Abstract
Background
Although it is well established that combined estrogen-progestin therapy (EPT) increases breast cancer risk, questions remain regarding the impact of different formulations of hormones, whether certain women are at particularly high risk, and whether risk varies by tumor subtype.
Methods
We investigated hormone therapy (HT) use in relation to breast cancer risk in the California Teachers Study cohort; after a mean follow-up of 9.8 years 2,857 invasive breast cancers were diagnosed.
Results
Compared to women who had never used HT, women who reported 15 or more years of estrogen therapy (ET) use had 19% greater risk of breast cancer (95% Confidence Interval (CI), 1.03-1.37), while women using EPT for 15 or more years had 83% greater risk (95% CI, 1.48-2.26). Breast cancer risk was highest among women using continuous combined EPT regimens. Risks associated with EPT and ET use were increased with duration of HT use for women with body mass index (BMI)<29.9 kg/m2 but not for women with BMI≥30 kg/m2. Elevated risks associated with EPT and ET use were confined to tumors that were positive for both estrogen and progesterone receptors and those that were HER2+ but were slightly diminished for HER2- tumors.
Conclusions
Breast cancer risks increased with longer duration of ET and EPT use, and risks were highest for continuous-combined EPT use. Further, risks varied by BMI and tumor subtype.
Impact
These findings underscore the need for personalized risk-benefit discussions with women contemplating HT use.
Introduction
There is substantial epidemiologic, experimental, and clinical evidence that risk of breast cancer is elevated with use of menopausal hormone therapy (HT), with formulations containing estrogen and progestin (EPT) resulting in a substantially higher risk than formulations containing estrogen only (ET) (1-13). Since the publication of the 2002 report from the Women's Health Initiative (WHI) clinical trial (12), sales of HT have dropped substantially both in the US (14-17) and elsewhere (18, 19). This decline in hormone use has been accompanied by an unprecedented decline in rates of invasive breast cancers (19), most of which is likely due to changes in HT use (19, 20).
Despite the evidence linking EPT to risk of developing breast cancer, different formulations of HT are still prescribed by general practitioners and gynecologists, who consider them to offer important relief from menopausal symptoms (21). Therefore, to the extent that HT continues to be prescribed, and because individual women need detailed information regarding risks in order to optimize their own risk-benefit assessments, it remains important to delineate the characteristics of women at the highest risk of HT-associated breast cancer, and how this risk varies with factors such as formulation and duration of HT.
In particular, it remains unclear whether number of days per month of progestin affects risk, specifically whether the continuous-combined EPT regimens (e.g., Prempro) differ from sequential regimens. Continuous-combined HT was associated with the highest risk of hormone-sensitive breast cancer in some (2, 8, 22, 23) but not all studies (6, 24). Lower body mass index (BMI) has also been flagged by a number of studies as being an important modifier of HT-associated breast cancer risk (1, 2, 7, 25-28). Some evidence supports a selective increase in risk of particular breast cancer subtypes associated with EPT use, namely the estrogen receptor positive and progesterone receptor positive subtype (ER+/PR+) (10, 29, 30). There is also a need to understand how HT affects development of triple negative (TPN; ER-/PR-/HER2-) breast cancer, the subtype having the poorest prognosis (31-33).
Materials and Methods
Study Population
The California Teachers Study (CTS) has been previously described in detail (34). Briefly, the CTS is a prospective cohort of women who were current, recent, or retired public school teachers and administrators participating in the California State Teachers Retirement System. Cohort members were mailed a detailed baseline questionnaire in 1995 characterizing information on personal medical history, family history of breast cancer, reproductive factors, HT use, and lifestyle factors such as physical activity, diet, alcohol consumption, smoking history, mammographic screening practices, and history of breast biopsy. The CTS has been approved by the Institutional Review Boards of the Northern California Cancer Center, the California Department of Public Health, the University of California, Irvine, the University of Southern California, and the City of Hope National Medical Center in accord with assurances filed with and approved by the U.S. Department of Health and Human Services.
The CTS cohort consists of 133,479 women. For this analysis of HT use, women were excluded, in sequence, if they were not California residents at the time of completing the baseline questionnaire (n=8,867), had previous or unknown history of breast cancer (n=6,351), were older than 80 years of age at baseline (n=4,344), were premenopausal (n=47,724), were of unknown menopausal status (n=5,317), or had unknown history of ever using HT (n=4,010).
Among the remaining 56,867 perimenopausal and postmenopausal women, 2,857 women (5%) were diagnosed with pathologically confirmed invasive breast cancer through December 31, 2006. Follow-up began on the date the baseline questionnaire was completed and ended at the occurrence of invasive cancer in the breast or a censoring event, which included a move outside of California, a diagnosis of in situ breast cancer, death or December 31, 2006. Incident invasive breast cancer diagnoses (International Classification of Disease Oncology code ICDO-C50) were identified through annual linkages with the California Cancer Registry (CCR) which receives reports of more than 99% of the incident cancer diagnoses occurring among California residents. National Cancer Institute designated Surveillance, Epidemiology and End Results (SEER) registries, including the CCR, routinely collect estrogen receptor (ER) and progesterone receptor (PR) as recorded in the medical records following a breast cancer diagnosis with the additional recording of HER2 status in California beginning in 2000, but only widely collected beginning in 2005. Among 2,857 invasive breast cancers, ER status was available for 2,452 (86%) cases and PR status was available for 2,347 (82%) cases. Joint ER and PR status were available for 2,344 (82%) cases and ER, PR, and HER2 status were available for 1,276 (46%) cases. A combination of annual mailings within the CTS cohort, linkages with the U.S. Postal Service National Change of Address Database, and participant change-of-address postcards was used to monitor changes in residence.
Characterization of Hormone therapy use
The baseline questionnaire contained detailed questions regarding the use of HT. The questionnaire included questions on ever use as well as duration of use of various HT regimens including: ET, progestin alone (PT), and combined EPT. This information was used to create progressively detailed HT variables. The least detailed HT variable compares never users to women with any history of HT. Each of the three classes of HT regimen, ET alone, PT alone, or EPT, was further characterized into current use at the time of baseline questionnaire or past use at the time of baseline questionnaire. Durations of ET and EPT use were calculated separately using questions on ages at start and stop of hormone use as well as total years of use. These separate durations of use were then categorized finely (never use, <2, 3-5, 6-9, 10-14, 15-19, and 20+ years) as well as in collapsed categories (never use, ≤5, 6-14, and 15+ years).
To determine how many days a month progestin was taken in EPT regimens, we used the responses to the question “When using a progestin or progesterone, for how many days each month would you usually take it?” EPT users reporting usually taking progestin for 10 or fewer days per month were classified as short-sequential (SS) EPT users, those usually taking the progestin component for longer than 10 days but fewer than 28 days were classified as long-sequential (LS) EPT users, while women with 28 or more days of progestin in their regimen were classified as continuous-combined (CC) EPT users. In analyses of duration of use, duration was calculated to include all regimens taken, thus current users of CC regimens who had used EPT for 15 or more years may have used sequential regimens for part of this period.
