APPENDIXES



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Oral Contraceptives & Breast Cancer APPENDIXES

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Oral Contraceptives & Breast Cancer This page in the original is blank.

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Oral Contraceptives & Breast Cancer A Oral Contraceptives and Breast Cancer: A Review of the Epidemiological Evidence with an Emphasis on Younger Women KATHLEEN E. MALONE The possibility of increased breast cancer risk related to oral contraceptive use is a major concern to American women and to the scientific community. Breast cancer incidence in Western countries is relatively high and apparently is increasing. That breast cancer appears to be influenced by other hormonally mediated factors leads to the hypothesis that the high rate of exposure to oral contraceptives among American women may also be associated with this increase. Examination of cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute suggests that there has been an overall increase in the incidence of breast cancer, with increases of the largest magnitude occurring among women over age 50 (according to SEER data, approximately 1.2 percent per year since 1974). Age-adjusted incidence rates for breast cancer in women under the age of 50 have also increased since 1973, but the increases have been of a much smaller magnitude—approximately 0.2 percent per year. The use of mammographic screening, which facilitates the detection of cases that might otherwise have gone unnoticed, or at the least detects cases at an earlier point in time, may explain some of this increase, especially in women over age 50. However, because screening recommendations apply Kathleen E. Malone is a Research Associate at the Fred Hutchinson Cancer Research Center, and a graduate student at the University of Washington, Seattle, Washington.

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Oral Contraceptives & Breast Cancer mainly to middle-aged and older women, screening may not account for much of the increased incidence in young women. Most of the early research on this topic (i.e., studies conducted prior to 1980) found no association between oral contraceptive use and breast cancer, reassuring many in the research and clinical communities that there was little or no increased risk (Henderson et al., 1974; Sartwell et al., 1977; Ravnihar et al., 1979; Vessey et al., 1979). Investigations reported in the early 1980s offered little to cause observers to change their minds. The majority of studies, including the largest case-control study in the United States, found no consistent suggestion of elevated risk (Kelsey et al., 1981; Vessey et al., 1981, 1982, 1983; Brinton et al., 1982; CASH, 1983; Janerich et al., 1983; Hennekens et al., 1984; Rosenberg et al., 1984; Stadel et al., 1985; Talamini et al., 1985), although several studies reported elevated risk estimates for particular aspects of oral contraceptive use (Paffenbarger et al., 1980; Pike et al., 1981, 1983; Royal College of General Practitioners, 1981; Trapido, 1981; McPherson et al., 1983; Olsson et al., 1985). There was no consistency among these elevated risk estimates. The picture seems to have changed since 1986. There are a number of studies during this period that do not support an increased risk related to oral contraceptive use, including more analyses of the Cancer and Steroid Hormone (CASH) Study data and the updated analysis of data from the United States nurses' cohort study (CASH, 1986; Ellery et al., 1986; La Vecchia et al., 1986; Lipnick et al., 1986; Romieu et al., 1989; Stanford et al., 1989). But an increasing number of studies have appeared that suggest an elevated risk in relation to some aspects of oral contractive use (Meirik et al., 1986, 1989; Paul et al., 1986; McPherson et al., 1987; Ravnihar et al., 1988; Kay and Hannaford, 1988; Miller et al., 1989; Olsson et al., 1989; U.K. National Case-Control Study Group, 1989). These studies, especially those with positive findings, have received much publicity and generated renewed concern over the safety of oral contraceptives. CHANGING PROFILE OF ORAL CONTRACEPTIVE USE Oral contraceptives were introduced in the early 1960s but did not find widespread acceptance until the late 1960s and early 1970s. There are four major types of oral contraceptives. Combination pills, which contain fixed amounts of estrogen and progestin and act by suppressing ovulation, were the first oral contraceptive approved in the United States (in the early 1960s) and have always been the most popular type of pill used. Sequential pills, in which estrogen alone is given for the first two weeks followed by an estrogen-progestin com-

