the risk of breast cancer based on age at presentation. For breast cancer presenting between ages 20 and 34, the risk was increased (RR = 1.4), whereas for breast cancer diagnosed between ages 45 to 54, the risk was slightly decreased (RR = 0.9) for those who had used OCs. Both risks were of borderline statistical significance, and there was no trend of increasing or decreasing cancer risk with increased duration of use. Other studies have failed to identify an increased risk of breast cancer in young women under the age of 45 even when examining subgroups Oral Contraceptives and Breast Cancer Before Age 45 For several groups, early analyses of data failed to reveal an increased risk. Only after further accumulation of data and/or further statistical analyses of subgroups, did an increased risk emerge for the cohort of women under age 45 at diagnosis. These include the Cancer and Steroid Hormone Study analyses, Miller et al./ 22 and Royal College of General Practitioners' Study. 54 Before the 1988 analysis, the Cancer and Steroid Hormone Study consistently failed to find an increased risk of breast cancer in young women with oc usey Stadel et al., 132 in the 1985 analysis of the Cancer and Steroid Hormone Study data, found no statistical change in the risk of breast cancer for women < age 45 but did find that with onset of OC use between ages 30 to 34, the risk increased slightly with duration of use: RR = 1.3 for 13 to 48 months of use and 1.5 for over 48 months of use; however, the statistical test for trend was not significant. Schlesselman et al., 110 in a later analysis ofthe Cancer and Steroid Hormone Study data, found no increased risk of breast cancer for women ages 20 to Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 807

10 44 with increased length of OC use, even with 10 to 14 years of use. On the contrary, Stadel and Lai, 121 in an even later analysis of the Cancer and Steroid Hormone Study data, found an increased RR of breast cancer before age 45 only in nulliparous women, who had menarche before age 13, and who used OCs for >8 years. For this group, the risk increased with increasing duration of OC use, from 2 to 3 years of use to > 12 years of use, but statistical significance was not reached until 8 or more years of use. The RR for >8 years of use was 3.8. In contrast, in the Centers for Disease Control analysis, performed independently from that by Stadel and Lai, 121 Wingo et al. 106 found that among women 20 to 34 years of age at diagnosis, ever users had a slight increased risk of breast cancer (RR = 1.4) compared with never users, which was of borderline statistical significance. There were no statistically significant trends of increasing risk with increasing duration of use. However, the youngest women consistently had elevated risks. Unlike Stadel and Lai's Cancer and Steroid Hormone Study analysis, 121 the increased risk for this age cohort was identified in all subgroups. Miller et alp 4 in a hospital-based, case-control study found no increased risk with increasing length of use. In a later study 122 conducted in the same manner, they found a statistically significant increased risk for breast cancer before age 45 with OC use >5 years (RR = 3.3) for women ages 25 to 34 and for women ages 35 to 44 (RR = 2.4). There was a statistically significant increased risk with increased length of use. Interestingly in this study, the increased risk pertained also to women using OCs for <3 months, which is biologically unlikely. In an early report from the Royal College of General Practitioners' prospective cohort study,l2 5 no overall increased risk for breast cancer was found. A nonsignificant increased risk (RR = 2.81) was found for women diagnosed with breast cancer before age 35. For women 30 to 34 years of age at diagnosis, the risk (RR = 3.33) was of borderline statistical significance. In a later analysis of the ongoing data, Kay and Hannaford 54 found a statistically significant increased risk of developing breast cancer for women ages 30 to 34 (RR = 3.33) compared with never users, but the trend of increasing risk with increased duration of use was not significant. Several other studies have identified an increased risk of breast cancer for the cohort under age 45 at diagnosis. The United Kingdom (UK) National Case-Control Study Group 123 found a significant increased risk of breast cancer before age 36 with OC use for >49 months. They also noted a highly significant trend with total duration of OC use. The RR for 49 to 96 months of use was 1.4 but was not significantly elevated until >97 months of use (RR = 1.7). The risk was present for all subgroups of this age cohort. A recent analysis of the UK data by subgroup 135 failed to identify an altered risk for any particular subgroup. The WHO collaborative study 120 identified a significantly increased RR of 3.0 for breast cancer in the youngest group of women (<age 29) in developing countries but not for women in developed countries. This risk was calculated on only 23 exposed cases and 644 exposed controls. Another case control study by Meirik et al. 136 from Sweden and Norway