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Oral Contraceptive Use and Risk of Breast Carcinoma In situ

¹ University of Wisconsin Paul P. Carbone Comprehensive Cancer Center and ² Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin; ³ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; ⁴ Departments of Community & Family Medicine and Pediatrics, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, New Hamsphire; and ⁵ Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Amy Trentham-Dietz, Room 307, University of Wisconsin Comprehensive Cancer Center, WARF Building, 610 Walnut Street, Madison, WI 53726. Phone: 608-263-1946; Fax: 608-265-5330. E-mail: trentham{at}wisc.edu

	Abstract

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There is some indication that oral contraceptive use may be associated with a small increase in risk of invasive breast cancer; however, oral contraceptive use in relation to breast carcinoma in situ (BCIS) has rarely been studied. We investigated oral contraceptive use in relation to risk of BCIS in a large population-based case-control study. Female residents of Wisconsin, Massachusetts, and New Hampshire aged 20 to 74 years with a new diagnosis of BCIS (n = 1,878) were identified from statewide tumor registries in 1997 to 2001. Age-matched female controls (n = 8,041) were randomly selected from population lists. Information on oral contraceptive use and other risk factors was collected during structured telephone interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. In multivariate models, ever use of oral contraceptives was associated with a small and marginally significant increase in BCIS overall (OR, 1.11; 95% CI, 0.99-1.25) and for ductal carcinoma in situ (OR, 1.15; 95% CI, 1.01-1.31). No strong associations were detected according to age started, duration, time since first or last use, or oral contraceptive use relative to the first full-term pregnancy. The slightly increased risk of BCIS seemed limited to former users (OR, 1.13; 95% CI, 1.00-1.27) and women without a family history of breast cancer (OR, 1.16; 95% CI, 1.01-1.32 for ever versus never use). Consistent with invasive breast cancer, these results suggest that oral contraceptive use is at most a minor contributor to BCIS risk. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2262–9)

	Introduction

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Greater exposure to higher levels of circulating endogenous and exogenous estrogens is generally thought to increase the risk of invasive breast cancer (1). Reproductive and menstrual factors associated with increased estrogen exposure, including younger ages at menarche, older ages at first birth, lower parity, older ages at menopause, and use of postmenopausal hormones, are established risk factors for invasive breast cancer. These factors are also associated with the risk of in situ breast cancer (2, 3).

A large number of studies have examined the association of oral contraceptive and postmenopausal hormone use with the risk of invasive breast cancer. Effect estimates for oral contraceptive use are typically small and inconsistent, with increases in invasive breast cancer risk apparent only in subgroups of recent users or women who initiated use at young ages, if at all (4, 5). In contrast, a stronger association is observed for postmenopausal hormones, possibly explained by the lower background levels of endogenous estrogens after menopause (6).

There are limited data on the association of oral contraceptive use with breast carcinoma in situ (BCIS). Although the incidence of invasive breast cancer has not increased in recent years, the diagnosis of in situ breast cancer has become more common. In 2007, an estimated 62,000 women will be diagnosed with BCIS (7). Although survival after diagnosis exceeds 95% (8), treatment options may be equally aggressive relative to invasive breast cancer (9). BCIS is thought to be a nonobligate precursor of invasive breast cancer (9). We sought to explore the association of oral contraceptive use with BCIS in a large population-based, case-control study.

	Materials and Methods

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This analysis was done using data from the Collaborative Breast Cancer Study, a population-based case-control study conducted in Wisconsin, Massachusetts, and New Hampshire. The study was conducted according to institutionally approved protocols at each study site.

Identification of Cases
Women of ages 20 to 74 residing in Wisconsin, Massachusetts (excluding metropolitan Boston), and New Hampshire with a new diagnosis of breast carcinoma in situ (ICD-O version 2 C50.0-C50.9) reported to each state's cancer registry during 1997 to 2001 were potentially eligible for this study (10). Eligibility was further limited to case subjects with listed telephone numbers, driver's licenses verified by self-report (if <65 years of age), and known dates of diagnosis. A total of 2,269 cases were eligible for the study. The physician of record for each eligible case was contacted by mail to ascertain if there were objections to their patients' participation. Physicians refused contact with 58 (2.6%) cases, 17 (0.7%) were deceased, 63 (2.8%) could not be located, and 244 (10.8%) refused to participate. Overall, 1,887 (83%) women were interviewed between February 1997 and May 2001. Participation rates were similar among the three states (Massachusetts, New Hampshire, and Wisconsin). Nine interviewed cases were considered unreliable by the interviewers, leaving 1,878 cases available for analysis. Of the interviewed cases, 99% were confirmed by positive histology according to the registry reports. For this study, in situ cases were distinguished according to the fifth digit behavior code (in situ = 2) of the morphology code (10). Subtypes of BCIS were defined as lobular morphology (8520) and ductal/nonlobular (8500, 8501, 8503, 8504, 8010, and 8140; ref. 10). Histologic classification (ductal or lobular) was not available for 10% (n = 184) of BCIS cases. Of the remaining 1,694 cases, 87% (n = 1,471) were ductal/nonlobular, and 13% (n = 223) were lobular.