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Oral Contraceptives & Breast Cancer bination during the last six days, were also introduced early but were removed from the U.S. market around 1977 (Piper and Kennedy, 1987). The minipills, or progestin-only pills, introduced in 1972 contain no estrogen and a lower amount of progestin. They do not affect ovulation but rather inhibit ovum transport and implantation by thickening the cervical mucus. They have never had a significant share of the market. Phasic oral contraceptives, combination pills that contain estrogen along with a progestin dose that varies in amount throughout the month, were introduced in 1983 and have since become increasingly popular. Following the advent of oral contraceptives, two major changes have occurred that must be considered in evaluating the research on oral contraceptives and breast cancer: (1) changes in the formulation of oral contraceptives and (2) changes in the patterns of their use and in the women who use them. Regarding the first change, over the past three decades, the formulations of oral contraceptives have undergone substantial modifications. Both the types and doses of steroids have changed; the doses of both estrogen and progestins have been greatly decreased; several new progestins have entered the market whereas others have been withdrawn; and sequential pills are no longer used. High-estrogen-potency oral contraceptives constituted 94 percent of the United States retail market in 1964, but by 1976 low-estrogen oral contraceptives (less than 50 μg of estrogen), which were introduced in 1967, dominated the market (Piper and Kennedy, 1987). Many of the formulations evaluated in past breast cancer studies are no longer being sold. The profiles of oral contraceptive users have also changed over time. Oral contraceptives were most commonly used first in the 1960s by married women to space pregnancies and only later by single women as a method to delay a first pregnancy (McPherson and Drife, 1986). Routine prescription to younger single women was not common until the early 1970s in Great Britain and the late 1970s in the United States (McPherson and Drife, 1986). These geographic differences in oral contraceptive prescription patterns have been posited as a possible explanation for some of the differences in study results that have been seen between the two countries. In the United States, only women born since the mid-1940s have had the opportunity to be exposed to long-term use of the pill early in life. At present the use of oral contraceptives is an extremely prevalent exposure among young women. With the recent epidemic of teenage pregnancies in the United States, routine prescription to teenage girls as young as age 13 is not uncommon. Unpublished data from a case-control study conducted by the author and colleagues of breast can-

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Oral Contraceptives & Breast Cancer cer diagnosed between 1983 and 1988 in young women born after 1944 in Seattle, Washington, showed that 92 percent of both the cases and controls reported “ever” having used oral contraceptives; among women under age 20 the proportion of “ever” use increased to 100 percent. BIOLOGICAL PLAUSIBILITY An important criterion for evaluating causality is the biological plausibility of the relationship. Estrogen causes proliferation of breast tissue and would be expected to increase breast cancer risk by stimulating growth of stem cells and intermediate cells (Thomas, 1984). Progestin causes alveolar cell growth in the estrogen-primed breast, but it also causes differentiation. It is unclear, therefore, whether the predicted net effect would be to increase or decrease breast cancer risk. The influence of estrogen and progestin on breast epithelium proliferation and differentiation appears to differ with age. Cancer risk is thought to be a function of the number of cells at risk, which varies with age. It is possible to posit that any carcinogenic risk of oral contraceptives may be strongly mediated by age of exposure or by the timing of exposure in relation to other events that are thought to affect epithelial proliferation or differentiation (e.g., menarche, first full-term pregnancy). The etiology of breast cancer has strong hormonal themes: oophorectomy decreases risk, early menarche and late menopause increase risk, late age at first full-term pregnancy increases risk. These effects seem to last for decades. Thus, if use early in life affects risk, it may be many years before deleterious outcomes are seen. It is possible that the studies conducted thus far have not allowed an adequate interval between exposure to oral contraceptives and the onset of breast cancer, so that even if an association were present, it might not yet be detectable. Thus, vigilance must be maintained and investigation of this issue should continue in the future—even though we might conclude, based on current data, that findings are too inconsistent to be alarming at present. EPIDEMIOLOGICAL STUDIES OF BREAST CANCER AND ORAL CONTRACEPTIVES As mentioned earlier, the studies conducted prior to 1980 carry little suggestion of an increased risk for breast cancer in relation to oral contraceptive use. These studies focused on cases diagnosed before 1975; therefore, they included a large proportion of women

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Oral Contraceptives & Breast Cancer who, because of their birth years, had little opportunity to have ever used oral contraceptives or to have used oral contraceptives for a long time, and virtually no opportunity for exposure at an early age. For these reasons, as well as the briefness of the time between exposure and diagnosis, studies conducted before 1980 cannot contribute any insight into the current controversy and are largely ignored in this review. Unfortunately, these same difficulties plague some of the studies published in the early 1980s as well. Therefore, although studies from the early 1980s are included in this review, the emphasis is on more recent research. “Ever” Use of Oral Contraceptives Table A-1 presents a summary of the findings related to “ever” use of oral contraceptives and risk of breast cancer. Twenty-five of the 30 studies for which a relative risk for “ever” use was reported had relative risks (RR) close to 1.0. Two of the five studies that report elevated risk estimates for “ever” use of the pill are ones for which questions with regard either to basic study design, low response rates, or low exposure prevalence have been raised (Olsson et al., 1989; Miller et al., 1989). Overall, there is no evidence of increased risk of breast cancer in women who meet the criterion of “ever” using oral contraceptives. The finding of no association between “ever” use of oral contraceptives and breast cancer risk has been quite consistent throughout the past 20 years of research. “Ever” use of oral contraceptives is probably too crude a measure to provide much insight into any relationship with breast cancer risk because such use is so common an exposure that it typically encompasses more than 90 percent of all young women. Further, interpretation is difficult because there are subgroups of women who try oral contraceptives but stop—because of side effects—soon after they start. Women who never use oral contraceptives may be a unique subgroup. For instance, they may have an increased family history of breast cancer, health problems that contraindicate the use of oral contraceptives, or an increased awareness or suspicion of undiagnosed infertility; these factors, in turn, may relate to both their decision not to use oral contraceptives and their risk for breast cancer. Duration of Oral Contraceptive Use There was little suggestion of increased risk related to long-term use of oral contraceptives in any of the studies published prior to 1986. Of the case-control studies published since that time, seven

