Abstract
Previous studies of oral contraceptives (OC) and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary OC formulations. This nested case-control study was among female enrollees in a large US integrated health care delivery system. Cases were 1,102 women ages 20–49 diagnosed with invasive breast cancer from 1990–2009. Controls were randomly sampled from enrollment records (n=21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed OC use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, odds ratios (OR), and 95% confidence intervals (CI). Recent OC use (within the prior year) was associated with an increased breast cancer risk (OR=1.5, 95% CI=1.3–1.9) relative to never or former OC use. The association was stronger for ER+ (OR=1.7, 95% CI=1.3–2.1) than ER− disease (OR=1.2, 95% CI=0.8–1.8), though not statistically significantly different (p=0.15). Recent use of OCs involving high dose estrogen (OR=2.7, 95% CI=1.1–6.2), ethynodiol diacetate (OR=2.6, 95% CI=1.4–4.7), or triphasic dosing with an average of 0.75 milligrams of norethindrone (OR=3.1, 95% CI=1.9–5.1, p for heterogeneity compared to using other OCs=0.004) was associated with particularly elevated risks, while other types including low dose estrogen OCs were not (OR=1.0, 95% CI=0.6–1.7). Our results suggest that recent use of contemporary OCs is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different OC types could impact discussions weighing recognized health benefits and potential risks.
Keywords: breast cancer, oral contraceptives, estrogen receptor, hormones, pharmacoepidemiology
INTRODUCTION
The relationship between oral contraceptive (OC) use and breast cancer risk has been extensively studied, yet the composition and patterns of OC use have evolved considerably over time and more recent formulations have received relatively little scrutiny. Notably, there have been changes in OC formulations since they were introduced in the United States (U.S.) in the 1960s, including decreased estrogen doses, the addition of new synthetic progestins, and the approval of extended cycle OCs (1–4). Given that OCs are the leading contraceptive method in the U.S. (5), ongoing evaluation of their benefits and harms is of critical public health importance.
In 1996 the Collaborative Group on Hormonal Factors in Breast Cancer published a pooled analysis of about 90% of the world’s studies consisting of 53,297 breast cancer cases and 100,239 women without breast cancer. It concluded that women have an increased breast cancer risk while taking OCs, but risk decreases with increasing time since last use and is no longer evident 10 years after ceasing use (6, 7). Risk was highest among current OC users (in the preceding 12 months; relative risk (RR)=1.24, 95% confidence interval (CI)=1.15–1.33) and there was little impact of duration of use after accounting for recency of use, suggesting that recent use is a relevant period (6, 7). There was no statistically significant risk variation by OC formulation; however, 74% of the cases in the pooled analysis were diagnosed during the 1980s, and thus more likely to be exposed to OC formulations less commonly used today, and only half of the contributing studies had formulation data (6, 7). A recent smaller study, the Nurses’ Health Study II, reported an excess breast cancer risk (RR=1.3, 95% CI=1.0–1.7) associated with current OC use and a marked increased risk associated with current use of one triphasic OC formulation (OR=3.1, 95% CI=2.0–4.7) (8), while the Women’s Contraceptive and Reproductive Experiences (CARE) Study found no elevated risk associated with current use of OCs (9) or with unique OC formulations (i.e., considering estrogen and progestin components) (10). Yet these studies and most other studies lack formulation data and/or are susceptible to exposure misclassification due to their reliance solely on participant recall. Additionally, comparatively few studies assessing recent OC use have stratified breast cancer risk by estrogen receptor status and existing results are mixed (11–16).
In order to evaluate recent use of contemporary OC formulations used from 1989 to 2009, we conducted a study among women enrolled in a large U.S. health plan and used pharmacy dispensing records to determine whether various OC types are associated with increased breast cancer risk.
METHODS
Study Population
We conducted a nested case-control study among women ages 20–49 enrolled continuously at Group Health Cooperative (GHC), an integrated health care delivery system serving the Seattle-Puget Sound area (17), for at least 12 months before diagnosis date (reference date) or a similar date for controls from January 1990 to October 2009. At reference date all women were required to reside in one of the 13 counties in western Washington state monitored by the Cancer Surveillance System (CSS), the local population-based cancer registry that participates in the Surveillance, Epidemiology, and End Results (SEER) program funded by the National Cancer Institute. All first primary invasive breast cancer cases were identified using the CSS and those with a prior history of in situ breast cancer or mastectomy at reference date were excluded. We randomly sampled up to 20 controls per case from enrollment records, individually matched on age, year (enrolled on the case’s diagnosis date), enrollment length before reference date (+/− 1 month), and medical chart availability (no/yes). We expanded the matching criteria for a small number of cases with fewer available controls, allowing controls to be matched to cases on enrollment length (+/−2 months), case’s birthdate (+/−365 days), and/or have a different medical chart availability than their case. A total of 1,105 cases and 22,100 matched controls met the eligibility criteria (21,755 of the 22,100 matched controls met the exact matching criteria). The Group Health Human Subjects Review Committee approved this study and a waiver of consent.
Oral Contraceptive Prescriptions
The GHC electronic pharmacy database began in 1977 and contains detailed information about pharmacy dispensings including date dispensed, drug name, dose, administration route, pill quantity, and days supply. Past GHC studies estimate that approximately 96% to 97% of GHC enrollees fill all or almost all of their prescriptions at GHC pharmacies (17), likely due to financial incentives. We focused on exposures in the 12 months prior to reference date due to the enrollment lengths of our study population and because of prior evidence indicating an increased breast cancer risk during this period (6, 7). We obtained all OC fills in the 12 months prior to reference date and classified them by formulation by identifying unique combinations of estrogen and progestin components, doses, and dosing schedules (monophasic or triphasic). Monophasic OCs contain the same estrogen and progestin dose in each hormone pill, whereas triphasic OCs contain three phases of estrogen and progestin dose combinations. We supplemented these data with claims data in the 12 months before reference date; thus, OCs filled outside of GHC pharmacies with a claim submitted were also captured (3.9% of OC prescriptions came from claims).