Identification of Controls
Community controls were randomly selected during 1997 to 2001 in each state using two sampling frames: those under 65 years of age were selected from lists of licensed drivers, and those 65 to 74 years of age were selected from a roster of Medicare beneficiaries compiled by the Centers for Medicare & Medicaid Services. Controls were selected at random within 5-year age strata to yield an age distribution similar to the cases enrolled in each state. Controls were required to have no personal history of breast cancer, a listed telephone number, and, if under 65 years of age, a self-reported driver's license. Of the 10,690 potential controls approached for participation, 86 (0.8%) were deceased, 475 (4.4%) could not be located, and 2,074 (19.4%) refused to participate. Interviews were obtained for 8,055 (75%) of these women. Fourteen interviewed controls were considered unreliable by the interviewers; hence, 8,041 controls were available for analysis.

Data Collection
Case and control women were sent letters briefly describing the study before they were contacted by trained telephone interviewers. Interviews for case and control participants were conducted contemporaneously. The 40-min interview elicited detailed information on reproductive/menstrual history, use of exogenous hormones (oral contraceptives and postmenopausal therapy), recreational physical activity, occupational history, smoking, alcohol consumption, height and weight, personal and family medical history, screening mammography, and demographic factors. Information about the woman's personal and family history of cancer was obtained at the end of the interview to maintain blinding. For 95% of cases and 93% of controls, the interviewers reported being unaware of the woman's case-control status until the end of the interview.

Exposure Definitions
Women were asked to report lifetime use of oral contraceptives, including the years use started, stopped, and the total duration for each period of use. Current use was defined as use during the year preceding the reference date. Oral contraceptive use was evaluated by ever, former, and current use, age started and stopped, total duration, time since first and last use, and use relative (before or after) to a first full-term pregnancy. Cut points for categories of age started, duration, and time since first and last use of oral contraceptive use were based on approximate quartiles among the control participants.

A woman was defined as postmenopausal if she reported a natural menopause (no menstrual periods for at least 6 months) before the reference date. Women who reported taking postmenopausal hormones and still having periods were classified as (a) premenopausal if their reference ages were in the first decile of age at natural menopause among the controls (<41 years of age for current smokers and <43 years of age for nonsmokers); (b) postmenopausal if their reference ages were in the highest decile for age at natural menopause in the control group (54 years of age for current smokers and 56 years of age for nonsmokers) with age at menopause defined as unknown; and (c) unknown menopausal status if at intermediate ages (second to ninth decile). Alcohol use was evaluated as the frequency of beer, red wine, white wine, or liquor consumption during the year previous to the reference date. Weight gain (or loss) was determined by subtracting each participant's weight at age 18 from her weight 1 year before the reference date ("recent weight").

Statistical Analysis
For each case, a reference date was defined as the registry-supplied date of breast carcinoma in situ diagnosis. For comparability, the control subjects interviewed contemporaneously with cases were assigned an individual reference date. Using the anticipated interview date of the control and a random number based on the normal distribution of days from diagnosis to interview in the cases already interviewed (based on state and 5-year age group relative to the control), the individual control reference date was calculated. This was done to maintain comparability between cases and controls and to maintain interviewer blinding to case-control disease status. Reference age was defined as the woman's age at the reference date. Only exposures that occurred before the assigned reference date were included in the analyses.

The following potential confounders were evaluated: age at menarche, age at first full-term pregnancy, parity, menopausal status, age at menopause, postmenopausal hormone use, family history of breast cancer, education, cigarette smoking, alcohol consumption, weight change since age 18, personal history of benign breast disease, and mammography use. Variables that were associated with BCIS risk (P 0.05) in age- and state-adjusted models were included in multivariate models. Our study population was 94.8% white (n = 1,799 cases; n = 7,605 controls); as such, we did not evaluate breast carcinoma in situ risk associations by race or ethnicity.

Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were obtained using multivariate logistic regression models (11) adjusted for age (<40, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, and 70), state (Massachusetts, New Hampshire, Wisconsin), age at menarche (<12, 12, 13, 14, unknown), age at first birth (<20, 20-24, 25-29, 30, unknown), parity (1, 2, 3, unknown), menopausal status (premenopausal, postmenopausal, unknown), age at menopause (<45, 45-49, 50-54, 55, unknown), postmenopausal hormone use (never, former, current), family history of breast cancer (yes, no, unknown), education (less than high school diploma, high school diploma, some college, college diploma, unknown), smoking status (never, former, current), weight at age 18 (continuous), height (continuous), weight change since age 18 (weight loss, weight gain of 0-15, 16-30, 31-50, >50 lb, unknown), personal history of benign breast disease (yes, no, unknown), and number of mammograms within 5 years before the reference date (none, less than five, five or more, unknown). To obtain P values for trend, we included select variables as continuous linear terms in regression models. Effect modification was evaluated by inclusion of cross-product terms in logistic models, with the change in log-likelihood evaluated using ² tests. Analyses were done using SAS version 9.1 software (SAS Institute, Inc.).

	Results

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The majority (77.5%; n = 1,456) of BCIS cases were detected by mammography screening. Among the cases, the average age at diagnosis was 55.3 years (range, 24-74 years). Histologic type was categorized as lobular in 11.9% (n = 223) of cases, ductal in 78.3% (n = 1,471), and "other" in 9.8% (n = 184). The "other" category was comprised of carcinoma in situ, not otherwise specified (n = 78); diagnoses involving both intraductal and lobular carcinoma in situ (n = 66); and unknown (n = 40).

In multivariate models, risk of BCIS increased with younger age at menarche, older age at first birth and/or menopause, low parity, postmenopausal hormone use, a personal history of benign breast disease, greater frequency of mammography screening, a family history of breast cancer, and (among postmenopausal women) weight gain since age 18. In age- and state-adjusted models, we observed an increased risk of BCIS associated with higher levels of education; however, this association was attenuated substantially in the fully adjusted model (Table 1 ).

Comparisons according to histology (lobular versus ductal carcinoma in situ) did not indicate statistical differences in associations according to oral contraceptive use (P > 0.05 by Wald test; Table 3 ). Estimates for ductal carcinoma in situ (DCIS) risk generally mirrored those for BCIS types combined, although the ORs were often of greater magnitude. Notably, starting oral contraceptive use at earlier ages seemed to increase risk of DCIS (OR, 1.34; 95% CI, 1.06, 1.68 for <20 years and OR, 1.19; 95% CI, 1.01, 1.41 for age 20-23 years, compared with never use). Lobular carcinoma in situ estimates were characterized by greater instability, reflecting the much smaller sample sizes.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In our data, oral contraceptive use was only weakly associated with risk of breast carcinoma in situ, with elevations in risk limited to short-term use. We found no evidence of a dose-response relation with age started, time since first use or last use, or use relative to the first full-term pregnancy. Although subgroup analyses were limited by small sizes, the modest increase in risk associated with ever use of oral contraceptives was limited to ductal carcinoma in situ and to women with no family history of breast cancer. In addition, we found no suggestion of effect modification by menopausal status.

A total of five published studies have examined the association of OCs with BCIS risk (2, 3, 12-14). The most recent of these (2006) indicated no association for ever use, duration, use relative to the first full-term pregnancy, or high (50 µg ethinyl estradiol or 75 µg mestranol) versus low estrogen dose formulation. Results were similar in analyses restricted to cases with ductal histology (14). Similarly, null results were reported in two studies by Claus et al. (3, 13). The authors stratified data according to histologic type and reported ORs of 0.92 (95% CI, 0.72-1.18) for ductal and 0.56 (95% CI, 0.30-1.05) for lobular carcinoma in situ according to ever use of oral contraceptives compared with never use (3). Associations for DCIS were null regardless of duration of use, age at first use, time since last use, or estrogen or progestin type; detailed results specific to LCIS risk were not presented (13). Trentham-Dietz et al. (2) reported an OR of 1.24 (95% CI, 0.91-1.68) for risk of BCIS associated with ever use of oral contraceptives, with no distinguishable pattern by duration. The association did not differ according to histologic type (ductal or lobular). Brinton et al. found no association in women under age 45 years, regardless of duration or time since last use (12).