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Oral Contraceptives & Breast Cancer TABLE A-1 Summary of Risk Estimates for “Ever” Use of Oral Contraceptives Author/Year Relative Risk a Confidence Interval Paffenbarger et al., 1980     Premenopausal 1.1 b   Postmenopausal 1.2 b   Pike et al., 1981 1.2 0.7-1.9 Royal College of General Practitioners, 1981 (cohort) 1.2 0.8-1.7 Trapido, 1981 (cohort) 0.8 0.7-1.2 Vessey et al., 1981 (cohort) 1.0 0.6-1.6 Brinton et al., 1982 1.1 0.8-1.4 Harris et al., 1982 0.8 0.6-1.3 Vessey et al., 1982 0.9 0.7-1.2 Vessey et al., 1983 1.0 0.8-1.2 Hennekens et al., 1984 1.0 0.9-1.2 Rosenberg et al., 1984 1.0 0.9-1.2 Stadel et al., 1985 (CASH d ) 1.0 0.9-1.2 Talamini et al., 1985 0.7 0.4-1.4 CASH, d 1986 1.0 0.9-1.1 Ellery et al., 1986 0.9 0.6-1.5 La Vecchia et al., 1986 1.1 0.8-1.5 Lipnick et al., 1986 1.0 0.8-1.3 Meirik et al., 1986 1.4 1.1-1.9 Miller et al., 1986 0.9 0.7-1.4 Paul et al., 1986 0.9 0.7-1.3 Lee et al., 1987 1.2 0.8-1.8 McPherson et al., 1987 1.2 0.8-1.6 Kay and Hannaford, 1988 (cohort)     Age at diagnosis     25-29 2.5 1.0-52.5 30-34 3.3 1.3-8.8 <35 2.4 1.0-5.8 35-39 0.9 0.3-3.2 0-44 1.0 0.9-1.1 45-49 1.8 0.8-4.2 50-54 1.8 0.2-20.3 All ages 1.2 0.9-1.6 Schlesselman et al., 1988 (CASH d ) 0.9 0.8-1.0 Ravnihar et al., 1988 1.6 1.3-2.1 Yuan et al., 1988 1.1 0.7-1.5 Miller et al., 1989 2.0 1.4-2.9 Olsson et al., 1989 1.8 c   Romieu et al., 1989 (cohort) 1.1 1.0-1.2 Stanford et al., 1989 1.0 0.9-1.2 WHO, d 1990 1.2 1.0-1.3 a Reference group = “never” users. b Confidence intervals not provided by author. c Crude relative risk calculated from data provided in paper. d WHO = World Health Organization; CASH = Cancer and Steroid Hormone Study.

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Oral Contraceptives & Breast Cancer reported an excess risk for use of long duration. Table A-2 presents a summary of reported risk estimates for long-term use. The largest case-control study of breast cancer conducted to date, the CASH study, showed no evidence of an association of breast cancer risk and long-term use of oral contraceptives among women aged 20 to 54 (CASH, 1986). Yet despite its size (the study comprised more that 4,700 cases and a similar number of controls in eight geographic regions of the United States) the majority of the women were over age 45. Coupled with the early diagnosis years (1980-1982), it is possible that this study was conducted too early to detect any association between oral contraceptives and breast cancer. The major reproductive years for most of these women occurred before the height of popularity of the pill. A number of the other studies among women up to the age of 65 have also found no pattern related to long durations of use, suggesting no increase in risk related to long-term oral contraceptive use in the aggregate or perhaps no increase in risk with long-term use that does not begin at an early age (Ellery et al., 1986; La Vecchia et al., 1986; Paul et al., 1986; Stanford et al., 1989). A Yugoslavian study of women under age 55, however, found an RR of 2.4 for oral contraceptive use exceeding seven years, as well as a significant dose-response pattern (Ravnihar et al., 1988). Recently, the World Health Organization (WHO) study, a multinational case-control study conducted in three developed and seven developing countries, reported a suggestive dose-response pattern of increasing risk with years of oral contraceptive use (WHO, 1990); this association, however, could well be attributable to a recency effect since risk was highest in current users and steadily declined with time since last exposure. In recent years, a large number of studies have focused on breast cancer risk in women under age 45. Meirik and colleagues (1986) published the first report suggesting a dose-response relationship with duration of oral contraceptive use among young women: for use of 8 to 11 years, an RR of 1.4 was found; for 12 or more years of use, a 2.2-fold excess risk of breast cancer was found. Paul and colleagues (1986) reported an RR of 4.6 for use of 10 or more years among women aged 25-34. McPherson and coworkers (1987) found an increased RR of 1.8 for use exceeding 11 years among a group of British women through age 45. The fact that U.K. prescription patterns were about five years ahead of those in the United States has been offered as a possible explanation for the earlier emergence of positive studies from the United Kingdom. A hospital-based case-control study conducted in the northeastern United States (Miller et al., 1989) among women under age 45 ob-