identified an increased risk of breast cancer in women before age 45 with increased duration of use. After 12 or more years of OC use, the RR = 2.2 was significant, but for those using OCs for 7 to 12 years, the risk was of borderline significance. In a further analysis, Meirik et al. 124 found a statistically significant increased risk of breast cancer for women under age 45 but only in nulliparous women using OCs for 8 or more years (RR = 4.3) or for 12 or more years after a first full term pregnancy (RR = 3.0). Others have found an increased risk for breast cancer before age or age only with OC use before a first term pregnancy. Each of these studies has demonstrated an increased risk for the development of breast cancer before age 45. Although the increased risk often occurs in somewhat different subgroups of women, there is a suggestion that long-term high-dose use of OCs confers an increased risk for the development of breast cancer at a young age. Association With Parity and With Use Before First Term Pregnancy Most studies have found no association with OC use before a first term pregnancy ns for the cohort of women under age 60 at diagnosis of breast cancer. A few have identified an association. Harris et al./ 37 in a case-control analysis, found an increased risk (RR = 2.2) for nulliparous women that was associated with an increased duration of use. Interestingly, the association could only be seen in women who eventually had a birth. Rohan and McMichaeP 02 found that premenopausal women who had used OCs for 19 months or more before a first pregnancy had a threefold but not significant increased risk of developing breast cancer. On the contrary, Paul et al. 114 found a pattern of decreasing risk with increasing duration of OC use before a first term pregnancy for parous and nulliparous women 808 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

11 combined. The trend approached statistical significance (P = 0.07). When the evaluation is limited to those women developing breast cancer before age 45, more data are available, and several studies have identified an increased risk of breast cancer for this cohort with increasing OC use before a first term pregnancy. Meirik et al.l2 4 found a statistically significant increased risk in nulliparous women using OCs for 8 or more years (RR = 4.3). For parous women, using OCs for the same length of time after a first term pregnancy, the risk (RR = 1.7) was not significantly increased. For women with > 12 years of use after a first term pregnancy, the risk was significant (RR = 3.0). In a recent analysis of the Cancer and Steroid Hormone Study data, Stadel et al. 121 identified a significantly elevated risk (RR = 3.8) of breast cancer before age 45 in women using OCs for >8 years who had started menarche before age 13 only for nulliparous women. This association was not found for women starting menarche after age 13 or with use < 8 years. The relative risk for 8 to 11 years of use was 2.7 and for over 12 years of use was Paul et al. 114 attempted to replicate the Cancer and Steroid Hormone Study analysis in their case-control study. They found a nonstatistically significant increased risk (RR = 1.2) for nulliparous women, < age 45, with menarche before age 13, and with 12 or more years of OC use. There was no trend in risk with increased duration of use. Pike et al., 126 in a case-control analysis, found an increased risk of breast cancer in very young women (<age 33) with OC use before a first term pregnancy. For 6 years of use, the RR was 2.2 and after 8 or more years of use was 3.5. The trend of increasing risk with increasing duration of OC use was statistically significant. McPherson et al., 127 in a casecontrol study, found an increased risk of breast cancer in women < age 45 with increasing duration of OC use before a first term pregnancy. The RR was 2.6 after >4 years of OC use. The increased risk with length of use showed a linear trend and was highly significant. They also found that exposure after a first pregnancy may have a slight but not significant protective effect. In a prospective analysis of the Royal College of General Practitioners' oral contraceptive study, Kay and Hannaford 54 found an independent increased risk for women of parity 1 at diagnosis (RR = 5.88) but not in women with no children or more than one child. The authors postulate that the use of OCs before the first term pregnancy conferred the risk to this group of women of parity 1 at diagnosis. This study also identified an independent increased risk for women developing breast cancer between the ages of 30 and 34 for women of all parities. The UK National Case-Control Study Group 123 found that the increased risk of breast cancer before age 36 was present with OC use before or after first term pregnancy and that the risk was only slightly increased for nulliparous women over parous women. This difference was not significant. Romieu et al. 109 performed a meta-analysis to summarize data on OC use and breast cancer. Study results were pooled using a model that accounted for both interstqdy and intrastudy variability. They found an