Effect modification due to differing hormone profiles or increased genetic susceptibility, as indicated by age, menopausal status, and family history of breast cancer, has also been investigated in previous studies. Gill et al. reported possible effect modification by age, with ORs for BCIS of less than one (but not statistically significant) associated with oral contraceptive use among women <50 years of age and greater than one for older women (14). The potential modifying effects of family history of breast cancer or menopausal status were not statistically significant in our data or in a report by Claus et al. (13). However, the latter study observed a suggested increase in DCIS risk among premenopausal women with a first-degree family history of breast cancer (OR, 2.3; 95% CI, 0.7-8.0), although the numbers of women in this category were quite small (n = 31 cases, 24 controls). We did not find this association in the current data; in fact, the OR for ever use of oral contraceptives (compared with never use) among premenopausal women with a family history of breast cancer was in the opposite direction and of borderline statistical significance (OR, 0.65; 95% CI, 0.39-1.06 based on n = 117 cases, 333 controls; data not shown).

To our knowledge, this is the largest case-control study to date of oral contraceptive use and risk of breast carcinoma in situ. Despite the large size of our study, the use of standardized instruments, and the wide range of oral contraceptive use characteristics reported, some limitations should be considered in interpreting our results. Early oral contraceptive prescriptions (pre-1977) were characterized by high estrogen levels (typically 50 µg estrogen or more); these levels have decreased over time (15-19). Because most women in our study population were in their fifties and sixties at the time of the study interview, their oral contraceptive use may have included both high and low estrogen dose formulas. This trend could have attenuated any overall association if one level of dosage, but not the other, was associated with BCIS risk. However, we examined BCIS associations with oral contraceptive use exclusively before and since 1977; results were similar and indicated at most a very modest positive association for ever OC use (OR, 1.12; 95% CI, 0.97-1.28 and OR, 1.18; 95% CI, 0.88-1.59 for use during 1960-1976 and 1977-2000, respectively). This provides indirect support for two previous studies, both of which reported no difference for low versus high estrogen dose oral contraceptive use and risk of breast carcinoma in situ (13, 14).

After 1976, sequential oral contraceptives were largely replaced with combination oral contraceptives that provided fixed amounts of estrogen and progestin taken for 20 to 21 days (20). Progestin types and dosages, like estrogen, have varied among oral contraceptive formulations over time. The synthetic progestins used in oral contraceptives are often chemically derived from levonorgestrel (called gonanes) or from norethindrone (called estranes). In their 2003 report, Claus et al. reported that among women who reported only ever using one type of progestin, estrane and gonane formulations did not differ significantly with respect to DCIS risk compared with never use of oral contraceptives. However, laboratory evidence suggests that some synthetic progestins in oral contraceptives may increase proliferation of estrogen receptor–positive, but not estrogen receptor–negative, human breast cancer cells (21). Information on the estrogen and progestin content of oral contraceptives used by the women in our study and on estrogen receptor status among cases was not available.

Since the introduction of population mammographic screening in the 1980s, the incidence of breast carcinoma in situ (BCIS) has increased more than 7-fold. Ductal carcinoma in situ, in particular, is often identified during screening mammography, whereas lobular carcinoma in situ is more likely to be identified as an incidental finding (22). To address concerns of surveillance bias and undetected disease among the controls, we additionally performed all analyses after restricting to case and control women who reported five mammograms in the 5-year period preceding the reference date (n = 1,023 cases, 3,328 controls), and our findings were virtually identical (OR, 1.17; 95% CI, 0.99, 1.38 for ever compared with never use of oral contraceptives).

In summary, the current results are consistent with previous studies and suggest that oral contraceptives make at most a minor contribution to the risk of breast carcinoma in situ.

	Acknowledgments

 
We are grateful to Drs. Henry Anderson, Patrick L. Remington, Meir J. Stampfer, Walter C. Willett, John A. Baron, and E. Robert Greenberg; Laura Stephenson and the staff of the Wisconsin Cancer Reporting System, Susan T. Gershman and the staff of the Massachusetts Tumor Registry; Marguerite Stevens and the staff of the New Hampshire Cancer Registry; and Julie McGregor, Mary Pankratz, Linda Haskins, Jerry Phipps, Heidi Judge, Laura Mignone, and Shafika Abrahams-Gessel, along with the study interviewers in all three states for assistance with data collection. We are especially grateful to the study participants, whose generosity made this research possible.

	Footnotes

 
Grant support: National Cancer Institute (CA67264, CA47147, CA47305, and CA69664).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Preliminary results of this study were presented at the annual meeting of the American Society of Preventive Oncology, Houston, TX, March 2007.

Received 5/21/07; revised 8/ 1/07; accepted 8/14/07.

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