Assessment of other Breast Cancer Risk Factors
We obtained information regarding other established risk factors for breast cancer from the self-administered baseline questionnaire, including race/ethnicity (White, Black, Hispanic, Asian/Pacific Islander, other/mixed/unknown), first degree family history of breast cancer (no, yes, unknown/adopted), BMI (<25.0, 25.0-30.0, >30.0 kg/m2, unknown), smoking status (never, former, current, unknown), alcohol intake in the year prior to completing the questionnaire (none, <20, ≥20 g/day, unknown), age at first full-term pregnancy (15-24, 25-29, 30+ years old, unknown), parity (nulliparous, 1-3 full-term pregnancies, ≥4 full-term pregnancies, unknown), age at menarche (≤10, 11-12, 13-14, 15-16, ≥17 years old, unknown), age at menopause (<35, 35-39, 40-43, 44-46, 47-49, 50-52, 53-55, ≥56 years old, unknown) and history of breast biopsy (no, yes). We combined age at first full-term pregnancy and parity into a single variable. We also considered whether the woman had a screening mammogram within the past two years (yes, no, unknown).
Menopausal status was classified using information regarding age at baseline, age at last menstrual period with corresponding reason for cessation, and surgical oophorectomy and/or hysterectomy status. Women reporting their last menstrual period within 6 months of baseline were considered to be perimenopausal. Women reporting that their last menses was more than 6 months prior to completing the baseline questionnaire, that they had had both ovaries removed, or who were older than 56 years and who did not specify that they were premenopausal were considered postmenopausal. Women who reported initiating HT use before experiencing menopause were considered menopausal but were assigned an unknown age at menopause.
Statistical Analysis
We used multivariable Cox proportional hazards regression methods (35) to estimate the association between HT and incident invasive breast cancer risk. Hazard rate ratios are presented as relative risks (RR) with associated 95% confidence intervals (CI) and were estimated using age in days at the start and end of follow-up as the time metric. Associations between each of the HT use variables with breast cancer risk were evaluated with two proportional hazard models, one simple model stratified by age at baseline and a multivariable adjusted model, which estimated the risk for invasive breast cancer associated with HT use stratified by age at baseline questionnaire and adjusted for a number of potentially confounding variables selected a priori, including baseline reports of race/ethnicity, first degree family history of breast cancer, BMI, smoking history, alcohol consumption during the year prior to baseline, mammographic screening over the past two years, parity/age at first full term pregnancy, age at menarche, age at menopause, and history of breast biopsy. Women who could not be classified into one of the HT exposure categories for each analysis were included in the model as a separate category (other/unknown HT). These categories are presented in Tables 1-2, but are not presented for the purpose of clarity in the remainder of the results.
Table 1.
Selected baseline characteristics of 56,867 perimenopausal and postmenopausal California Teachers Study participants, by baseline status of various types of hormone therapy (HT) use: never use of any HT, estrogen therapy (ET) only users, estrogen and progestin therapy (EPT) only users and users of both ET and EPT as well as those with use of an unknown HT
| HT use at baseline† |
|||||
|---|---|---|---|---|---|
| Characteristic | N (total) | HT never users N (%) | ET only users N (%) | EPT only users N (%) | Mixed HT/Unknown N (%) |
| Participants | 56,867 | 12,331 | 16,529 | 19,663 | 8,344 |
| Invasive breast cancer cases | 2,857 | 493 | 764 | 1153 | 447 |
| Age at baseline (mean ± SD) | 60,492 | 63.3±9.3 | 63.7±9.7 | 56.7±7.2 | 61.2±9.1 |
| Race | |||||
| Non-Hispanic White | 50,681 | 10,498 (85.1) | 14,730 (89.1) | 17,880 (90.9) | 7,573 (90.8) |
| Black | 1,628 | 583 (4.7) | 567 (3.4) | 305 (1.6) | 173 (2.1) |
| Hispanic | 1,410 | 363 (2.9) | 386 (2.3) | 465 (2.4) | 196 (2.4) |
| Asian/Pacific Islander | 1,719 | 504 (4.1) | 397 (2.4) | 611 (3.1) | 207 (2.5) |
| Other/Mixed/Unknown | 1,429 | 383 (3.1) | 449 (2.7) | 402 (2.0) | 195 (2.3) |
| First degree family history of breast cancer | |||||
| No | 47,391 | 9,969 (80.9) | 13,709 (82.9) | 16,680 (84.8) | 7,033 (84.3) |
| Yes | 7,532 | 1,856 (15.1) | 2,212 (13.4) | 2,388 (12.1) | 1,076 (12.9) |
| Unknown / Adopted | 1,944 | 506 (4.1) | 608 (3.7) | 595 (3.0) | 235 (2.8) |
| BMI, kg/m2 | |||||
| <25.0 | 30,474 | 5,871 (47.6) | 8,277 (50.1) | 11,662 (59.3) | 4,664 (55.9) |
| 25.0-29.9 | 15,440 | 3,373 (27.4) | 4,790 (29.0) | 5,070 (25.8) | 2,207 (26.5) |
| ≥30.0 | 8,154 | 2,221 (18.0) | 2,450 (14.8) | 2,367 (12.0) | 1,116 (13.4) |
| Unknown | 2,799 | 866 (7.0) | 1,012 (6.1) | 564 (2.9) | 357 (4.3) |
| Smoking status | |||||
| Never | 33,218 | 7,478 (60.6) | 9,862 (59.7) | 11,127 (56.6) | 4,751 (56.9) |
| Former | 19,657 | 3,749 (30.4) | 5,591 (33.8) | 7,265 (37.0) | 3,052 (36.6) |
| Current | 3,642 | 1,028 (8.3) | 963 (5.8) | 1,165 (5.9) | 486 (5.8) |
| Unknown | 350 | 76 (0.6) | 113 (0.7) | 106 (0.5) | 55 (0.7) |
| Alcohol intake (past year) | |||||