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Oral Contraceptives & Breast Cancer TABLE A-2 Summary of Risk Estimates for Lifetime Duration of Oral Contraceptive Use Author/Year Age Diagnosis Dates Duration of Use (years) Relative Risk a Confidence Interval Vessey et al., 1983 16-50 1968-80 <1 0.9 0.7-1.1       >1-4 1.0 0.8-1.3       >4-8 1.2 0.8-1.6       >8 1.0 0.7-1.5 Hennekens et al., 1984 30-55 1960-76 <1 1.1 0.9-1.4       1-2 1.1 0.9-1.5       3-4 0.7 0.5-1.1       5-9 1.1 0.8-1.4       10+ 0.7 0.4-1.3 Rosenberg et al., 1984 20-59 1976-81 <1 0.9 0.7-1.1       1-4 0.9 0.8-1.2       5-9 1.3 1.0-1.7       10+ 0.8 0.5-1.3 CASH, b 1986 20-54 1980-82 6-9 1.0 c         10-14 1.1         15+ 0.6   Ellery et al., 1986 25-64 1980-82 2.1-6 0.7 0.3-1.5       6+ 1.0 0.5-2.0 La Vecchia et al., 1986 <60 1982-85 <2 1.0 0.7-1.4       >2 1.1 0.7-1.6 Lipnick et al., 1986 30-55 in 1976 1976-80 <1 0.9 0.7-1.3       1.2 0.8 0.6-1.1       3-4 1.0 0.7-1.4       5-9 1-2 0.8-1.5       10+ 1.3 0.9-1.9 Meirik et al., 1986 <45 1984-85 4-7 1.2 0.8-1.9       8-11 1.4 0.8-2.3       12+ 2.2 1.2-4.0 Paul et al., 1986 25-54 1983-85 6-9 0.8c         10+ 1.0   Lee et al., 1987 25-58 1982-84 5-9 1.2 0.6-2.3       10+ 1.0 0.4-2.6 McPherson et al., 1987 16-64 1980-84       Among women <45   4-12 1.2 0.8-1.8       13+ 1.8 0.8-3.9 Among women 45+   4-12 1.1 0.7-1.6       13+ 0.8 0.4-1.8 Kay and Hannaford, 1988 (cohort) 15-45 in 1968-69         Among ages 30-34   4-5 4.1 1.1-14.5       6-7 2.2 0.4-11.8       8-9 2.5 0.3-22.4       10+ 10.2 1.1-91.0 Ravnihar et al., 1988 25-54 1980-83 4-7 1.7 1.2-2.5       8+ 2.4 1.5-2.8