increased risk of breast cancer for women < age 45 exposed to OCs for prolonged durations. This risk was significantly elevated among women who used OCs for at least 4 years before their first term pregnancy (RR = 1.72). On the contrary, Miller et al. 122 found an increased risk of breast cancer before age 45 for women using OCs for >5 years. The risk was no greater for use before a term pregnancy. Overall, Paul et al. 114 failed to identify an association between OC use and breast cancer risk before age 45 at diagnosis but found that for nulliparous women and parous women, OC use before a first term pregnancy was associated with a decreased risk of breast cancer before age 45 with increasing duration of OC use, but the trend was not statistically significant. Overall, the data are suggestive of a slight increased risk of breast cancer before age 45 with increasing length of high -dose OC use before a first term pregnancy. However, there are significant inconsistencies in the studies, making any definitive conclusions difficult. Use at Young Ages The question of whether early onset of OC use and/or prolonged use at a young age is an important determinant of risk has been addressed by many studies. 55,102,104,109,114,119,120,123,132,134,136 Most studies define use at a young age to be either use before age 20 or before age 25. Olsson et al., 138 in a case-control study from Sweden, found that women starting OCs before age 20 had a nearly sixfold increased risk for developing breast cancer. For women using OCs for >5 years before age 25, there was a fivefold increased risk. The trends for increased risk with duration of use before age 25 and with earlier starting ages were significant. Olsson's study has been criticized because the interviews may have been biased. 139 Pike et al. 140 found an increased risk of breast cancer before age 37 for women using "high progestogen content" OCs with increasing length of use before age 25. The trend of increasing risk with du- Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 809

12 ration was highly significant. In the 1985 analysis of the Cancer and Steroid Hormone Study data, 132 Stadel and Lai121 found no association with OC use before age 20. In a later analysis of the Cancer and Steroid Hormone Study data by subgroups, Stadel and Lai121 found that for women developing breast cancer before age 45, with menarche before age 13, and for use > 8 years, there was an increased risk with use before age 20 (RR = 5.6) relative to use after age 20 (RR = 2.6). No mention is made as to whether these two numbers are significantly different. On the contrary, in the recent Centers for Disease Control analysis of the Cancer and Steroid Hormone Study data by Wingo et al.,106 among women 45 to 54 years of age, there was a statistically significant trend of decreasing breast cancer risk with decreasing age at first use. The protective effect was most pronounced among women who first used OCs before age 25 (RR = 0.5). The WHO collaborative study,120 which found a borderline increased risk for OC use overall (RR = 1.15 for women < age 60) found no significant variation among women who first used OCs at various ages. The highest risk (RR = 1.42) was observed in women who first began using OCs after age 35. No trend for increasing risk with increased duration of OC use before age 25 was found. However, the RRs for users of >2 years' duration before age 25 were increased and were of borderline statistical significance. Rohan and McMichael102 found that first use of OCs before age 32 was associated with a nonsignificant lower risk of breast cancer than never users, whereas first use of OCs after age 33 was associated with a nonsignificant increased risk. A recent case-control analysis by Paul et al.114 from New Zealand evaluated the effect of OC use at a young age on breast cancer risk. New Zealand is noted to be a suitable place for study of this cohort because national population surveys show that a high proportion of young New Zealanders (ages 15 to 24) use OCs. They failed to find an increased risk with use starting at very young ages, even before age 17. Most studies failed to find an increased risk of breast cancer with duration of OC use at a young age55,109,114,120,123,132,134,136 or with early onset of OC use.102,104,114,u9,12o,136 Overall, the largest and best conducted studies evaluating risk based on age at first use and prolonged use at a young age have failed to identify an association with breast cancer and OC use for this group, suggesting that these are not significant risk factors. However, in view of a few studies suggesting some association, more data are required. Evidence of Latent Effect It has been suggested that a long-term latent effect may be present in which women are at an increased risk of breast cancer many years after the onset of OC use. If this were true, it suggests that OCs may play a role in cancer initiation. Most of the data fail to support a long-term latent effect of OCs on the development of breast cancer. Ravnihar et al. 119 found an overall increased risk of breast cancer for women ages 24 to 54 with