| None | 17,591 | 4,574 (37.1) | 5,266 (31.9) | 5,257 (26.7) | 2,494 (29.9) |
| <20 grams/day | 31,135 | 6,017 (48.8) | 8,821 (53.4) | 11,630 (59.2) | 4,667 (55.9) |
| ≥20 grams/day | 5,430 | 1,090 (8.8) | 1,537 (9.3) | 2,010 (10.2) | 793 (9.5) |
| Unknown | 2,711 | 650 (5.3) | 905 (5.5) | 766 (3.9) | 390 (4.7) |
| Screening mammogram within 2 yrs | |||||
| Yes | 51,343 | 9,701 (78.7) | 15,144 (91.6) | 18,657 (94.9) | 7,841 (94.0) |
| No | 4,816 | 2,404 (19.5) | 1,195 (7.2) | 814 (4.1) | 403 (4.8) |
| Unknown | 708 | 226 (1.8) | 190 (1.2) | 192 (1.0) | 100 (1.2) |
| Age at first full term pregnancy (FFTP) and parity (p) | |||||
| Nulliparous | 11,878 | 2,880 (23.4) | 3,178 (19.2) | 4,137 (21.0) | 1,683 (20.2) |
| Age at FFTP 15-24 & 1-3 P | 14,737 | 2,599 (21.1) | 4,705 (28.5) | 5,073 (25.8) | 2,360 (28.3) |
| Age at FFTP 15-24 & ≥4 P | 4,728 | 1,112 (9.0) | 1,573 (9.5) | 1,312 (6.7) | 731 (8.8) |
| Age at FFTP 25-29 & 1-3 P | 14,714 | 3,008 (24.4) | 4,175 (25.3) | 5,413 (27.5) | 2,118 (25.4) |
| Age at FFTP 25-29 & ≥4 P | 2,155 | 637 (5.2) | 647 (3.9) | 577 (2.9) | 294 (3.5) |
| Age at FFTP ≥30 & 1-3 P | 7,155 | 1,703 (13.8) | 1,701 (10.3) | 2,783 (14.2) | 968 (11.6) |
| Age at FFTP ≥30 & ≥4 P | 302 | 105 (0.9) | 83 (0.5) | 81 (0.4) | 33 (0.4) |
| Unknown | 1,198 | 287 (2.3) | 467 (2.8) | 287 (1.5) | 157 (1.9) |
| Menopausal age | |||||
| <35 years old | 969 | 109 (0.9) | 494 (3.0) | 137 (0.7) | 229 (2.7) |
| 35-39 years old | 1,751 | 213 (1.7) | 856 (5.2) | 308 (1.6) | 374 (4.5) |
| 40-43 years old | 3,458 | 670 (5.4) | 1,370 (8.3) | 798 (4.1) | 620 (7.4) |
| 44-46 years old | 5,417 | 1,202 (9.8) | 1,913 (11.6) | 1,495 (7.6) | 807 (9.7) |
| 47-49 years old | 8,462 | 2,252 (18.3) | 1,990 (12.0) | 3,095 (15.7) | 1,125 (13.5) |
| 50-52 years old | 11,628 | 3,509 (28.5) | 2,053 (12.4) | 4,650 (23.7) | 1,416 (17.0) |
| 53-55 years old | 7,537 | 2,336 (18.9) | 1,133 (6.9) | 3,075 (15.6) | 993 (11.9) |
| ≥56 years old | 2,893 | 652 (5.3) | 434 (2.6) | 1,221 (6.2) | 586 (7.0) |
| Unknown | 14,752 | 1,388 (11.3) | 6,286 (38.0) | 4,884 (24.8) | 2,194 (26.3) |
| Age at menarche ‡ | |||||
| ≤10 years old | 4,049 | 831 (6.7) | 1,182 (7.2) | 1,431 (7.3) | 605 (7.3) |
| 11-12 years old | 23,907 | 5,031 (40.8) | 6,978 (42.2) | 8,289 (42.2) | 3,609 (43.3) |
| 13-14 years old | 23,490 | 5,218 (42.3) | 6,675 (40.4) | 8,199 (41.7) | 3,398 (40.7) |
| 15-16 years old | 3,947 | 903 (7.3) | 1,191 (7.2) | 1,306 (6.6) | 547 (6.6) |
| ≥17 years old | 527 | 130 (1.1) | 160 (1.0) | 174 (0.9) | 63 (0.8) |
| Unknown | 947 | 218 (1.8) | 343 (2.1) | 264 (1.3) | 122 (1.5) |
| History of breast biopsy | |||||
| No | 45,691 | 10,426 (84.6) | 13,019 (78.8) | 15,854 (80.6) | 6,392 (76.6) |
| Yes | 11,176 | 1,905 (15.5) | 3,510 (21.2) | 3,809 (19.4) | 1,952 (23.4) |
| Hysterectomy | |||||
| No | 36,474 | 10,472 (84.9) | 3,386 (20.5) | 18243 (92.8) | 4,373 (52.4) |
| Yes | 19,334 | 1,638 (13.3) | 12,797 (77.4) | 1072 (5.5) | 3,827 (45.9) |
| Unknown | 1,059 | 221 (1.8) | 346 (2.1) | 348 (1.8) | 144 (1.7) |
Abbreviations: HT, hormone therapy; SD, standard deviation; BMI, body mass index; kg, kilograms; m2, meters squared; yrs, years; FFTP, first full-term pregnancy; TP, term pregnancies
All comparisons between the various users and HT never users were statistically significant (χ2 p-values <= 0.0001), exceptions are indicated
p-values for comparison with never HT users were 0.008, 0.0003 and 0.0002 respectively.
Table 2.
Relative risk of breast cancer associated with types of HT use assessed at study baseline, California Teachers Study.
| Breast cancer cases, no. | RR (95% CI) |
|||
|---|---|---|---|---|
| Hormone therapy assessed at baseline | Observed person-years | Age adjusted* | Multivariable adjusted† | |
| Never/ever HT use | ||||
| HT never users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| HT users | 436,339 | 2,364 | 1.39 (1.26, 1.53) | 1.40 (1.26, 1.55) |
| Type and pattern of HT use | ||||
| Never used any HT | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| ET only | 159,680 | 764 | 1.17 (1.04, 1.31) | 1.21 (1.07, 1.36) |
| EPT only | 195,135 | 1,153 | 1.65 (1.48, 1.84) | 1.59 (1.42, 1.78) |
| PT Only | 8,726 | 32 | 1.28 (0.89, 1.84) | 1.22 (0.85, 1.75) |
| Mixed ET and EPT | 61,192 | 356 | 1.41 (1.23, 1.62) | 1.42 (1.23, 1.63) |
| Mixed PT and EPT | 6,318 | 38 | 1.64 (1.17, 2.28) | 1.59 (1.14, 2.22) |
| Mixed PT and ET | 3,036 | 7 | 0.60 (0.28, 1.26) | 0.59 (0.28, 1.24) |
| Other/Unknown | 2,252 | 14 | 1.98 (1.16, 3.38) | 2.02 (1.18, 3.45) |
| Type and recency of HT at baseline | ||||
| Never used any HT | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| Former HT, ET only | 37,700 | 166 | 0.97 (0.81, 1.16) | 0.99 (0.83, 1.18) |
| Former HT, EPT only | 23,919 | 107 | 1.17 (0.95, 1.45) | 1.13 (0.92, 1.40) |
| Current HT, ET only | 112,034 | 556 | 1.26 (1.11, 1.42) | 1.33 (1.17, 1.51) |
| Current HT, EPT only | 167,268 | 1,019 | 1.73 (1.55, 1.94) | 1.69 (1.50, 1.90) |
| Other/Unknown | 95,418 | 516 | 1.39 (1.23, 1.57) | 1.40 (1.24, 1.60) |
Abbreviations: RR, relative risk; CI, confidence interval; HT, hormone therapy; ET, estrogen hormone therapy; PT, progestin hormone therapy; EPT, estrogen-progestin combination hormone therapy
Age (days) is used as the time metric for the Cox proportional hazards models; models are stratified by age (at completion of the baseline questionnaire).