We categorized combined OC formulations, which contain estrogen and progestin, as low (20 micrograms (mcg) ethinyl estradiol (EE)), moderate (30–35 mcg EE or 50 mcg mestranol), or high (50 mcg EE or 80 mcg mestranol) dose estrogen. We examined progestin types individually, and grouped by chemical structure (estranes included norethindrone, norethindrone acetate, and ethynodiol diacetate; gonanes included levonorgestrel, norgestimate, norgestrel, and desogestrel) (18–20). For each woman, we summed all OC hormone pills and pills by estrogen dose, progestin type, and formulation in the year prior to reference date. We classified the number of pills as <190 or ≥190 in order to estimate exposure for greater than half of the year prior and to assess a potential dose-response effect.
We defined recent users as women who filled at least one OC prescription in the year prior to reference date and compared them to women who did not fill an OC prescription in the year before reference date. Progestin-only OC use was uncommon; therefore, we excluded women with exclusively progestin-only OC fills in the year before reference date (3 cases and 148 controls). Our final analyses included the remaining 1,102 cases and 21,952 controls.
Additional Data Sources
Using SEER data, we classified cases as estrogen receptor positive (ER+) or negative (ER−). We determined race and Hispanic ethnicity from a combination of data sources including SEER, death files, and self-administered breast cancer screening questionnaires from the Group Health Breast Cancer Surveillance Project (21). The breast cancer screening questionnaire collects information about demographics and breast cancer risk factors (22).
To evaluate possible confounding by parity, oophorectomy history, breast and/or ovarian cancer family history, and body mass index we completed medical record reviews for all cases ages 20–44 with reference dates from May 1995 to October 2009 and two of their matched controls. Medical record reviews were restricted to this subset because of data abstracting costs and the greater likelihood of OC exposure among younger women. Since GHC administers breast cancer screening questionnaires systematically among women ages 40 and older, medical record data for women ages 40–49 were additionally supplemented with data from these questionnaires as available.
Statistical Analysis
We used conditional logistic regression on the matched case-control sets to calculate odds ratios (OR) and 95% confidence intervals (CI) as estimates of the relative risk. We used two-sided tests and ORs with a p-value <0.05 were considered statistically significant. The reference group for all analyses was women who did not fill an OC prescription in the year before reference date. Since results were comparable when defining recent users as filling at least two OC prescriptions in the year before reference date, all of our analyses defined recent use as filling at least one OC prescription in the prior year. The OC formulation analyses used separate regression models for each OC exposure category. Therefore, the exposure categories were not mutually exclusive and women could be exposed in multiple models. We used unconditional logistic regression adjusted for the matching factors to test for heterogeneity between OC exposure groups by calculating a p-value comparing recent users of a specific OC formulation to recent users of any other OC formulation. In addition, we examined risk by age group (ages 20–39, 40–44, 45–49), but found no evidence of effect modification when comparing regression models using a likelihood ratio test (p=0.35); thus, results were not stratified by age.
We systematically assessed potential confounders (in Tables 1 and 2) among women with available data. We also conducted a sensitivity analysis to evaluate possible confounding due to prior breast cancer screening among women ages 40–49, since systematic screening is not recommended for younger women. We obtained non-symptomatic screening mammography data from GHC’s Breast Cancer Surveillance Project for all women ages 40–49 with reference dates beginning in June 1998.
Table 1.
Characteristics of controls and cases: Demographic, anthropometric, and screening mammography among all and reproductive and breast and ovarian cancer family history characteristics among a subset
| All Controls (n=21952) No. (%) |
All Cases (n=1102) No. (%) |
Medical Record Review Subset* | ||
|---|---|---|---|---|
| Controls (n=682) No. (%) |
Cases (n=3441) No. (%) |
|||
| Reference year† | ||||
| 1990–94 | 6454 (29.4) | 323 (29.3) | 0 (0.0) | 0 (0.0) |
| 1995–99 | 6532 (29.8) | 328 (29.8) | 297 (43.5) | 150 (43.6) |
| 2000–04 | 4772 (21.7) | 240 (21.8) | 202 (29.6) | 102 (29.7) |
| 2005–09 | 4194 (19.1) | 211 (19.1) | 183 (26.8) | 92 (26.7) |
| Age (case’s age in years)† | ||||
| 20–29 | 197 (0.9) | 10 (0.9) | 18 (2.6) | 9 (2.6) |
| 30–34 | 1141 (5.2) | 58 (5.3) | 69 (10.1) | 36 (10.5) |
| 35–39 | 2944 (13.4) | 148 (13.4) | 173 (25.4) | 87 (25.3) |
| 40–44 | 6730 (30.7) | 338 (30.7) | 422 (61.9) | 212 (61.6) |
| 45–49 | 10940 (49.8) | 548 (49.7) | 0 (0.0) | 0 (0.0) |
| Length of continuous GHC enrollment prior to reference date (months)† | ||||
| Median | 35.0 | 36.0 | 36.0 | 36.0 |