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Oral Contraceptives & Breast Cancer Stadel et al., 1988 20-54 1980-82 8-11 d       20-44               Menarche <13 2.7 1.2-6.3       Menarche 13+ 0.9 0.5-2.1   45-54               Menarche <13 0.4 0.1-2.2       Menarche 13+ 0.8 0.2-3.1 Jick et al., 1989 <43 1975-83 10+ 1.4 0.4-4.6 Miller et al., 1989 25-44 1983-86 5-9 1.9 1.1-3.3       10+ 4.1 1.8-9.3 Romieu et al., 1989 (cohort) 30-55 in 1976 1976-86 5-<10 1.1 1.0-104       10-<14 1.1 0.8-1.4       15+ 1.1 0.5-2.4 Stanford et al., 1989 Older 1973-80 <1 0.9 0.7-1.2       2-4 0.8 0.6-1.1       5-9 1.2 0.9-1.6       10-14 1.0 0.7-1.5       15+ 0.7 0.3-1.6 U.K. National Case-Control Study Group, 1989 <36 1982-85 4-8 14.4 1.0-2.1       >8 1.7 1.2-2.6       Parous women 4-8 1.4 c         >8 1.6         Nulliparous 4-8 women 1.4         >8 2.3   WHO, b 1990 <63 1979-86 <1 1.1 1.0-1.3       1-2 1.0 0.8-1.2       3-8 1-2 1.0-1.4       >8 1.6 1.2-2.0 a Reference group = “never” users. b WHO = World Health Organization; CASH = Cancer and Steroid Hormone Study. c Confidence intervals not provided by author. d Years of use among nulliparous women only. served a twofold excess risk for oral contraceptive use of five to nine years' duration and a fourfold excess risk for use of 10 or more years. Questions have been raised about Miller's findings because of concern about the appropriateness of the hospitalized control group and because there appears to be a lower proportion of exposed controls than would be expected from national data. A well-conducted study in the United Kingdom (U.K. National Case-Control Study Group, 1989) among women under age 36 recently reported a significant dose-response pattern for duration of use. Oral contraceptive use of 49 to 96 months was associated with a 1.4-fold excess risk, and use exceeding 96 months was associated with a 1.7-fold excess breast cancer risk. This case-control study was one of the few that was able to validate the self-reported data on oral contraceptive use so as to rule out the often-raised criticism of recall bias.served a twofold excess risk for oral contraceptive use of five to nine years' duration and a fourfold excess risk for use of 10 or more years. Questions have been raised about Miller's findings because of concern about the appropriateness of the hospitalized control group and because there appears to be a lower proportion of exposed controls than would be expected from national data. A well-conducted study in the United Kingdom (U.K. National Case-Control Study Group, 1989) among women under age 36 recently reported a significant dose-response pattern for duration of use. Oral contraceptive use of 49 to 96 months was associated with a 1.4-fold excess risk, and use exceeding 96 months was associated with a 1.7-fold excess breast cancer risk. This case-control study was one of the few that was able to validate the self-reported data on oral contraceptive use so as to rule out the often-raised criticism of recall bias.

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Oral Contraceptives & Breast Cancer Miller et al., 1986 a 1977-83 <45 96? 521 60       96?   (59) Paul et al., 1986 1983-85 <55 79 433 72       (81)   (79) Lee et al., 1987 1982-84 <59 67 171 34       (93)   (43) McPherson et al., 1987 a 1980-84 <65 n.a. 1,125 38       n.a.   (39) Ravnihar et al., 1988 a 1980-83 <55 n.a. 534 30       n.a.   (30) Yuan et al., 1988 1984-85 <70 94 534 18       (99)   (18) Jick et al., 1989 a 1975-83 <43 70 127 61       (69)   (71) Meirik et al., 1989, 1986 1984-85 <45 88 422 77       (85)   (78) Miller et al., 1989 a 1983-86 <45 96 407 72           (59) Olsson et al., 1989 1979-85 <46 n.a. 174 82       (92)   (72) Stanford et al., 1989 (screening program) 1973-80 <82 78 2,022 24       (83)   (24) U.K. National Case-Control Study Group, 1989 1982-85 <36 72 755 91       (89)   (89) WHO, 1990 a 1979-86 <63 94.2 2,116 34       (94.6)   (34)     Cohort Studies     Kay and Hannaford, 1988 c 1968-85 28.8 d   239 60 Romieu et al., 1989 a 1976-86 30-55 in 1976   1,799 48 Vessey et al., 1989 b 1968-87 25-39 in 1968 n.a. 189             52 NOTE: WHO = World Health Organization; n.a. = not available; CASH = Cancer and Steroid Hormone Study. a Controls were recruited from hospitals. b The study dropped women who had ever used oral contraceptives but whose use was less than 8 years in duration. c Of the original cohort, 61.7 percent were lost to follow-up. d Mean age in 1968.

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Oral Contraceptives & Breast Cancer The sample size of a study must be large enough to allow the detection of an effect or to rule out with a certain amount of confidence the presence of an effect. A number of past studies (i.e., Kelsey et al., 1978; Harris et al., 1982; Olsson et al., 1985; Ellery et al., 1986; Lee et al., 1987; Jick et al., 1989) may not have had adequate power to evaluate the relationship of oral contraceptives and breast cancer. In addition, sample sizes need to be even larger to examine the interrelationships of other risk factors with oral contraceptive use (Green-land, 1983; Smith and Day, 1984). In a case-control study, the method of ascertaining cases and controls should be carefully considered, as well as the degree to which the controls represent the population from which the cases were drawn. Concern has been raised about the validity of conducting studies in hospital settings, especially referral or tertiary care hospitals, because it is virtually impossible to identify the population from which the cases arose. The usual approach for selecting controls is to recruit them from among the other patients in the same hospital who are seeking care for other diseases. The difficulty lies in deciding what conditions these patients can and cannot have in order to be an appropriate comparison group. Any condition known to be associated with the exposure or with the disease should be excluded. As the number of exclusions increases, questions arise as to the select nature of the control group; unfortunately, it is impossible to be sure of the direction of the bias that might result from such selectivity. One could hypothesize that the controls with these other medical conditions that have led to hospitalization are less likely to be oral contraceptive users; in that case, however, the controls would produce an underestimate of the population's use of the pill, and the observed risks would be spuriously high. Quite a few of the reviewed studies were conducted in hospital settings (Paffenbarger et al., 1980; Kelsey et al., 1981; Vessey et al., 1982, 1983; McPherson et al., 1983, 1987; Rosenberg et al., 1984; Talamini et al., 1985; Ellery et al., 1986; La Vecchia et al., 1986; Miller et al., 1986, 1989; Ravnihar et al., 1988). Most recently, the study by Miller and colleagues (1989) was criticized because of its low proportion of pill-exposed controls; the proportion exposed was lower than that observed in national survey data for women in the age group studied. This result raises questions about bias in the selection of the hospital controls (Spirtas, 1989). A second issue involves any bias that might arise in the ascertainment of exposure. All of the case-control studies reviewed here relied on interview data, although one—the U.K. National Case-Control Study Group (1989)—was able to review medical records to evaluate recall.