Stratified by age and adjusted for categories of race, family history of breast cancer, BMI, smoking, alcohol consumption, mammographic screening, parity and age at full term pregnancy, age at menopause, age at menarche, and history of breast biopsy
Because a combined EPT pill was marketed just as our baseline questionnaire was being distributed, there is a possibility that some women who used this pill reported it as ET. Considering that this misclassification of ET use should be less likely in hysterectomized women, we conducted one analysis where we examined the association between ET and breast cancer risk among hysterectomized women only. Similarly, we conducted one analysis where we examined the association between EPT use and breast cancer risk among nonhysterectomized women, and finally one analyses where we only included women reporting natural menopause. These sensitivity analyses indicated that the results were similar across types of menopause, and the results are not shown. Additionally, we repeated the analyses halting follow-up at the end of 2002 to explore the possible impact of changes in HT use associated with the release of the WHI findings, when large numbers of US women reported stopping HT use (12, 14, 36).
Tests for trend within each of the HT variables were performed by fitting the median value for each HT duration category as a continuous variable in the multivariable age-stratified model (35) and the statistical significance for the β slope parameter estimate (Wald p-value) is reported. We examined several potential modifiers of the HT – breast cancer association, including baseline BMI, alcohol consumption, parity, and mammographic screening. We also determined whether risk differed by tumor size or tumor subtype defined by ER, PR, and HER2 status. Differences in the risk association between strata were examined by conducting a test for effect modification using a likelihood ratio test for heterogeneity of trends (35).
The validity of the proportional hazards assumption inherent to Cox proportional hazards modeling (37) was confirmed by visual inspection of Kaplan-Meier survival curves and plotted scaled Schoenfeld residuals to assess the correlation of residuals to time on study. All reported p-values are two-sided. The SAS software program (SAS version 9.1, SAS Institute Inc, Cary, NC) was used to perform all statistical analyses.
Results
The mean (± standard deviation) age at diagnosis of women with incident invasive breast cancer was 67.1 (± 9.0) years. Compared to women with no history of HT use, women who reported ever having used ET only, EPT only, or any combination of the two, or could not indicate with form of HT they had used were younger, more likely to self-identify as non-Hispanic white, report no family history of breast cancer, be parous, have a younger age at menarche and lower baseline BMI, have ever smoked or consumed alcohol, have had a screening mammogram within the two years prior to baseline, be younger at menopause, and report a history of breast biopsy (Table 1).
Overall risk of breast cancer associated with HT
Compared to women with no history of HT use, women who had ever used HT were at a 40% elevated risk of breast cancer (95% CI, 1.26-1.55) (Table 2). Women who had used ET or EPT were at an increased risk of breast cancer, and EPT users were at increased risk regardless of the pattern of use, i.e. regardless of whether they had used EPT only, or also had used ET or PT. Additionally, current use of either ET or EPT was associated with higher risk than past use of the corresponding hormone regimen. The greatest risk elevation was associated with current EPT use where EPT was the only formulation ever used (RR, 1.69; 95% CI, 1.50-1.90).
Risk associated with duration of HT use
In general, former HT users were more likely to be short duration users than current HT users. While 74% of former ET users had used ET ≤ 5 years and only 8% had used it ≥15 years, the numbers were 26% and 43% among current ET users. Similarly, among former EPT users 85% had used EPT ≤ 5 years and 1% had used EPT ≥ 15 years, while the numbers were 60% and 6% among current EPT users. The associations of increasing duration of both ET and EPT use with increasing breast cancer risk were statistically significant. Compared to women who had never taken HT, women with 20 or more cumulative years of ET use at baseline were at a 28% increased risk (95% CI, 1.09-1.51; Ptrend = 0.01), while EPT users for 20 or more years were at 92% increased risk (95% CI, 1.36-2.72; Ptrend < 0.0001) (Table 3). Compared to never users, ET use for more than 15 years among current users was associated with a RR of 1.35 (95% CI, 1.15-1.58), while 15 or more years of EPT use among current users was associated with a RR of 1.94 (95% CI, 1.53-2.44).
Table 3.
Relative risk of breast cancer associated with duration and recency of HT use at baseline.
| Observed person-years | Breast cancer cases, no. | RR (95% CI) |
||
|---|---|---|---|---|
| Hormone therapy use assessed at baseline | Age adjusted* | Multivariable adjusted† | ||
| Duration of ET‡ | ||||
| HT Never Users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| <2 yrs | 39,229 | 163 | 0.96 (0.81, 1.14) | 0.97 (0.82, 1.14) |
| 3-5 yrs | 35,559 | 176 | 0.99 (0.85, 1.16) | 1.02 (0.87, 1.19) |
| 6-9 yrs | 32,136 | 160 | 1.00 (0.85, 1.18) | 1.05 (0.89, 1.24) |
| 10-14 yrs | 30,257 | 144 | 0.97 (0.81, 1.15) | 1.02 (0.85, 1.22) |
| 15-19 yrs | 21,246 | 105 | 1.00 (0.82, 1.22) | 1.08 (0.88, 1.33) |
| 20+ yrs | 37,154 | 217 | 1.17 (1.01, 1.37) | 1.28 (1.09, 1.51) |