| Mean | 42.4 | 42.4 | 43.4 | 43.4 |
| Race‡ | ||||
| White | 12728 (80.0) | 905 (82.1) | 364 (77.1) | 274 (79.7) |
| Asian | 1611 (10.1) | 82 (7.4) | 58 (12.3) | 31 (9.0) |
| Black | 826 (5.2) | 60 (5.4) | 31 (6.6) | 20 (5.8) |
| Other | 739 (4.6) | 55 (5.0) | 19 (4.0) | 19 (5.5) |
| Missing | 6048 | 0 | 210 | 0 |
| Ethnicity | ||||
| Non-Hispanic | 16511 (95.0) | 1038 (94.4) | 464 (94.7) | 314 (91.3) |
| Hispanic | 860 (5.0) | 61 (5.6) | 26 (5.3) | 30 (8.7) |
| Missing | 4581 | 3 | 192 | 0 |
| Body mass index (kg/m2, available for reference dates from June 1998 and later)§ | ||||
| <25 | 3196 (41.6) | 224 (44.2) | 188 (42.0) | 107 (44.2) |
| 25.0–29.9 | 2097 (27.3) | 148 (29.2) | 122 (27.2) | 62 (25.6) |
| 30+ | 2389 (31.1) | 135 (26.6) | 138 (30.8) | 73 (30.2) |
| Missing | 3254 | 43 | 42 | 5 |
| Recent screening mammogram (within 18 months prior to reference date, available for women ≥40 years of age with reference dates from June 1998 and later)** | ||||
| No | 6087 (70.4) | 249 (57.4) | 213 (75.8) | 86 (61.0) |
| Yes | 2560 (29.6) | 185 (42.6) | 68 (24.2) | 55 (39.0) |
| Parous | ||||
| No | -- | -- | 168 (27.6) | 95 (29.0) |
| Yes | -- | -- | 441 (72.4) | 233 (71.0) |
| Missing | 73 | 16 | ||
| Number of live births | ||||
| 0 | -- | -- | 168 (28.6) | 95 (29.3) |
| 1 | -- | -- | 113 (19.3) | 71 (21.9) |
| 2 | -- | -- | 202 (34.4) | 111 (34.3) |
| 3+ | -- | -- | 104 (17.7) | 47 (14.5) |
| Missing | 95 | 20 | ||
| Removal of both ovaries | ||||
| No | -- | -- | 610 (97.3) | 335 (99.1) |
| Yes | -- | -- | 17 (2.7) | 3 (0.9) |
| Missing | 55 | 6 | ||
| First-degree family history of breast cancer (includes mother, sisters, and daughters) | ||||
| No | -- | -- | 497 (91.5) | 271 (86.0) |
| Yes | -- | -- | 46 (8.5) | 44 (14.0) |
| Missing | 139 | 29 | ||
| First-degree family history of ovarian cancer (includes mother, sisters, and daughters) | ||||
| No | -- | -- | 475 (97.7) | 284 (96.3) |
| Yes | -- | -- | 11 (2.3) | 11 (3.7) |
| Missing | 196 | 49 | ||
Includes all cases ages 20–44 with reference dates from May 1995 and later and up to two of their matched controls. Information came from medical records and breast cancer screening questionnaires.
Matching variables. All 1-month enrollment gaps were considered administrative and ignored.
The other race category includes women classified as multiple races.
Body mass index (BMI) prior to reference date (closest to 1 year prior) from medical records and breast cancer screening questionnaires. Months between weight value and reference month: all controls (median=12, range=0–60), all cases (median=12, range=0–54).
Among women with 18+ months of enrollment prior to reference date. Excludes symptomatic and diagnostic mammograms. Mammography data were complete for all women with reference dates from June 1998 and later.
Table 2.
Selected characteristics among controls who were never/former OC users and recent OC users
| Combined OC Use† | Medical Record Review Subset* Combined OC Use† |
|||
|---|---|---|---|---|
| Never/former use (n=19953) No. (%) |
Recent use (n=1999) No. (%) |
Never/former use (n=579) No. (%) |
Recent use (n=103) No. (%) |
|
| Age (years)‡ | ||||
| 19–29 | 132 (0.7) | 65 (3.3) | 13 (2.3) | 5 (4.9) |
| 30–34 | 839 (4.2) | 302 (15.1) | 49 (8.5) | 20 (19.4) |
| 35–39 | 2518 (12.6) | 426 (21.3) | 140 (24.2) | 33 (32.0) |
| 40–44 | 6185 (31.0) | 549 (27.5) | 377 (65.1) | 45 (43.7) |
| 45–50 | 10279 (51.5) | 657 (32.9) | 0 (0.0) | 0 (0.0) |
| Race | ||||
| White | 11519 (79.8) | 1209 (82.6) | 311 (76.8) | 53 (79.1) |
| Asian | 1490 (10.3) | 121 (8.3) | 51 (12.6) | 7 (10.4) |
| Black | 757 (5.2) | 69 (4.7) | 27 (6.7) | 4 (6.0) |
| Other | 674 (4.7) | 65 (4.4) | 16 (4.0) | 3 (4.5) |
| Missing | 5513 | 535 | 174 | 36 |
| Ethnicity | ||||
| Non-Hispanic | 15083 (95.1) | 1428 (94.4) | 401 (95.0) | 63 (92.6) |
| Hispanic | 775 (4.9) | 85 (5.6) | 21 (5.0) | 5 (7.4) |
| Missing | 4095 | 486 | 157 | 35 |
| Body mass index (kg/m2, available for reference dates from June 1998 and later)§ | ||||
| <25 | 2771 (40.9) | 425 (46.8) | 148 (40.4) | 40 (48.8) |
| 25.0–29.9 | 1862 (27.5) | 235 (25.9) | 100 (27.3) | 22 (26.8) |
| 30+ | 2140 (31.6) | 249 (27.4) | 118 (32.2) | 20 (24.4) |
| Missing | 2869 | 385 | 38 | 4 |
| Recent screening mammogram (within 18 months prior to reference date, available for women ≥40 years of age with reference dates from June 1998 and later)** | ||||
| No | 5580 (71.2) | 507 (62.5) | 186 (75.6) | 27 (77.1) |
| Yes | 2256 (28.8) | 304 (37.5) | 60 (24.4) | 8 (22.9) |
| Parous | ||||
| No | -- | -- | 126 (24.7) | 42 (42.4) |
| Yes | -- | -- | 384 (75.3) | 57 (57.6) |
| Missing | 69 | 4 | ||
| First-degree family history of breast cancer (includes mother, sisters, and daughters) | ||||
| No | -- | -- | 416 (91.0) | 81 (94.2) |
| Yes | -- | -- | 41 (9.0) | 5 (5.8) |
| Missing | 122 | 17 | ||
| First-degree family history of ovarian cancer (includes mother, sisters, and daughters) | ||||
| No | -- | -- | 399 (98.0) | 76 (96.2) |
| Yes | -- | -- | 8 (2.0) | 3 (3.8) |
| Missing | 172 | 24 | ||
Includes up to two of the controls matched to all cases ages 20–44 with reference dates from May 1995 and later. Information came from medical records and breast cancer screening questionnaires.