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Oral Contraceptives & Breast Cancer Another study (Olsson et al., 1989) violated a basic design principle by having a different interviewer for cases and controls. Third, it is necessary to understand and incorporate into analyses (when appropriate) the other important breast cancer risk factors, such as age of first full-term pregnancy, number of live births, age of menarche, family history of breast cancer, and history of benign breast disease. Some of these risk factors, as well as some other factors, may also affect the decision to use oral contraceptives, the age of first and last use, and the lifetime duration of use. These and other factors may modify or be modified by the relationship of oral contraceptives to breast cancer risk. Fourth, whether the women in a study had the opportunity to be exposed to oral contraceptives deserves attention. The most obvious example of this issue is when a study includes a large number of women who were born early enough that oral contraceptives were not even on the market during their prime reproductive years. All of the studies before 1980 as well as a number of the studies in the early 1980s were constrained in this way. Extreme examples include La Vecchia and colleagues (1986), with only 14 percent of the study subjects having ever used oral contraceptives; Stanford and coworkers (1989), with 24 percent having used them; and Lee and colleagues (1987), with 41 percent having used them. When birth year and opportunity for exposure to oral contraceptives are examined in the context of the possible latency period for breast cancer, it becomes apparent that many of the already completed studies may have been unable to evaluate the relationship of oral contraceptives and breast cancer, especially in regard to use at younger ages as well as premenopausal disease onset. For example, the studies of radiation effects on breast cancer suggest a latency interval of at least 15 years, which must be factored into efforts to detect an expected association. Presuming oral contraceptives have a promotion-al effect, the time interval until a detectable lesion is present is unknown. Studies that include women diagnosed before a certain point in time may not have allowed an adequate interval between exposure to oral contraceptives and onset of breast cancer. In this instance, even if an association were present, it might not be detectable in these women. More subtle examples related to exposure opportunity that need consideration in future analyses include sterilization, hysterectomy, and infertility, all of which necessarily affect the need and timing for any method of contraception.

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Oral Contraceptives & Breast Cancer DISCUSSION The one conclusive statement that can be made concerning the sum of the epidemiological evidence of a relationship between oral contraceptives and breast cancer is that there has been a remarkable lack of consistency in the findings. However, an increasing number of the recent studies suggest that there are subgroups of women who may be at increased risk of breast cancer owing to their pattern of oral contraceptive use. Of these groups, the one of most concern may be those women with long-term use beginning at a young age. The findings for use before the first full-term pregnancy or before age 25, or just for overall long duration of use are certainly suggestive and do not permit the conclusion that there is no relationship between use of the pill and breast cancer risk. Use of oral contraceptives at a young age has increased over the past 20 years, and the possible risk of breast cancer associated with early use is an important public health issue. Why would we only now be seeing an increased risk for long-term use at a young age? There are several possible explanations: Women who use oral contraceptives are required to visit their health care provider on a regular basis to secure a renewal of their prescription. Thus, it is possible that oral contraceptive users are seen by the health care system more frequently than other women, and may receive more frequent medical surveillance, including breast exams and even mammograms. This hypothesis has led to the suggestion that women with breast cancer who use oral contraceptives are detected and diagnosed earlier than nonusers. Little is known about the natural progression of breast lesions; thus, the detection of breast cancer through mammography may indeed pick up some cases of breast cancer that might have otherwise gone undetected for many years. (This may be especially true of in situ breast cancers.) Several recent studies have incorporated into their analyses a consideration of such factors as the stage of disease, the frequency of breast self-exams and physician exams, and the frequency of mammograms as a way to account for the impact of increased surveillance (McPherson et al., 1987; Kay and Hannaford, 1988; U.K. National Case-Control Study Group, 1989). Because oral contraceptives have always required prescriptions, it seems unlikely that detection bias could be contributing enough new noise to the analyses of breast cancer and oral contraceptives to account completely for the emergence of these recent positive findings. In recent years, the controversy about the relationship between oral contraceptive use and breast cancer risk has received much atten-