| P trend | p = 0.0131 | |||
| Duration of EPT‡ | ||||
| HT Never Users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| <2 yrs | 93,487 | 429 | 1.18 (1.05, 1.32) | 1.12 (1.00, 1.27) |
| 3-5 yrs | 65,209 | 393 | 1.49 (1.32, 1.69) | 1.42 (1.26, 1.61) |
| 6-9 yrs | 45,231 | 298 | 1.55 (1.35, 1.77) | 1.50 (1.31, 1.72) |
| 10-14 yrs | 29,203 | 222 | 1.70 (1.47, 1.98) | 1.67 (1.44, 1.95) |
| 15-19 yrs | 7,770 | 64 | 1.77 (1.37, 2.28) | 1.79 (1.39, 2.32) |
| 20+ yrs | 3,777 | 34 | 1.88 (1.33, 2.66) | 1.92 (1.36, 2.72) |
| P trend | p < 0.0001 | |||
| | ||||
| Collapsed duration of ET‡ | ||||
| HT Never Users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| ≤ 5 yrs | 74,787 | 339 | 0.98 (0.86, 1.10) | 0.99 (0.88, 1.12) |
| 6-14 yrs | 62,393 | 304 | 0.98 (0.87, 1.11) | 1.03 (0.90, 1.17) |
| 15+ yrs | 58,399 | 322 | 1.09 (0.96, 1.24) | 1.19 (1.03, 1.37) |
| P trend | p = 0.0394 | |||
| Collapsed duration of EPT‡ | ||||
| HT Never Users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| ≤ 5 yrs | 158,696 | 822 | 1.32 (1.20, 1.45) | 1.26 (1.14, 1.39) |
| 6-14 yrs | 74,433 | 520 | 1.61 (1.44, 1.80) | 1.57 (1.40, 1.76) |
| 15+ yrs | 11,547 | 98 | 1.80 (1.46, 2.22) | 1.83 (1.48, 2.26) |
| P trend | p < 0.0001 | |||
| | ||||
| Duration of current HT use** | ||||
| HT Never Users | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| Current ET (≤ 5 yrs) | 36,394 | 148 | 1.23 (1.02, 1.49) | 1.23 (1.02, 1.49) |
| Current ET (6-14 yrs) | 47,491 | 222 | 1.21 (1.03, 1.42) | 1.28 (1.08, 1.51) |
| Current ET (15+ yrs) | 52,931 | 291 | 1.24 (1.07, 1.43) | 1.35 (1.15, 1.58) |
| P trend | p = 0.0001 | |||
| Current EPT (≤ 5 yrs) | 109,984 | 614 | 1.67 (1.47, 1.90) | 1.61 (1.41, 1.83) |
| Current EPT (6-14 yrs) | 65,316 | 466 | 1.80 (1.58, 2.05) | 1.78 (1.55, 2.03) |
| Current EPT (15+ yrs) | 10,332 | 86 | 1.89 (1.50, 2.38) | 1.94 (1.53, 2.44) |
| P trend | p < 0.0001 | |||
| PT (past or present) | 8,726 | 32 | 1.28 (0.89, 1.84) | 1.22 (0.85, 1.76) |
| Past ET or EPT | 68,695 | 303 | 1.03 (0.90, 1.19) | 1.04 (0.90, 1.20) |
| | ||||
| Effects of HT through 2002** | ||||
| HT Never Users | 80,280 | 310 | 1 [Reference] | 1 [Reference] |
| Current ET (≤ 5yrs) | 24,031 | 97 | 1.33 (1.06, 1.68) | 1.34 (1.06, 1.70) |
| Current ET (6-14 yrs) | 31,438 | 161 | 1.42 (1.17, 1.73) | 1.52 (1.24, 1.85) |
| Current ET (15+ yrs) | 35,719 | 197 | 1.31 (1.09, 1.56) | 1.44 (1.19, 1.75) |
| P trend | p < 0.0001 | |||
| Current EPT (≤ 5 yrs) | 72,475 | 414 | 1.88 (1.61, 2.21) | 1.81 (1.53, 2.12) |
| Current EPT (6-14 yrs) | 43,465 | 356 | 2.22 (1.90, 2.59) | 2.18 (1.86, 2.56) |
| Current EPT (15+ yrs) | 6,966 | 64 | 2.20 (1.68, 2.88) | 2.25 (1.71, 2.96) |
| P trend | p < 0.0001 | |||
| PT (past or present) | 5,687 | 24 | 1.66 (1.09, 2.54) | 1.60 (1.05, 2.44) |
| Past ET or EPT | 46,187 | 202 | 1.09 (0.91, 1.30) | 1.09 (0.91, 1.30) |
Abbreviations: RR, relative risk; CI, confidence interval; YRS, years; HT, hormone therapy; ET, estrogen hormone therapy; PT, progestin hormone therapy; EPT, estrogen-progestin combination hormone therapy
Age (days) is used as the time metric for the Cox proportional hazards models; models are stratified by age (at completion of the baseline questionnaire).
Stratified by age and adjusted for categories of race, family history of breast cancer, BMI, smoking, alcohol consumption, mammographic screening, parity and age at full term pregnancy, age at menopause, age at menarche, and history of breast biopsy
Mutually adjusted with additional adjustments for PT use and other/unknown HT use
Women who could not be classified into these exposure categories were included in the model as a separate category of “use of other/unknown” HT”, but results are not presented
To address the concern that the elevated risks associated with current ET might be confounded by past EPT use, we conducted a separate analysis restricted to current ET users without any history of EPT. The effect estimates for each of the ET duration categories remained stable and demonstrated a clear dose-response trend, with the RRs for ≤5, 6-14, and 15+ years among current users being 1.23 (95% CI, 0.99-1.54), 1.38 (95% CI, 1.14-1.67), and 1.44 (95% CI, 1.21-1.71) respectively (results not shown). Further, when restricting the analysis to women with a self-reported hysterectomy, the risk estimates for ET use were similar (results not shown).
When we restricted analyses of EPT use to current users who reported having only used EPT, the RRs for ≤5, 6-14, and 15+ years of use were 1.60 (95% CI, 1.39-1.86), 1.74 (95% CI, 1.51-2.02), and 1.78 (95% CI, 1.36 – 2.33) respectively (results not shown).
Because of concern that many women may have ceased HT use after the publication of the WHI trial results (12), we ran one analysis excluding follow-up after December 31, 2002. The resulting risk estimates became slightly stronger; the RR for more than 15 years of current ET use was 1.44 (95% CI, 1.19 -1.75) and the RR for long term current EPT use was 2.25 (95% CI, 1.71-2.96).
Effects of different EPT regimens
We further characterized the risk associated with current EPT use by classifying the HT regimen according to the usual length of use per month of the progestin component. We found that risk increased with the usual number of days per month of progestin in the current EPT regimen, with the greatest risk among current CC (continuous-combined) EPT users (RR, 1.83; 95% CI, 1.61-2.08; p-trend = 0.0113) (Table 4).
Table 4.
Relative risk of breast cancer associated with use of various EPT regimens at baseline.