Recent use is defined as filling at least one combined OC script in the year prior to reference date.
Some controls are outside of the 20–49 age range due to expanded matching criteria.
Body mass index (BMI) prior to reference date (closest to 1 year prior) from medical records and breast cancer screening questionnaires.
Among women with 18+ months of enrollment prior to reference date. Excludes symptomatic and diagnostic mammograms. Mammography data were complete for all women with reference dates from June 1998 and later.
We used two conditional logistic regression models restricted to either ER+ or ER− cases and their matched controls to calculate ER-specific ORs. We classified borderline ER results as positive (n=4) and excluded cases with unknown ER status (n=91) from these analyses. To test for a difference between ER case groups we calculated a p-value using unconditional logistic regression limited to cases and adjusted for the matching factors. We performed all analyses using Stata/MP version 12.0 (StataCorp LP, College Station, TX).
RESULTS
Distributions of reference year, age, and months of GHC enrollment were similar among cases and controls (Table 1). As expected, cases were more likely than controls to have a screening mammogram during the 18 months prior to the reference date because screening mammograms closer to the reference date were likely to lead to cancer detection in cases. Cases were somewhat more likely to be white and leaner than controls. Among women with available information, a first-degree family history of breast cancer among female relatives was more common among cases than controls. Cases were somewhat less likely than controls to have three or more live births and have both ovaries removed. Among control women, recent OC users were more likely to be younger than 40 years of age, leaner, to have a screening mammogram in the 18 months prior to reference date, and somewhat more likely to be white compared to never or former OC users (Table 2). Among controls with reproductive and family history of cancer information, recent OC users were less likely than never or former OC users to be parous and somewhat less likely to have a first-degree family history of breast cancer, but slightly more likely to have a first-degree family history of ovarian cancer.
None of the potential confounders assessed (in Tables 1 and 2) changed the OR for any OC use in the prior year and breast cancer risk by ≥10% when individually added to the model. Thus none were adjusted for in our final statistical models. Inclusion of recent screening mammogram receipt in our model only changed the OR for OC use and breast cancer risk by 5%; therefore it was not included in our final statistical models.
Recent OC use was associated with a 50% elevated breast cancer risk (95% CI=1.3–1.9) relative to never or former OC use (Table 3). Recent OC use was more strongly related to ER+ compared to ER− cancer, though this difference was not statistically significant (p=0.15). Risk of overall breast cancer and ER+ cancer increased with increasing number of hormone pills dispensed over the past year (p for trend <0.001 for both).
Table 3.
Recent oral contraceptive use and invasive breast cancer risk by estrogen receptor status
| Controls (n=21952) No. (%) |
All Cases (n=1102) No. (%) |
OR (95% CI)* | Controls (n=14704) No. (%) |
ER+ Cases‡ (n=738) No. (%) |
OR (95% CI)* | Controls (n=5433) No. (%) |
ER−Cases‡ (n=273) No. (%) |
OR (95% CI)* | |
|---|---|---|---|---|---|---|---|---|---|
| Combined OC use† | |||||||||
| Never/former use | 19953 (90.9) | 957 (86.8) | Reference | 13394 (91.1) | 637 (86.3) | Reference | 4889 (90.0) | 240 (87.9) | Reference |
| Recent use | 1999 (9.1) | 145 (13.2) | 1.5 (1.3–1.9) | 1310 (8.9) | 101 (13.7) | 1.7 (1.3–2.1) | 544 (10.0) | 33 (12.1) | 1.2 (0.8–1.8) |
| Total number of combined OC hormone pills | |||||||||
| <190 | 899 (4.1) | 50 (4.5) | 1.2 (0.9–1.6) | 582 (4.0) | 33 (4.5) | 1.2 (0.8–1.8) | 254 (4.7) | 14 (5.1) | 1.1 (0.6–2.0) |
| 190+ | 1082 (4.9) | 93 (8.5) | 1.8 (1.5–2.3) | 714 (4.9) | 66 (9.0) | 2.0 (1.5–2.6) | 288 (5.3) | 19 (7.0) | 1.4 (0.8–2.2) |
| Missing | 18 | 2 | 14 | 2 | 2 | 0 | |||
| p for trend§ | <0.001 | <0.001 | 0.16 | ||||||
Abbreviations: CI, confidence interval; ER, estrogen receptor; OC, oral contraceptive; OR, odds ratio.
All ORs are implicitly adjusted for the matching factors (age, year, months of enrollment prior to reference date, and medical chart availability).
Recent use is defined as filling at least one combined OC script in the year prior to reference date.
91 cases were excluded because of unknown ER status. Cases with borderline ER results were coded as positive (n=4). There was no statistically significant difference between recent OC use and risk of ER+ compared to ER− breast cancer (p=0.15).
P for trend in the prior year (maximum number of pills=365) using the continuous linear variable and a reference group comprised of never/former OC users).
The proportions of use of different OC types varied by OC estrogen dose, progestin type, and reference year among controls who were recent OC users (Table 4). Low dose estrogen OCs were not associated with an increased breast cancer risk (OR=1.0, 95% CI=0.6–1.7), while moderate and high dose OCs were associated with elevations in risk (OR=1.6, 95% CI=1.3–2.0 and OR=2.7, 95% CI=1.1–6.2, respectively, Table 5). None of the estrogen dose risk estimates were statistically significantly different than the risk estimates for using other estrogen doses, though low dose estrogen OCs approached statistical significance (p for heterogeneity=0.08). Risk increased with increasing number of pills dispensed of moderate (p for trend <0.001) and high dose estrogen OCs (p for trend=0.01) in the prior year, though few women used high dose estrogen OCs.
Table 4.