a history of OC use (RR = 1.6) and found that the highest risk was for women starting OCs 4 to 8 years before the diagnosis, with a decreased risk with a longer latency time. The Royal College of General Practitioners' study54 found a significant increased risk of breast cancer for women after discontinuing OCs for 10 or more years (RR = 1.85). When the analysis was limited to women of parity 1 at the time of breast cancer diagnosis, the RR was 13.2 and for women ages 30 to 34 at diagnosis who had stopped using OCs 8 to 10 years previously, the RR was These RRs, although significant statistically, were based on very small numbers of breast cancer cases, 3 and 1 patient per thousand-womenyears, respectively. Romieu et al.,56 in a prospective study, found no linear association with increasing time since last OC use; they found a slightly greater risk 15 years or more after last OC use than for current OC users. Paul et al.114 found that women who had used OCs for <2 years and who completed this use 5 to 9 years earlier had a significantly elevated risk (RR = 2.8). However, there was no increased risk (RR = 1.0) in women who had used OCs for 10 or more years starting 15 or more years earlier. On the contrary, Rohan and McMichael102 found that women who first used OCs 19 or more years ago, for > 7 years, had a lower risk of breast cancer than women who had never used them (RR = 0.3). Schlesselman et al.,53 in an analysis of the Cancer and Steroid Hormone Study data, found no increased risk for women with a latency interval of at least 15 years for up to 6 years of OC use. Ellery et al. 104 found that the risk of breast cancer declined but not significantly with increasing number of years since first OC use. In this study, there was no association with breast cancer risk for those women using OCs for >6 years, starting over 15 years before. Several other studies have failed to identify an increased risk with a latency period Based on these studies, there are little data to suggest an elevated risk of breast cancer within 10 to 20 years of stopping OCs, even with long-term use. 810 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

13 Association With Hormone Content Several studies have evaluated the effect of OC formulation on the risk of breast cancer. Although a few studies suggest one formulation or another may be associated with an increased risk, there is no consensus. Because most of the data are based on retrospective analyses, there is the problem of recall, which makes the quality of data questionable. Overall, based on these studies there is no particular formulation or hormone type that is associated with an increased risk of breast cancer. In an analysis of the Cancer and Steroid Hormone Study data, Stadel and Lai121 found that many of the women in the subgroup of patients with breast cancer developing before age 45, early menarche, and use for >8 years, had used OCs that contain ethynodiol diacetate as the progestogen. No further assessment of risk based on hormone formulation could be made. Harris et al.137 found that higher dose OCs and OCs with an increase in the progestogen/e ratio had a nonsignificant lower risk for breast cancer. McPherson et at.l27 found an increased risk for ethinyl E2 containing OCs relative to mestranol for use for 4 or more years before first term pregnancy. There are little data specifically analyzing the effect of E dose. However, a recent study by the UK National Case-Control Study Group123 found that OCs containing <50 11g of E have a lower risk than higher dose pills. For women developing breast cancer before age 36, the RR per year of OC use was 1.10 for high-dose (~50 J.Lg) E OCs versus 1.04 for low-dose (<50 J.Lg) E OCs. The differences were only marginally statistically significant. They also found that progestogen-only pills may have some protective effect with use over 12 months (RR = 0.59 after 2 years of use). This RR is based on only four cases and 13 controls and the difference between it and controls was only marginally significant. These findings suggest that there may be a dose-response effect based on E content and that the current lower dose E contraceptives and progestogen-only OCs may confer a lower risk. In contrast to the UK National Case-Control study findings, Pike et at.l26 found that OCs containing a "high potency" content of progestogen were associated with a significantly increased risk of developing breast cancer before age 37 with increasing duration of OC use. The assigned potencies of progestins were derived from delay of menses data. The study of Pike et al.126 has been highly criticized based on the definition of progestin potencies, 142 the method of interpreting the data and study methodology.143 Most of the pills that Pike considered of high progestogen potency could be easily classified as high E potency using other criteria Furthermore, data from the Cancer and Steroid Hormone study146 were analyzed in the same manner as Pike's data and were unable to confirm these results. The Cancer and Steroid Hormone study, with much larger numbers of women, failed to reveal an increased risk of breast cancer with any particular type of OC for duration of >5 years. Numerous other studies have been unable to identify a change in breast cancer risk associated with a particular OC formulation. 