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Oral Contraceptives & Breast Cancer tion in the lay press. Unfortunately, there are indications that positive studies receive greater publicity than negative studies. Recent studies therefore have been conducted in an environment in which many participants are familiar with the hypothesis of interest. Many epidemiological studies rely heavily on a woman's memory to ascertain details of pill use; consequently, the issue of recall bias has been raised as a possible explanation for some of the positive studies. The specific scenario of concern is one in which women with breast cancer, because of their diagnosis, ruminate about possible causes and dwell heavily on an exposure that they believe may have caused their disease (and thus remembering every detail about their use of oral contraceptives). In contrast, typically healthy women without breast cancer, who have no similar drive to ruminate about their history, may fail to remember the details of their exposure as accurately and thus may underreport their use of oral contraceptives. Cohort studies avoid this problem by securing exposure information prior to disease onset. Women have worried for many years about the relationship of oral contraceptives to adverse health outcomes, and it seems difficult to believe that possible recent increases in levels of worry and awareness might affect recall and thus findings in recent studies. Also, although it is conceivable that this type of selective memory might operate with a fairly unmemorable exposure (e.g., aspirin use 10 years earlier), oral contraceptive use is so strongly linked with other reproductive experiences that it is unlikely that only in recent studies would controls have been underreporting their oral contraceptive use because of an inability to recall exposure. Some other methodological problem(s) may have been introduced in these recent studies that have yet to be identified, although there is no evidence supporting this hypothesis. These recent findings could simply be due to chance. The fact that there is some consistency to the positive findings, namely involving prolonged use at an early age, decreases our ability to attribute these findings to chance. Little is known about the relationship between various formulations of the pill and breast cancer risk, largely because no reliable classification system of the effects on the breast of oral contraceptives and their components has been developed. Many of the women in the recent studies may well have been exposed to both high- and low-dose pills. Although removal of the high-dose pills successfully decreased deleterious cardiovascular and other side effects experienced by pill users, it is not actually known if the newer formulations are necessarily associated with a lower, higher, or unchanged risk of

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Oral Contraceptives & Breast Cancer breast cancer. It is possible that there are some aspects of oral contraceptive formulations whose effects on breast cancer risk have only recently become apparent. Only studies of women born since the mid-1940s could have included large numbers of women exposed to oral contraceptives at a young age. Although no one is sure of the exact latency period for breast cancer, studies of atomic bomb survivors and the risk patterns observed in breast cancer for other factors such as menarche and age at first birth suggest a long latency period of at least 15 years. If hormones have a promotional effect, it is not yet known which time-related factors may be most relevant. Studies conducted in the latter half of the 1980s may be the first conducted in women born recently enough to have used oral contraceptives at a young age and for a long enough duration and whose use preceded the diagnosis of disease by a sufficient amount of time to be consistent with a latent period for breast carcinogenesis. Oral contraceptives may have a differential effect on young breast tissue, and this effect may just have become detectable in the more recent studies. Alternatively, the effect on young breast tissue may not translate into detectable breast cancer until 30 or more years later, in which case current studies will not be able to detect this association. If risk increases in relation to use at an early age, recent findings supporting this premise may represent only the tip of the iceberg because the cohort of women who could have used the pill at an early age has yet to enter the highest breast cancer incidence age cohorts. THE FUTURE Many questions remain concerning the relationship between oral contraceptives and breast cancer risk. Gaining insight will entail a collaborative interdisciplinary effort by epidemiologists, clinicians, and basic scientists. Specific future endeavors could include some of the activities noted below. Appropriate methods should be developed to classify the potency of oral contraceptives. More information is needed on the basic biology of estrogen and progestin as separate components as well as combined products. A better understanding is required of the biological effects of hormones on breast tissue. (Most past classification systems of hormonal effects have been based on effects on the endometrium.) In the past decade, as the state of the art in epidemiological design has advanced, the criteria for what constitutes a methodologically