Proportions of use of different types of oral contraceptives over time among controls who were recent OC users*
| OC type† | Reference year | |||
|---|---|---|---|---|
| 1990–1994 % | 1995–1999 % | 2000–2004 % | 2005–2009 % | |
| Low estrogen dose | 6.4 | 19.5 | 19.2 | 23.8 |
| Moderate estrogen dose | 91.5 | 81.7 | 82.8 | 78.2 |
| High estrogen dose | 6.1 | 3.6 | 0.8 | 0.4 |
| Progestin types | ||||
| Estrane progestin | 83.6 | 80.8 | 71.2 | 62.2 |
| Norethindrone | 59.7 | 44.1 | 36.5 | 30.8 |
| Norethindrone acetate | 23.3 | 34.6 | 32.3 | 28.5 |
| Ethynodiol diacetate | 3.9 | 6.8 | 5.2 | 3.5 |
| Gonane progestin | 20.3 | 22.9 | 35.6 | 36.8 |
| Levonorgestrel | 15.8 | 17.4 | 16.9 | 19.9 |
| Norgestimate | 0.0 | 3.1 | 16.7 | 13.8 |
| Norgestrel | 4.6 | 2.3 | 1.3 | 1.4 |
| Desogestrel | 0.0 | 0.5 | 1.5 | 2.5 |
Abbreviations: EE, ethinyl estradiol; mcg, micrograms; ME, mestranol; OC, oral contraceptive.
Percent of controls filling at least one combined OC script among recent OC users by reference year. Recent use is defined as filling at least one combined OC script in the year prior.
OC types are not mutually exclusive. Low estrogen dose=20 mcg EE, moderate estrogen dose=30–35 mcg EE or 50 mcg ME, and high estrogen dose=50 mcg EE or 80 mcg ME. Estrane progestins include norethindrone, norethindrone acetate, and ethynodiol diacetate. Gonane progestins include levonorgestrel, norgestimate, norgestrel, and desogestrel.
Table 5.
Recent oral contraceptive use by estrogen dose and progestin type and invasive breast cancer risk, by all cases (left) and ER positive cases (right)
| Number of pills† | Controls (n=21952) No. (%) |
All Cases (n=1102) No. (%) |
OR (95% CI)* | Controls (n=14704) No. (%) |
ER+ Cases (n=738) No. (%) |
OR (95% CI)* |
|---|---|---|---|---|---|---|
| Never/former use | 19953 (90.9) | 957 (86.8) | Reference | 13394 (91.1) | 637 (86.3) | Reference |
| Low estrogen dose | 367 (1.7) | 18 (1.6) | 1.0 (0.6–1.7) | 256 (1.7) | 14 (1.9) | 1.2 (0.7–2.0) |
| <190 | 228 (1.0) | 11 (1.0) | 1.0 (0.6–1.9) | 155 (1.1) | 10 (1.4) | 1.4 (0.7–2.6) |
| 190+ | 138 (0.6) | 7 (0.6) | 1.1 (0.5–2.3) | 100 (0.7) | 4 (0.5) | 0.9 (0.3–2.3) |
| p for trend‡ | 0.94 | 0.81 | ||||
| Moderate estrogen dose | 1654 (7.5) | 126 (11.4) | 1.6 (1.3–2.0) | 1063 (7.2) | 86 (11.7) | 1.8 (1.4–2.2) |
| <190 | 734 (3.3) | 45 (4.1) | 1.3 (1.0–1.8) | 463 (3.2) | 29 (3.9) | 1.4 (0.9–2.0) |
| 190+ | 919 (4.2) | 81 (7.4) | 1.9 (1.5–2.4) | 600 (4.1) | 57 (7.7) | 2.1 (1.5–2.8) |
| p for trend‡ | <0.001 | <0.001 | ||||
| High estrogen dose | 47 (0.2) | 6 (0.5) | 2.7 (1.1–6.2) | 32 (0.2) | 6 (0.8) | 3.9 (1.6–9.4) |
| p for trend‡ | 0.01 | 0.01 | ||||
| Progestin types§ | ||||||
| Estrane progestin§ | 1472 (6.7) | 111 (10.1) | 1.6 (1.3–2.0) | 973 (6.6) | 76 (10.3) | 1.7 (1.3–2.2) |
| <190 | 741 (3.4) | 43 (3.9) | 1.2 (0.9–1.7) | 487 (3.3) | 28 (3.8) | 1.2 (0.8–1.8) |
| 190+ | 729 (3.3) | 68 (6.2) | 2.0 (1.5–2.6) | 485 (3.3) | 48 (6.5) | 2.1 (1.6–2.9) |
| p for trend‡ | <0.001 | <0.001 | ||||
| Norethindrone | 819 (3.7) | 59 (5.4) | 1.5 (1.2–2.0) | 519 (3.5) | 35 (4.7) | 1.5 (1.0–2.1) |
| <190 | 415 (1.9) | 20 (1.8) | 1.0 (0.7–1.6) | 252 (1.7) | 9 (1.2) | 0.8 (0.4–1.5) |
| 190+ | 403 (1.8) | 39 (3.5) | 2.1 (1.5–2.9) | 267 (1.8) | 26 (3.5) | 2.1 (1.4–3.2) |
| p for trend‡ | <0.001 | <0.001 | ||||
| Norethindrone acetate | 609 (2.8) | 46 (4.2) | 1.6 (1.2–2.2) | 425 (2.9) | 36 (4.9) | 1.8 (1.3–2.6) |
| <190 | 339 (1.5) | 27 (2.5) | 1.7 (1.1–2.5) | 240 (1.6) | 22 (3.0) | 2.0 (1.3–3.1) |
| 190+ | 269 (1.2) | 19 (1.7) | 1.5 (0.9–2.4) | 184 (1.3) | 14 (1.9) | 1.6 (0.9–2.8) |
| p for trend‡ | 0.06 | 0.06 | ||||
| Ethynodiol diacetate | 100 (0.5) | 12 (1.1) | 2.6 (1.4–4.7) | 64 (0.4) | 9 (1.2) | 3.1 (1.5–6.2) |
| <190 | 59 (0.3) | 2 (0.2) | 0.7 (0.2–3.0) | 38 (0.3) | 1 (0.1) | 0.6 (0.1–4.2) |
| 190+ | 41 (0.2) | 10 (0.9) | 5.2 (2.6–10.5) | 26 (0.2) | 8 (1.1) | 6.7 (3.0–15.1) |
| p for trend‡ | <0.001 | <0.001 | ||||
| Gonane progestin§ | 597 (2.7) | 40 (3.6) | 1.4 (1.0–2.0) | 385 (2.6) | 29 (3.9) | 1.6 (1.1–2.4) |