| Breast cancer cases, no. | RR (95% CI) |
|||
|---|---|---|---|---|
| Hormone therapy use assessed at baseline* | Observed person-years | Age adjusted† | Multivariable adjusted§* | |
| Lifetime effects by most commonly used EPT regimen | ||||
| Never used any HT | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| Ever used EPT (SS) | 71,263 | 377 | 1.44 (1.26, 1.65) | 1.40 (1.21, 1.61) |
| Ever used EPT (lS) | 71,854 | 408 | 1.53 (1.34, 1.74) | 1.49 (1.30, 1.71) |
| Ever used EPT (CC) | 89,919 | 600 | 1.81 (1.60, 2.04) | 1.75 (1.54, 1.98) |
| P trend | p = 0.0006 ‡ | |||
| Current effects by most commonly used EPT regimen | ||||
| Never used any HT | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| Current EPT (SS) | 52,011 | 295 | 1.59 (1.37, 1.84) | 1.54 (1.32, 1.79) |
| Current EPT (LS) | 53,034 | 306 | 1.60 (1.38, 1.85) | 1.55 (1.34, 1.80) |
| Current EPT (CC) | 79,871 | 552 | 1.89 (1.67, 2.14) | 1.83 (1.61, 2.08) |
| P trend | p = 0.0113 * | |||
| Duration effects by most commonly used EPT regimen** | ||||
| Never used any HT | 120,039 | 493 | 1 [Reference] | 1 [Reference] |
| Current SS (≤ 5 yrs) | 27,571 | 133 | 1.49 (1.22, 1.81) | 1.42 (1.16, 1.75) |
| Current SS (6-14 yrs) | 19,489 | 128 | 1.67 (1.38, 2.04) | 1.62 (1.33, 1.98) |
| Current SS (l5+ yrs) | 3,450 | 28 | 1.87 (1.28, 2.74) | 1.85 (1.26, 2.72) |
| P trend | p < 0.0001 | |||
| Current LS (≤ 5 yrs) | 30,121 | 154 | 1.54 (1.27, 1.85) | 1.47 (1.21, 1.78) |
| Current LS (6-14 yrs) | 18,278 | 118 | 1.62 (1.32, 1.98) | 1.58 (1.29, 1.94) |
| Current LS (l5+ yrs) | 3,307 | 27 | 1.85 (1.25, 2.72) | 1.88 (1.27, 2.78) |
| P trend | p < 0.0001 | |||
| Current CC (≤ 5 yrs) | 49,130 | 308 | 1.81 (1.56, 2.10) | 1.72 (1.48, 2.00) |
| Current CC (6-14 yrs) | 25,680 | 202 | 1.97 (1.67, 2.32) | 1.93 (1.63, 2.29) |
| Current CC (15+ yrs) | 3,113 | 26 | 1.89 (1.28, 2.81) | 1.92 (1.29, 2.86) |
| P trend | p < 0.0001 | |||
Abbreviations: RR, relative risk; CI, confidence interval; HT, hormone therapy; EPT, estrogen-progestin combination hormone therapy; SS, short sequential EPT regimen; LS, long sequential EPT regimen; CC, continuous combined EPT regimen; YRS, years
The classification of EPT was based on the woman's report at baseline of the usual number of days of progestin per month. The SS, LS and CC categories are mutually exclusive categories. Women who could not be classified into these categories were included in the model as a separate category of “use of other/unknown HT”, but results are not presented in the table.
Age (days) is used as the time metric for the Cox proportional hazards models; models are stratified by age (at completion of the baseline questionnaire).
Stratified by age and adjusted for categories of race, family history of breast cancer, BMI, smoking, alcohol consumption, mammographic screening, parity and age at full term pregnancy, age at menopause, age at menarche, and history of breast biopsy
These p for trend values are amongst users of EPT
Total duration of use of all regimens, i.e. current SS users of 15+ years include those women who at baseline reported they were current users of a SS EPT, and who have in total used EPT (any regimen) for 15+ years.
Effect modification of risks by BMI and other risk factors
The dose-response relationships between duration of EPT and of ET use and risk for invasive breast cancer appeared to be modified by BMI. Both the magnitude and trend in risk estimates diminished as BMI increased from <25.0 to >30.0 kg/m2 (Table 5). However, these apparent effect modifications by BMI were not statistically significant (P values for effect modification by BMI of the ET and EPT effects were both > 0.20). We observed no statistically significant evidence to indicate effect modification of any associations by level of alcohol intake, parity, or mammographic screening within the last two years (p values > 0.25; results not shown).
Table 5.
Relative risk of breast cancer associated with HT use assessed at baseline stratified by body mass index.
| Body mass index at baseline (kg/m2)† |
||||||
|---|---|---|---|---|---|---|
| Hormone therapy use assessed at baseline | <25.0 (n=30,474) RR (95% CI) | 25.0-30.0 (n=15,440) RR (95% CI) | >30 (n=8,154) RR (95% CI) | |||
| Duration of current HT use‡ | CASES | CASES | CASES | |||
| Never used any HT | 212 | 1 [Reference] | 150 | 1 [Reference] | 97 | 1 [Reference] |
| Past ET or EPT | 128 | 1.00 (0.80, 1.25) | 104 | 1.13 (0.87, 1.45) | 58 | 1.11 (0.80, 1.54) |
| | ||||||
| Current ET (≤ 5yrs) | 73 | 1.33 (1.01, 1.75) | 36 | 0.94 (0.65, 1.37) | 34 | 1.48 (0.98, 2.23) |
| Current ET (6-14 yrs) | 123 | 1.46 (1.16, 1.84) | 54 | 0.97 (0.70, 1.34) | 31 | 1.17 (0.76, 1.79) |
| Current ET (15+ yrs) | 146 | 1.36 (1.08, 1.70) | 92 | 1.43 (1.08, 1.90) | 33 | 1.11 (0.73, 1.70) |
| P trend § | p = 0.0038 | p = 0.0309 | p = 0.5690 | |||
| | ||||||
| Current EPT (≤ 5 yrs) | 350 | 1.74 (1.45, 2.10) | 167 | 1.47 (1.15, 1.88) | 79 | 1.54 (1.10, 2.15) |
| Current EPT (6-14 yrs) | 267 | 1.86 (1.54, 2.24) | 143 | 1.83 (1.44, 2.32) | 40 | 1.47 (1.00, 2.15) |
| Current EPT (15+ yrs) | 54 | 2.14 (1.58, 2.91) | 25 | 1.90 (1.24, 2.93) | 4 | 1.21 (0.44, 3.34) |
| P trend § | p < 0.0001 | p < 0.0001 | p = 0.1105 | |||
| | ||||||
| PT (past or present) | 14 | 1.22 (0.70, 2.11) | 9 | 1.24 (0.62, 2.50) | 9 | 1.37 (0.67, 2.78) |
Abbreviations: HT, hormone therapy; ET, estrogen hormone therapy; PT, progestin hormone therapy; EPT, estrogen-progestin combination hormone therapy; YRS, years
Stratified by age and adjusted for categories of race, family history of breast cancer, BMI (except for BMI stratified analysis), smoking, alcohol consumption, mammographic screening, parity and age at full term pregnancy, age at menopause, age at menarche, and history of breast biopsy
Women who could not be classified into these exposure categories were included in the model as a separate category of “use of other/unknown HT”, but were not presented.
Trend tests exclude past users
Risks according to breast cancer subtype
We examined risks separately by ER/PR receptor status of tumor as well as by a combined ER/PR/HER2 classification scheme (Table 6). The associations with current ET use and current EPT use were statistically significant only for tumors that were ER+PR+. Compared to non-HT users, women with 15+ years of ET who were current users were at a 33% increased risk (95% CI, 1.08-1.66; Ptrend =0.0036) while women with 15+ years of EPT use had an 84% increased risk of breast cancer (95% CI, 1.32-2.56; Ptrend < 0.0001). The risk associated with current EPT was even stronger for ER+PR+ tumors that over-expressed HER2, but the numbers for this subtype-specific analysis were limited. Specifically, long duration of EPT use among current users was most strongly associated with breast cancer tumors that were either ER+ or PR+ and HER2+, where women who were current users with 15+ years of EPT had more than a two and a half-fold risk elevation compared to hormone never users (RR, 2.64; 95% CI, 1.07-6.53; Ptrend =0.02). There was no evidence that long duration of current EPT use was associated with triple negative (ER-PR-HER2-) tumors.