54,55,120,122 Association With History of Benign Breast Disease Several studies have evaluated the risk of breast cancer with OC use in women with a history of benign breast disease. Unfortunately, many of these studies have failed to confirm the diagnosis of benign breast disease by a history of previous biopsy. Pike et al.126 found an increased risk of breast cancer before age 32 in women with a history of benign breast disease, in those women using OCs before first term pregnancy. Fasal and Paffenbarger79 found a significantly increased risk (RR = 11.2) for women with a history of benign breast disease who had used OCs for >6 years. Rohan and McMichael102 found a nonsignificant increased risk for OC users (RR = 1. 77) with a history of benign breast disease. Stanford et al.113 found a twofold increased risk of breast cancer for OC users with a history of two or more breast biopsies. Numerous other studies have found no increased risk. 56,114,116,119,120,134,141 An analysis of the Cancer and Steroid Hormone study data131 demonstrated a significantly decreased risk (RR = 0. 7) of breast cancer for women with a history of OC use and surgery for benign breast disease relative to non-oc users who had benign breast disease. Based on the inconsistent study designs and data, Stadel and Schlesselman published a review147 assessing the overall risk of women with existing benign breast disease and OC use. They point out that the designs of many studies fail to exclude clearly the possibility that some patients included developed benign breast disease subsequent to the initiation of OCs. They conclude that there is insufficient evidence to show that OC use increases the risk of breast cancer in women with a pre-existing history of benign breast disease and make a plea for inclusion of only women with documented benign breast disease before OC use when evaluating this risk factor. Association With Family History of Breast Cancer Studies have varied considerably as to their conclusions about the risk of breast cancer in an OC Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 811

14 user with a family history of breast cancer. Ravnihar et al. 119 found that those patients who had used OCs and had a positive family history had a RR of 7.36 compared with OCs users with no family history of breast cancer (RR = 1.54). Black et al. 148 found that women with a grandmother or aunt with a positive family history for breast cancer had an increased risk for developing breast cancer before age 45 with usage of OCs. However, they also found that OC use with a negative family history was associated with a significant decreased risk of breast cancer (RR = 0.4 for current users and 0.58 for ever users). In a recent analysis of the data from the UK National Case-Control Study Group, 135 although women with a family history of breast cancer had a slightly greater risk associated with OC use than those without, the difference in trends was not significant. A recent analysis of the Cancer and Steroid Hormone study data/ 49 the largest study to date evaluating this subject, failed to identify a positive association between OC use and family history of breast cancer. In fact, among women with a firstdegree family history, a significantly decreased risk (RR = 0.4) occurred for women who used OCs for 73 to 96 months. However, there was no pattern of increasing or decreasing risk by duration of use. Paul et al. 114 found that in women with a first degree relative with breast cancer, the risk declined with increased use of OCs, but the trend was not statistically significant (P = 0.11). The risk of breast cancer was not affected by OC use among women with only a second degree relative with breast cancer. Other studies have similarly failed to find a positive association. 56,102,107,111,113,114,116,120,134,135 Although the data are not clear, the largest and best conducted studies thus far suggest that women with a family history of breast cancer are not at an increased risk of breast cancer because of OC use. Association With Disease at Presentation and Prognosis of Breast Cancer There are very little data evaluating whether OCs change the type of breast cancer that occurs after its exposure. Data on unopposed E exposure for postmenopausal women suggest that E use is associated with a well-differentiated, early stage and often easily treatable type of endometrial cancer. Preliminary data do not suggest that OC exposure results in a more curable type of breast cancer. An evaluation of the histopathology of breast cancer tissue in women with a history of OC use demonstrated no significant difference from breast cancer tissue in controls Similarly, Spencer et al. 151 found no differences in the histologic features of tumor or extent of axillary node disease in patients with breast cancer who had taken OCs compared with those who never took OCs. Rosner et al. 152 found no difference between OC users