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Oral Contraceptives & Breast Cancer suitable study have increased. A number of the studies reviewed here were plagued with limitations that, at the very least, render these studies suboptimal. Future case-control studies should be carefully designed so as to avoid some of these pitfalls. More work is needed to address the possibility of recall bias, although it is hard to believe that reporting of long-term use is compromised enough to explain the recent emergence of positive findings. Validation of a reported history of oral contraceptive use through medical record review would be ideal, but is quite difficult in the United States or any country where people are mobile and do not have a centralized source of health care. Case-control or small validation studies conducted in health maintenance organizations, or studies in countries with national health care systems, both of which have lifelong medical records for study subjects, might be the best way to evaluate the question of misclassification of oral contraceptive use because of recall bias. Future case-control studies should be population based, achieve high levels of response, and be designed to minimize the likelihood of introducing bias. The causes of the increase in breast cancer incidence should be investigated further, and the extent to which increased breast screening contributes to the increased incidence should be evaluated. In turn, for case-control studies, the degree to which increased screening of oral contraceptive users affects case identification needs to be evaluated. In existing and future data, especially those studies with large enough numbers of subjects, more effort is needed to tease out the effects of long duration of exposure versus exposure at specific ages—as well as other patterns of use that may be associated with adverse or protective effects. In particular, the effect of use at an early age should be further evaluated to distinguish the timing of exposure from the longer duration of exposure that is associated with beginning use at an earlier age. Besides examining oral contraceptive use at young ages, there are unanswered questions concerning use during the perimenopausal years. The recent FDA decision to lift the recommended upper age limit for use of oral contraceptives will probably lead to increased use in the over-40 age group. The relationship between oral contraceptives and breast cancer risk also needs to be examined in other subgroups, such as women with a strong family history of breast cancer and women with previous benign breast disease, using data sets with sufficient numbers of subjects. In conclusion, the current picture of the relationship between oral contraceptives and breast cancer is rather confusing. It is not clear whether we should be reassured or alarmed, or whether it is just too

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Oral Contraceptives & Breast Cancer early to know. Despite the more than 40 epidemiological studies conducted thus far, the end result seems to be more questions than answers. REFERENCES Brinton, L. A., R. Hoover, M. Szklo, and F. J. Fraumeni, Jr. 1982. Oral contraceptives and breast cancer. International Journal of Epidemiology 11: 316-322 (CASH) Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Long-term oral contraceptive use and the risk of breast cancer. 1983. Journal of the American Medical Association 249: 1591-1595 Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral-contraceptive use and the risk of breast cancer. 1986. New England Journal of Medicine 315(7): 405-411 Ellery, C., R. MacLennan, G. Berry, and R. P. Sherman. A case-control study of breast cancer in relation to the use of steroid contraceptive agents. Medical Journal of Australia 144: 173-176 Fasal, E., and R. S. Paffenbarger. 1975. Oral contraceptives as related to cancer and benign lesions of the breast. Journal of the National Cancer Institute 55: 767-773 Greenland, S. 1983. Tests for interaction in epidemiologic studies: A review and a study of power. Statistics in Medicine 2: 243-251 Harris, N. V., N. S. Weiss, A. M. Francis, and L. Polisar. 1982. Breast cancer in relation to patterns of oral contraceptive use. American Journal of Epidemiology 116: 643-651 Henderson, B. E., D. Powell, I. Rosario, et al. 1974. An epidemiologic study of breast cancer. Journal of the National Cancer Institute 53: 609-614 Hennekens, C. H., F. E. Speizer, R. J. Lipnick, B. Rosner, C. Bain, C. Belanger, M. Stampfer, W. Willett, and R. Peto. 1984. A case-control study of oral contraceptive use and breast cancer. Journal of the National Cancer Institute 72: 39-42 Janerich, D. T., A. P. Polednak, D. M. Glebatis, and C. E. Lawrence. 1983. Breast cancer and oral contraceptive use: A case-control study. Journal of Chronic Diseases 36(9): 639-646 Jick, S. S., A. M. Walker, A. Stergachis, and H. Jick. 1989. Oral contraceptives and breast cancer. British Journal of Cancer 59: 618-621 Kay, C. R., and P. C. Hannaford. 1988. Breast cancer and the pill—A further report from the Royal College of General Practitioners' oral contraception study. British Journal of Cancer 58: 675-680 Kelsey, J. L., T. R. Holford, C. White, E. S. Mayer, S. E. Kilty, and R. M. Acheson. 1978. Oral contraceptives and breast disease. American Journal of Epidemiology 107: 236-244 Kelsey, J. L., D. B. Fischer, T. R. Holford, V. A. Livolsi, E. D. Moston, I. S. Goldenberg, and C. White. 1981. Exogenous estrogens and other factors in the epidemiology of breast cancer. Journal of the National Cancer Institute 67: 327-333 La Vecchia, C., A. Decarli, M. Fasoli, S. Franceschi, A. Gentile, E. Negri, F. Parazzini, and G. Tognoni. 1986. Oral contraceptives and cancers of the breast and the female reproductive tract. Interim results from a case-control study. British Journal of Cancer 54(2): 311-317 Lee, N. C., L. Rosero-Bixby, M. W. Oberle, C. Grimaldo, A. S. Whatley, and E. Z. Rovira. 1987. A case-control study of breast cancer and hormonal contraception in Costa Rica. Journal of the National Cancer Institute 79(6): 1247-1254 Lees, A. W., P. E. Burns, and M. Grace. 1978. Oral contraceptives and breast disease

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