Table 6.
Relative risk of subtypes of breast cancer defined by hormone receptors associated with HT use assessed at baseline.†
| Tumor ER/PR Receptor Status‡ |
Tumor ER/PR/HER2 Receptor Status* |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hormone therapy variable | ER- and PR- (n=339) RR (95% CI) | ER+ and PR- (n=338) RR (95% CI) | ER+ and PR+ (n=1647) RR (95% CI) | ER-, PR-, and HER2- (n=121) RR (95% CI) | ER+ or PR+ w/ HER2- (n=949) RR (95% CI) | ER+ or PR+ w/ HER2+ (n=181) RR (95% CI) | ||||||
| Duration of HT use** | CASES | CASES | CASES | CASES | CASES | CASES | ||||||
| Never used any HT | 72 | 1 [Reference] | 71 | 1 [Reference] | 261 | 1 [Reference] | 25 | 1 [Reference] | 159 | 1 [Reference] | 26 | 1 [Reference] |
| Past ET or EPT | 42 | 1.02 (0.69, 1.50) | 30 | 0.72 (0.46, 1.10) | 169 | 1.09 (0.90, 1.33) | 14 | 1.01 (0.52, 1.95) | 103 | 1.09 (0.85, 1.40) | 21 | 1.47 (0.82, 2.62) |
| | ||||||||||||
| Current ET (≤ 5yrs) | 18 | 0.82 (0.48, 1.40) | 14 | 0.76 (0.42, 1.38) | 90 | 1.49 (1.16, 1.90) | 7 | 0.88 (0.37, 2.11) | 47 | 1.19 (0.85, 1.66) | 9 | 1.35 (0.62, 2.96) |
| Current ET (6-14yrs) | 24 | 0.82 (0.50, 1.33) | 35 | 1.43 (0.93, 2.20) | 128 | 1.43 (1.15, 1.79) | 11 | 1.01 (0.48, 2.15) | 75 | 1.30 (0.97, 1.73) | 19 | 2.08 (1.11, 3.87) |
| Current ET (15+ yrs) | 35 | 1.13 (0.73, 1.77) | 35 | 1.21 (0.78, 1.88) | 150 | 1.33 (1.08, 1.66) | 11 | 1.02 (0.46, 2.23) | 83 | 1.20 (0.90, 1.59) | 11 | 1.06 (0.50, 2.25) |
| P trend § | p = 0.7830 | p = 0.1586 | p = 0.0036 | p = 0.8926 | p = 0.1104 | p = 0.3711 | ||||||
| | ||||||||||||
| Current EPT (≤ 5 yrs) | 66 | 0.96 (0.66, 1.40) | 65 | 1.12 (0.77, 1.62) | 381 | 1.95 (1.64, 2.32) | 27 | 1.04 (0.57, 1.91) | 229 | 1.77 (1.41, 2.21) | 41 | 2.10 (1.23, 3.60) |
| Current EPT (6-14 yrs) | 42 | 0.98 (0.66, 1.46) | 42 | 1.07 (0.72, 1.60) | 301 | 2.21 (1.86, 2.64) | 14 | 0.90 (0.45, 1.77) | 155 | 1.80 (1.42, 2.27) | 27 | 1.99 (1.13, 3.49) |
| Current EPT (15+ yrs) | 9 | 1.41 (0.70, 2.86) | 9 | 1.39 (0.69, 2.82) | 42 | 1.84 (1.32, 2.56) | 1 | 0.46 (0.06, 3.47) | 29 | 2.07 (1.38, 3.09) | 6 | 2.64 (1.07, 6.53) |
| P trend § | p = 0.6422 | p = 0.6398 | p < 0.0001 | p = 0.4875 | p < 0.0001 | p = 0.0243 | ||||||
| | ||||||||||||
| PT (past or present) | 7 | 1.28 (0.57, 2.86) | 4 | 0.92 (0.33, 2.57) | 18 | 1.40 (0.86, 2.27) | 2 | 0.99 (0.22, 4.36) | 10 | 1.16 (0.61, 2.22) | 3 | 1.93 (0.56, 6.60) |
Abbreviations: HT, hormone therapy; ET, estrogen hormone therapy; PT, progestin hormone therapy; EPT, estrogen-progestin combination hormone therapy; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; TPN, triple negative tumor (ER-/PR-/HER2-)
Stratified by age and adjusted for categories of race, family history of breast cancer, BMI, smoking, alcohol consumption, mammographic screening, parity and age at full term pregnancy, age at menopause, age at menarche, and history of breast biopsy and additionally adjusted for use of other/unknown HT
Trend tests exclude past users
Analysis excludes 406 tumors with unknown receptor status as well as 20 tumors classified as ER-/PR+
Analysis excludes 1,533 tumors with unknown HER2 status, an additional 10 with unknown ER or PR status as well as 63 tumors with ER-/PR- and HER2+.
Women who could not be classified into these exposure categories were included in the model as a separate category of “use of other/unknown HT”, but were not presented.
When considering breast tumor size, we found that current EPT use was associated with increased risk of tumors irrespective of size, while current ET use was only associated with small (<1 cm) or large (>5 cm) breast tumors although the number of large breast tumors among current ET users was small (n=21) (Supplementary Table 1). Further, when categorizing breast tumors by histology, we found that the associations with ET and EPT use was similar for ductal (ICD-O code 8500) and lobular tumors (ICD-O code 8520), and somewhat stronger for tumors with mixed ductal and lobular histology (ICD-O code 8522), although the numbers for this subtype-specific analysis were limited (Supplementary Table 2).
Discussion
In this prospective observational study of California women, we found that cumulative measures of ET and EPT use assessed at study entry were associated with subsequent development of invasive breast cancer. Elevated risk was limited to women who were current HT users at baseline. The greatest risk elevations were seen among current long duration EPT users, but increased risk was also seen for ET users in most analyses.
In general our findings were consistent with those from previous studies describing an increased relative risk for breast cancer related to HT. We found a higher risk associated with ever use of menopausal hormones than some (1, 4, 12, 24) but not all (38, 39) studies. This likely reflects the fact that in the CTS, approximately 75% of ever HT users were current users at baseline; this is a higher fraction than seen in several other studies (1, 24). The fact that current users at baseline have higher risk than past users is consistent with previous studies reporting that increased risk due to HT diminishes with time since last use (1, 24, 36, 40).