and nonusers for extent of disease at presentation, histologic features of tumor, or axillary node involvement nor with disease-free interval or survival. The WHO collaborative study 120 failed to identify a difference in tumor size at presentation for OC versus non-oc users. Several studies have found that a history of OC use results in a more favorable prognosis in women with breast cancer. Matthews et ai.l 53 found that tumors in women who had used OCs had more favorable clinical and histologic features than controls. When considering only those who had had a radical mastectomy, those who had taken OCs survived significantly longer, even when differences in nodal state were taken into account. Vessey et al. 141 found that women who had used OCs presented with less advanced tumors compared with those who had not been using OCs during the year before detection of the cancer. Furthermore, they found that recent OC users had a lower mortality than past users who had a lower mortality than never users. The differences were not statistically significant. The UK National Case-Control Study Group 123 found that patients who had ever used OCs were more likely to have a lower clinical stage and less likely to have positive axillary nodes than never users. On the contrary, several studies have identified a history of OC use to be associated with poor prognostic factors. Olsson et al. 154 found that women who had used OCs at an early age ( < age 20) had decreased survival with breast cancer. They presented at more advanced stages, as compared with those who had never used them or those who started at age 20 or later. Stanford et al. 113 found an increased risk for invasive cancer of the breast with 5 or more years of OC use (RR = 1.5 and 1.4, respectively, for small and large lesions), but these risks were not significantly elevated. The same study found a concurrent decreased risk (RR = 0.59) for in situ cancer of borderline statistical significance for OC use for 5 or more years. Kay and Hannaford 54 found that in women under age 35 at diagnosis, a nonstatistically significant increased number of women had more invasive (grade III) tumors compared with controls. Similarly, for this group, the 5-year survival was significantly lower than controls (37% versus 100%). Romieu et al. 56 found no difference between past users and non-oc users in the frequency of histologic type, tumor size, and lymph node involvement. However, they found that current users tended 812 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

15 to have tumors that were larger and more likely to be metastatic at diagnosis. Based on the inconsistent data, it is unclear whether a history of OC use changes the stage at presentation or the prognosis of breast cancer. Association With Receptor Status Several groups have examined E or progestogen receptor status in relationship to history of OC use. Romieu et al. 56 found that breast cancers diagnosed in women who were past OC users were more likely to be positive for E receptors than those diagnosed in women who had never used OCs. No relationship was noted between OC use and the progestogen receptor status. In contrast, in a prospective study of women with breast cancer, 155 the effect of OC use and family history of breast cancer were examined with reference to their effects on E receptor status. Among premenopausal and perimenopausal women, those patients with a family history of breast cancer in only a first degree relative showed a borderline significant association between prior OC usage and subsequent tumor E receptor protein expression. The use of OCs was consistently associated withe receptor-negative tumors, whereas of 29 patients who had no prior OC exposure, 17 had E receptor-negative tumors. Lesser et al. 156 found that women taking OCs at the time of diagnosis of breast carcinoma had lower median E receptor-binding levels. They suggested that present OC hormone use may cause spuriously low E receptor protein levels. Stanford et al. 157 demonstrated that women who had ever taken OCs had a 16% decreased RR for receptor-positive and a 22% increased RR for receptor-negative cancer compared with nonusers. A history of prolonged OC use (>6 years) was associated with a 70% increased RR of receptor-negative cancer. Similarly, Cooper et al_1 58 found a nonsignificant increased risk of E receptornegative cancer and little association with E receptor-positive cancer. Olsson et au 54 found that women who had used OCs had decreased E (significantly) and progestogen (nonsignificantly) receptor concentrations of the primary tumor compared with never users or late users. Based on these data, there is a suggestion that current or past OC use may influence the subsequent receptor status of breast cancer by decreasing the amount of E receptor tumor protein in breast cancers. The effect of OCs on progestogen receptor status is less clear. Because of the paucity of data and some inconsistencies, more data are required to answer these questions. Risk in Developed Versus Developing Countries There are very little data available on OC use and breast cancer risk in