| <190 | 269 (1.2) | 17 (1.6) | 1.4 (0.8–2.3) | 165 (1.1) | 12 (1.6) | 1.6 (0.9–2.9) |
| 190+ | 312 (1.4) | 21 (1.9) | 1.4 (0.9–2.3) | 207 (1.4) | 15 (2.0) | 1.6 (0.9–2.7) |
| p for trend‡ | 0.12 | 0.11 | ||||
| Levonorgestrel | 352 (1.6) | 25 (2.3) | 1.5 (1.0–2.3) | 222 (1.5) | 16 (2.2) | 1.6 (0.9–2.6) |
| <190 | 141 (0.6) | 14 (1.3) | 2.2 (1.2–3.8) | 80 (0.5) | 9 (1.2) | 2.4 (1.2–4.9) |
| 190+ | 211 (1.0) | 11 (1.0) | 1.1 (0.6–2.1) | 142 (1.0) | 7 (1.0) | 1.1 (0.5–2.3) |
| p for trend‡ | 0.45 | 0.61 | ||||
| Norgestimate | 188 (0.9) | 10 (0.9) | 1.2 (0.6–2.2) | 130 (0.9) | 8 (1.1) | 1.4 (0.6–2.8) |
| <190 | 112 (0.5) | 4 (0.4) | 0.8 (0.3–2.1) | 80 (0.5) | 4 (0.5) | 1.1 (0.4–3.1) |
| 190+ | 76 (0.4) | 6 (0.5) | 1.7 (0.7–3.9) | 50 (0.3) | 4 (0.5) | 1.7 (0.6–4.9) |
| p for trend‡ | 0.22 | 0.20 | ||||
Abbreviations: CI, confidence interval; EE, ethinyl estradiol; ER, estrogen receptor; mcg, micrograms; ME, mestranol; OC, oral contraceptive; OR, odds ratio.
All ORs are implicitly adjusted for the matching factors.
Recent use is defined as filling at least one combined OC script in the year prior to reference date. Includes mono- and triphasic OCs. Categories are not mutually exclusive and numbers may not add up to column totals because of missing values. Low estrogen dose=20 mcg EE, moderate estrogen dose=30–35 mcg EE or 50 mcg ME, and high estrogen dose=50 mcg EE or 80 mcg ME.
P for trend in the prior year (maximum number of pills=365) using the continuous linear variable and a reference group comprised of never/former OC users.
Estrane progestins include norethindrone, norethindrone acetate, and ethynodiol diacetate. Gonane progestins include levonorgestrel, norgestimate, norgestrel, and desogestrel. ORs for recent use of norgestrel and desogestrel are not displayed because <5 cases were exposed to these progestin types.
Estrane progestin OCs were associated with a 60% increased risk (95% CI=1.3–2.0) and a greater number of pills dispensed increased this risk (p for trend <0.001). All of the individual estrane progestins were associated with elevated risks and had statistically significant trends for increasing number of pills, except for norethindrone acetate. Ethynodiol diacetate OCs were infrequently used, but were associated with an elevated risk (OR=2.6, 95% CI=1.4–4.7). Gonane progestin OCs were associated with an increased risk (OR=1.4, 95% CI=1.0–2.0), but risk did not increase with additional pills dispensed. While norgestimate OCs did not appear to be associated with an increased risk (OR=1.2, 95% CI=0.6–2.2), levonorgestrel OCs were (OR=1.5, 95% CI=1.0–2.3), though neither OR was statistically significantly different than using other progestin types.
We further assessed risk by the most commonly used OC formulations. One monophasic formulation (low dose estrogen and norethindrone acetate 1.0 milligram (mg)) comprised most of the low dose users (Table 6). Among monophasic moderate dose estrogen users, there was considerable variation in risk estimates and some neared statistical significance when compared to users of other OC formulations. Norethindrone 0.50 mg was not associated with an increased risk (OR=0.8, 95% CI=0.4–1.6, p for heterogeneity=0.05), while norethindrone acetate 1.5 mg was associated with an increased risk (OR=2.1, 95% CI=1.4–3.1, p for heterogeneity=0.08), and ethynodiol diacetate 1.0 mg was associated with the greatest risk (OR=2.8, 95% CI=1.5–5.2, p for heterogeneity=0.08). There was some suggestion that risk increased as norethindrone dose increased (1.0 versus 0.50 mg). Triphasic OCs with an average dose of 0.75 mg norethindrone were associated with the greatest risk of all formulations (OR=3.1, 95% CI=1.9–5.1). This formulation was the only OC exposure (by estrogen dose, progestin type, or unique formulation) that was statistically significantly different than using other OC formulations (p for heterogeneity=0.004). Most risk estimates by estrogen dose, progestin type, and unique OC formulation increased somewhat after limiting to ER+ cases, though confidence intervals widened.
Table 6.
Recent oral contraceptive use by monophasic and triphasic formulations and invasive breast cancer risk, by all cases (left) and ER positive cases (right)
| OC formulation† | Controls (n=21952) No. (%) |
All Cases (n=1102) No. (%) |
OR (95% CI)* | Controls (n=14704) No. (%) |
ER+ Cases (n=738) No. (%) |
OR (95% CI)* |
|---|---|---|---|---|---|---|
| Never/former use | 19953 (90.9) | 957 (86.8) | Reference | 13394 (91.1) | 637 (86.3) | Reference |
| Monophasic OCs | ||||||
| Any monophasic OC | 1614 (7.4) | 114 (10.3) | 1.5 (1.2–1.9) | 1068 (7.3) | 79 (10.7) | 1.6 (1.2–2.0) |
| By estrogen dose and progestin type and dose | ||||||
| Low estrogen dose | ||||||
| Norethindrone acetate | ||||||
| 1.00 mg | 328 (1.5) | 17 (1.5) | 1.1 (0.7–1.8) | 228 (1.6) | 13 (1.8) | 1.2 (0.7–2.1) |
| Moderate estrogen dose | 1259 (5.7) | 95 (8.6) | 1.6 (1.3–2.0) | 816 (5.6) | 64 (8.7) | 1.7 (1.3–2.2) |
| Any norethindrone | 616 (2.8) | 40 (3.6) | 1.4 (1.0–1.9) | 398 (2.7) | 22 (3.0) | 1.2 (0.8–1.9) |
| 0.50 mg | 229 (1.0) | 9 (0.8) | 0.8 (0.4–1.6) | 148 (1.0) | 5 (0.7) | 0.7 (0.3–1.8) |
| 1.00 mg | 358 (1.6) | 27 (2.5) | 1.6 (1.1–2.4) | 230 (1.6) | 13 (1.8) | 1.2 (0.7–2.2) |
| 1.00 mg‡ | 46 (0.2) | 5 (0.5) | 2.3 (0.9–5.9) | 26 (0.2) | 5 (0.7) | 4.2 (1.6–11.1) |
| Norethindrone acetate | ||||||
| 1.50 mg | 300 (1.4) | 30 (2.7) | 2.1 (1.4–3.1) | 205 (1.4) | 24 (3.3) | 2.5 (1.6–3.9) |
| Ethynodiol diacetate | ||||||
| 1.00 mg | 86 (0.4) | 11 (1.0) | 2.8 (1.5–5.2) | 55 (0.4) | 8 (1.1) | 3.2 (1.5–6.7) |
| Levonorgestrel | ||||||
| 0.15 mg | 166 (0.8) | 10 (0.9) | 1.3 (0.7–2.5) | 104 (0.7) | 5 (0.7) | 1.0 (0.4–2.6) |
| Norgestimate | ||||||
| 0.25 mg | 96 (0.4) | 6 (0.5) | 1.4 (0.6–3.2) | 67 (0.5) | 5 (0.7) | 1.7 (0.7–4.2) |
| Triphasic OCs | ||||||
| Any triphasic OC | 456 (2.1) | 37 (3.4) | 1.8 (1.2–2.5) | 283 (1.9) | 25 (3.4) | 1.9 (1.3–3.0) |
| By progestin type and dose§ | ||||||
| Moderate estrogen dose | ||||||
| Norethindrone | ||||||
| 0.71 mg | 97 (0.4) | 8 (0.7) | 1.8 (0.9–3.7) | 54 (0.4) | 6 (0.8) | 2.4 (1.0–5.7) |
| 0.75 mg | 132 (0.6) | 19 (1.7) | 3.1 (1.9–5.1)** | 76 (0.5) | 12 (1.6) | 3.5 (1.9–6.4) |
| Levonorgestrel | ||||||
| 0.09 mg | 153 (0.7) | 13 (1.2) | 1.8 (1.0–3.3) | 94 (0.6) | 9 (1.2) | 2.1 (1.0–4.2) |
| Norgestimate | ||||||
| 0.22 mg | 96 (0.4) | 5 (0.5) | 1.1 (0.5–2.8) | 67 (0.5) | 4 (0.5) | 1.3 (0.5–3.7) |
Abbreviations: CI, confidence interval; EE, ethinyl estradiol; ER, estrogen receptor; mcg, micrograms; ME, mestranol; mg, milligrams; OC, oral contraceptive; OR, odds ratio.
All ORs are implicitly adjusted for the matching factors.
Recent use is defined as filling at least one combined OC script in the year prior to reference date. Categories are not mutually exclusive and numbers may not add up to column totals because of missing values. OC formulations with <5 controls or invasive cases as recent users are not displayed. Low estrogen dose=20 mcg EE and moderate estrogen dose=30–35 mcg EE or 50 mcg ME.
Contains the estrogen mestranol rather than ethinyl estradiol.
All triphasic formulations contain moderate estrogen dose. Average progestin doses are listed. The dosing schedules are as follows: (a) Norethindrone 0.71 mg=35 mcg EE/0.5 mg (7 days), 1.0 mg (9 days), 0.5 mg (5 days) norethindrone; (b) norethindrone 0.75 mg=35 mcg EE/0.5 mg (7 days), 0.75 mg (7 days), 1.0 mg (7 days) norethindrone; (c) levonorgestrel 0.09 mg=30 mcg EE/0.05 mg levonorgestrel (6 days), 40 mcg EE/0.075 mg levonorgestrel (5 days), 30 mcg EE/0.125 mg levonorgestrel (10 days); (d) norgestimate 0.22 mg=35 mcg EE/0.18 mg (7 days), 0.215 mg (7 days), 0.25 mg (7 days) norgestimate.
P for heterogeneity <0.05 comparing recent users of the formulation to recent users of other formulations.
DISCUSSION
To our knowledge, this is the first study evaluating specific OC formulations used in the U.S. during the 1990s and 2000s, determined by high quality electronic pharmacy dispensing records, and breast cancer risk among young women. Our findings suggest that recent use of contemporary OC formulations is associated with an increased breast cancer risk among women ages 20–49. This risk may be more strongly associated with ER+ than ER− breast cancer and may increase with increasing number of pills dispensed. Our results also suggest that risk may vary by OC formulation. High dose estrogen, ethynodiol diacetate, higher dose norethindrone, and specific triphasic OCs are possibly associated with increased breast cancer risks, while low dose estrogen OCs and other formulations may not be associated with elevated risks.
The increased breast cancer risk associated with recent OC use that we observed is consistent with some studies, including the large Collaborative Group pooled analysis which found the greatest breast cancer risk associated with OC use in the prior year (6), and the Nurses’ Health Study II (8), though not consistent with all studies (9, 23, 24). Collectively, these results suggest that OCs may act as tumor promoters, which is supported by evidence demonstrating increased breast cell proliferation among OC users (25–28).