women in developing countries. Lee et al. 103 in a case-control analysis from Costa Rica found no increased risk overall for breast cancer. The WHO Collaborative case-control study 120 is the only study comparing the risk in women in developed versus developing countries for the development of breast cancer based on OC exposure. The study included women from 11 different countries throughout the world. The risks were nonsignificantly elevated for both. For developed versus developing countries, the RRs were 1.07 and 1.24, respectively, and were not significantly different statistically. Furthermore, RRs in all women under age 35 were similar in developing and developed countries, although a significantly increased RR of 3.05 was found in the youngest group of women (<age 29) in developing countries. Clinical Implications Despite the fact that there is an enormous amount of data available on the relationship between OCs and breast cancer, there still remains significant controversy. Although there are some consistencies, much of the data is conflicting and confusing. Epidemiologists use five criteria to evaluate the evidence: (1) strength of association, (2) temporal sequence, (3) dose-response relationships, (4) biological plausibility, and ( 5) consistency of results. 159 The first criteria, strength of association or magnitude by which the risk of a disease is changed, is significant only in some studies and usually just for a very small fraction of OC users. The second criteria, temporal sequence, is present in each study. Women were exposed to OCs before the development of breast cancer. The third criteria, dose-response relationship, is demonstrated in several studies. Those studies that demonstrate a trend of increasing RR with increased duration of OC use (dose) are more convincing than those in which there is an increased RR without an associated trend. The fourth criteria, biological plausibility, is again demonstrated in most of the studies. However, for the study by Miller et al., 122 an increased risk was found after only 3 months of OC use. This is not biologically plausible. The fifth criteria, consistency of results, is the biggest problem with the data. For example, considering recent studies evaluating breast cancer in women before age 45, Stadel and Lai's Cancer and Steroid Hormone Study analysis 121 found an increased risk in nulliparous women with menarche before age 13 with long-term use. In contrast, the recent Centers Vol. 56, No.5, November 1991 McGonigle and Huggins Oral contraceptives and breast disease 813

16 for Disease Control analysis of the Cancer and Steroid Hormone Study data 106 suggests a borderline increased risk for women 20 to 34 years of age at diagnosis and a protective effect for women 45 to 54 years of age at diagnosis, which was more pronounced for use of OCs at a young age. The Royal College of General Practitioners' Study 54 found independent increased risks for women of parity 1 and for women ages 30 to 34 at diagnosis, whereas the UK National Case Control Study 123 found an increased risk for parous and nulliparous women before age 36. Meirik et al. 136 found use before first term pregnancy to be significant, while Olsson et al. 138 found use at a young age and early age at onset to be most significant. Thus with five different studies and two different analyses of the same study, there are six somewhat different findings. The one most consistent finding is an increase in risk for breast cancer at a young age. The apparent inconsistencies in epidemiologic findings are perplexing and investigators have analyzed their study designs for an explanation. Skegg 160 noted that case-control studies may be influenced by bias through (1) the selection of cases and controls that are not truly compatible; (2) the potential differences in recall of information by patients with breast cancer compared with controls; and (3) a difference in surveillance for breast cancer for OC users versus controls, i.e., more frequent breast examination of women using OCs can result in earlier diagnosis and an apparent excess of cases in the younger age group who have used OCs. Despite some inconsistencies in the data, one cannot ignore that so many of the major epidemiologic studies have identified an increased risk in one subgroup or another for the development of breast cancer at a young age. Stadel et al. 161 have suggested that this may represent a promotional effect with long-term use of the discontinued, highdose OC formulations in subgroups of women. If so, an increased incidence of breast cancer in young women may be associated with a concurrent decreased incidence in older women. In such a case, the lifetime risk of breast cancer would not be increased, but the disease would occur at younger ages. This theory is supported by an analysis of the Cancer and Steroid Hormone study data in which the increased risk found in nulliparous women 20 to 44 years of age is followed by an apparently decreased risk in women ages 45 to 54 (Fig. 8). 