Our results by estrogen dose, progestin type, and dosing schedule differ from the Collaborative Group analysis, which overall did not find risk variations by OC formulation among recent users (6, 7), but this could be due to two important study design differences. First, 21 of the 27 studies with OC formulation data in the Collaborative Group analysis relied only on self-report and the remaining 6 relied partially or exclusively on medical records (7), while our study used pharmacy records. Although validation studies suggest that women recall ever using OCs, duration of use, and timing of use relatively well, recall of specific OC brand names is less accurate (29–33). Second, many of the OC formulations examined in the Collaborative Group analysis are not comparable to OCs used today. In particular, the mean ethinyl estradiol dose dropped from approximately 56 mcg per pill in 1972, to 34 mcg in 1994, and now OCs with <30 mcg ethinyl estradiol account for an increasing proportion of hormonal contraception prescriptions (1–4). This change allowed us to evaluate 20 mcg ethinyl estradiol OCs, which was not possible in earlier studies.
Some of our OC formulation results are consistent with studies since the Collaborative Group analysis, though all of these studies relied exclusively on self-report. The Nurses’ Health Study II reported an increased breast cancer risk among women <55 years of age who were current OC users and one triphasic formulation containing levonorgestrel accounted for much of the excess risk (RR=3.1, 95% CI=2.0–4.7) (8). We also found an increased risk associated with this formulation (OR=1.8, 95% CI=1.0–3.3). However, another triphasic OC (average dose of 0.75 mg norethindrone) was associated with the greatest risk in our study and was the only OC formulation with a statistically significantly different risk compared to using other OC formulations. In contrast, the CARE study found no increased risk associated with unique OC formulations, high dose estrogen OCs, or progestin types among women ages 35–64, with the exception of an elevated risk associated with current use of ethynodiol diacetate OCs (OR=3.5, 95% CI=1.1–10.7), yet numbers were quite small (9, 10). Another study included in the Collaborative Group analysis, but with more recent diagnosis dates, reported non-statistically significant risk estimates of similar magnitudes to our progestin type results, a greater risk associated with higher than lower dose estrogen OCs, and an elevated risk associated with ethynodiol diacetate OCs among the youngest women, but data were sparse (34). Future studies are necessary to identify mechanisms explaining possible differences in risk by estrogen dose, progestin type, dosing schedule, and specific OC formulation.
Although we did not find statistically significant differences between ER case groups, our ER status findings add to the varying results on recent OC use and breast cancer risk among young women. While one prior study observed a stronger association between recent OC use and risk of ER+/PR+ than ER−/PR− cancer (13), others found the opposite where OC use was more strongly related to ER− compared to ER+ cancer (11, 12), and another study found no association between recent use and luminal A or triple-negative breast cancer risk (14). Two studies including both pre- and postmenopausal women observed greater risks of ER− than ER+ cancer associated with recent use, though the differences were not statistically significant (15, 16). Differences in results may be due to varying age distributions or to having insufficient power to detect modest differences. Additional studies with ER, PR, and HER2-neu data are needed to clarify how risk potentially varies by molecular subtype.
Our main study limitation was the relatively short durations of continuous GHC enrollment before reference date, which restricted the exposure length we could evaluate. While the large Collaborative Group analysis did not find any significant impact of duration of OC use after accounting for recency of use (6, 7), some individual studies since then have found long durations of OC use associated with increased risk among women <60 years of age (23, 24, 35). Additionally, never and former OC users comprised our reference group since we did not have lifetime OC use data. Data on potentially relevant confounders were unavailable for all women, though we collected information on a sizeable subset of matched sets and found that each had a minimal impact. While some residual confounding may still be present, confounding of any appreciable magnitude is unlikely because prior studies reporting age-adjusted and multivariable-adjusted results generally do not suggest strong confounders (8, 36), and we would not expect strong associations between covariates and specific OC formulations. Several of our analyses by OC type, such as for low and high dose estrogen, were limited by a small number of exposed cases and some of the statistically significant findings may be due to chance as a result of the number of analyses performed.
A key strength of this study is the utilization of electronic pharmacy data which reduced misclassification and allowed all OC episodes to be categorized by formulation. Electronic mammography data enabled the accurate identification of screening mammograms without relying on participant recall. These data, along with the minimal impact of adjustment for recent screening mammography on the odds ratio, equal opportunity for screening among all women ages 40–49, and excluding in situ breast cancer cases, increase our confidence that our findings are not due to detection bias. Additional strengths include the large number of controls and including all eligible women, since no direct contact was required.
Our results indicating possible variations in risk by OC formulation require replication in larger studies and should be interpreted cautiously. Additionally, prior evidence indicates that the increased risk associated with recent OC use declines after ceasing use (6, 7). However if confirmed, these results could contribute to evidence-based discussions between women and their providers regarding the benefits and harms of the various commonly prescribed hormonal contraceptive options. Although these results suggest an increased risk of breast cancer, the many established health benefits associated with OC use, including reproductive planning, menses regulation, decreased dysmenorrhea, and decreased risk of benign breast conditions (37, 38), must also be considered when making individual choices.
Acknowledgments
Financial support: This study was funded by grant number R03CA141485 from the National Cancer Institute (NCI) at the National Institutes of Health (NIH) and through the National Cancer Institute-funded Group Health Breast Cancer Surveillance Registry (U01CA063731). Dr. Beaber and this publication were also supported by grant number T32CA09168 from the NCI, NIH. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH. The collection of cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-CN-67009 and N01-PC-35142 from the Surveillance, Epidemiology and End Results (SEER) Program of the NCI with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington.
The authors would like to acknowledge and thank the efforts of numerous Group Health Research Institute staff members who contributed to the medical record review, data extraction, and project management aspects of this research study.
The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.
Footnotes
Potential conflicts of interest: None of the authors have any potential conflicts of interest.
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