161 Studies to date do not evaluate the risk of breast cancer for OC exposure in women currently over age 60, those women with the highest underlying risk. Because of the significantly higher baseline inci- 10 I 0. I l l l.1. 1 Women Aged Women Aged never > II 12+ never > Years of OC Use Figure 8 Relative risk of premenopausal breast cancer by duration of OC use for nulliparous women. (Adapted from Stadel et al. 161 ) dence of disease in this population, an increase or decrease in RR would be quite significant. The Centers for Disease Control Cancer and Steroid Hormone Study analysis 106 found that women ages 45 to 54 who have used OCs have a 10% decreased risk of breast cancer. If such a decrease in risk continues to be seen as OC-exposed women age, a significant number of the aging population would actually be protected from breast cancer. There are significant data indicating that premenopausal and postmenopausal breast cancers are quite different diseases. They differ in biological behavior, hormone receptor expression, and risk factors. It is reasonable to expect that there may also be a differential effect of OCs on the breast for the development of premenopausal versus postmenopausal breast cancer. Furthermore, it is important to evaluate what an increased risk means to a given population. In the Cancer and Steroid Hormone study analysis 121 in which an increased risk of breast cancer before age 45 was found only for nulliparous women who had menarche before age 13 and had used OCs for >8 years, only 1.3% of the cases of breast cancer occurred in the "at risk group" (39 women). Furthermore, for the Royal College of General Practitioners' study 54 in which a 40% to 70% increased risk was found for all subgroups, the authors calculate that the absolute excess risk is about 1 in 7,000 everusers per year < age 35. Given how inconsistent the data from various studies are, it is likely that the risk, if present, even for subgroups of women, is small. In terms of evaluating the risk to current OC users, it is important to remember these data are based on the use of the high-dose formulations used in the 1960 to 1970s. It is reasonable to expect that the current lower dose formulations carry even less risk, as is suggested by data from the UK National Case-Control Study Group in which combination OCs with a lower dose of E conferred less risk. 814 McGonigle and Huggins Oral contraceptives and breast disease Fertility and Sterility

17 The etiology of the rising breast cancer incidence is largely unexplained. However, it is unlikely that OCs have contributed significantly to the increasing incidence of breast cancer: (1) The increase began in the mid-1940s, long before the introduction of OCs. (2) The increased incidence is noted in all age groups. However, the rise is greatest for older women (age > 50) who were less commonly exposed to OCs (Fig. 1). 6 The aggregate data suggest that if there is an increased risk of OCs for breast cancer, it is in women< age 45 at diagnosis. (3) The data suggest that a very small number of women, if any, may have developed breast cancer as a result of OC exposure. Accordingly, national incidence data would unlikely be affected. The noncontraceptive health benefits of OCs must also be weighed against the small potential risks. The decreased risk of ovarian and endometrial cancers associated with OC use is estimated to be responsible for averting 1,700 cases of ovarian 162 and 2,000 cases of endometrial cancer 10 in the United States each year. Oral contraceptives are also known to decrease the incidence of ectopic pregnancy, 99 pelvic inflammatory disease, 163 benign ovarian cysts, 164 iron-deficiency anemia/ 65 and rheumatoid arthritis. 166 Based on all the evidence, authoritative bodies in the United States, Great Britain, and other countries independently came to similar conclusions in These include the United States Food and Drug Administration's Fertility and Maternal Health Drugs Advisory Committee, American College of Obstetricians and Gynecologists, the United Kingdom Committee on the Safety of Medicines, the Swedish national drug authorities, the World Health Organization, and the International Planned Parenthood Federation. Each has recommended no change in OC labeling, prescribing, or use However, in August 1990, the manufacturers of OCs in the United Kingdom, as a result of discussions with the United Kingdom Medicines Control Agency, have inserted a statement in the OC leaflets about the possible association between the prolonged use of OCs and breast cancer in young women. 168 SUMMARY Epidemiologic data support the hypothesis that the types of OCs used before the mid-1970s protected against most forms of benign breast disease. It is unclear whether current low-dose progestogen OCs will confer the same protection. Further studies are necessary to clarify this. For breast cancer, the relationship is more complex. It is possible that prolonged use of high-dose OCs exert a small increased risk for breast cancer development in women before age 45. Furthermore, prolonged use before a first term pregnancy may result in a small increase in risk for breast cancer before age 45. 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