The baseline questionnaire used to characterize HT use was completed in 1995-1996 while follow-up for breast cancer diagnoses continued through 2006. With the early termination of the WHI randomized controlled clinical trial in 2002, national trends in the prescription of EPT decreased markedly (14, 36). As a result of this change in practice, substantial misclassification of current HT use, as measured at study baseline, may have occurred. It is also possible that some of the perimenopausal women in our study commenced HT use after completing the baseline questionnaire. However, both types of misclassification are likely to have been non-differential with respect to the outcome, and hence would most likely have resulted in a bias towards the null in our findings for current HT use. Consistent with this, when we truncated follow-up after December 2002, we observed that the measured associations with current ET and EPT became stronger. On the other hand, there is an alternative explanation of the latter result. It could be that EPT users who decided to discontinue their HT use in 2002 may have had higher risk of developing breast cancer compared to women who used EPT at baseline and continued EPT after 2002. Since we did not have information on reason for stopping EPT in 2002, we cannot address this issue.
We found evidence of a dose-response pattern with the cumulative duration of ET and EPT use measured at baseline. A number of previous studies have found a dose-response pattern in the duration of EPT use, although our findings were somewhat stronger than some (1) but not all previous studies (24, 38, 39). It is possible that we may have underestimated the duration women have used EPT or ET as a result of continued use after baseline at least until 2002. Consequently, some of the women contributing to the hazard estimate for current short duration EPT or ET use may in fact be longer duration current users.
Our findings are consistent with previous studies suggesting a stronger effect of EPT than ET on the risk for breast cancer (1, 6, 7, 24). This can be explained by an increased mitogenic effect of progesterone in the breast tissue (4, 6). In our study, when EPT use was categorized by the usual number of days per month progestin was taken, we saw that the risk of breast cancer increased with the number of days per month the progestin component was used. These findings would support the growing evidence that continuous-combined EPT elevates breast cancer risk more than short or long sequential regimens (SS or LS) of EPT (2, 8, 23, 24, 40). However, some observational studies, including one from Los Angeles (6), have shown a lower relative risk associated with use of CC EPT regimens than with sequential regimens and this remains a point for further investigation.
While the risk estimates associated with overall ET use in this study are similar to those of some previous studies (1, 41), our estimates for the risk associated with current ET use, particularly for the short duration of use, were somewhat higher than some studies (7, 42). This observation was not due to past EPT use, as seen in the analysis restricted to ET only users. Further, to better understand this finding, we confirmed that women who reported changing from EPT to ET use had largely (84%) done so after hysterectomy. This proportion of women who had undergone hysterectomy was substantially higher than those observed among never users of HT (13%) and women who changed from ET to EPT (17%). Another possible explanation for the risk estimates we observed for long duration of ET use could involve longer true duration of ET use among the current users than indicated in the baseline questionnaire resulting in an upward bias in the RR estimates.
A collaborative reanalysis of the effect of HT on breast cancer risk reported increased HT-related breast cancer risk in postmenopausal women with lower BMI (1). This effect modification by BMI has been corroborated by subsequent studies (2, 7, 25-28). Our findings, although not statistically significant, are consistent with these previous studies in that the relative risks for ET and EPT by duration were stronger in women with lower BMI. In the absence of endogenous ovarian hormones, peripheral aromatase activity in the fat tissue is the primary source of circulating estrogens (43). Therefore, in the absence of significant adipose-derived estrogen, in women with low BMI, we would expect to see stronger breast cancer risk related to HT use.
Previous studies have shown the strongest associations between HT and hormone receptor positive breast tumors (10, 29, 44). Accordingly, we found elevated risk associated with current ET and current EPT only in breast tumors that were ER+ and PR+. Interestingly, the point estimates were slightly higher for the subset of tumors that were ER+ or PR+ and HER2+, but this may be a statistical fluke as the numbers for this subtype-specific analysis were very limited since information on HER2 status was not recorded in the cancer registry records until the year 2000. Risk was not elevated in triple-negative breast tumors and this is consistent with other studies (45) and is clinically relevant, given the poor prognosis associated with these tumors (32, 46).
In this study the EPT association was of similar magnitude and trend across all tumor sizes, while the association with long duration ET seemed to be confined to tumors between 1 and 5 cm. This is consistent with the reported findings of some (47) but not all previous studies (10). The persistence of association in larger tumor sizes suggests that the increased risk associated with both ET and EPT use cannot only be due to increased screening in HT users. The findings with respect to histology are similar to what has been reported previously, the association with EPT seems to be strongest for cancers with a lobular component (10, 47, 48).
An important limitation of our analysis includes the characterization of HT use at cohort entry only, as it is clear that the most correct assessment of a woman's HT use during this time period 1995-2006 would have necessitated frequent assessments of HT use and analyses taking into account repeated measures over time. We were also limited by the numbers of women with complete data needed for some subtype analyses, as there were substantial numbers of women with missing information regarding HER2, which was not collected widely for breast cancers of all stages until the year 2005.
Strengths of the presented findings include the CTS prospective cohort design, and the large number of participants. Detailed information on reproductive variables, including the use of HT, provided an opportunity to find associations by duration and formulation. Breast cancer case ascertainment was through linkage with the highly complete California Cancer Registry. The relative uniformity of the cohort with respect to education is another strength, as is the high rate of medical insurance coverage among the women comprising the CTS, ensuring similar access to health care and mammographic screening. The relatively high rate of HT use resulted in substantial power to detect effects of long-term HT use.
Conclusions
In our observational study, we found an overall increase in breast cancer risk associated with both ET and EPT use after an average of 9.8 years of follow-up, although the risk was stronger for EPT use. Both HT formulations show increasing risk associated with recent as compared to prior use, and with increasing duration of total use. The individual characteristics of a woman taking HT, such as her BMI, as well as the specific regimen of HT a woman uses, may modify the extent to which a woman's risk for breast cancer is elevated as well as the receptor profile for the malignancy. These findings, taken in context of the larger literature on this topic, continue to underscore the need to personalize risk-benefit discussions for women contemplating use of HT.
Supplementary Material
Acknowledgments
We acknowledge the late Dr. Ronald Ross for his major contribution in establishing the California Teachers Study cohort. We also acknowledge the entire CTS project team for their efforts.
This research was supported by grants R01 CA77398, K05 CA136967 and P01 CA017054 from the National Cancer Institute and contract 97-10500 from the California Breast Cancer Research Fund. The funding sources did not contribute to the design or conduct of the study, nor to the writing or submission of this manuscript. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors and endorsement by the State of California, Department of Health Services, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred.
References
- 1.Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047–59. [PubMed] [Google Scholar]
- 2.Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I. Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer. 1999;81:339–44. doi: 10.1002/(sici)1097-0215(19990505)81:3<339::aid-ijc5>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
- 3.Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control. 1999;10:253–60. doi: 10.1023/a:1008909128110. [DOI] [PubMed] [Google Scholar]
- 4.Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. American journal of epidemiology. 2000;152:950–64. doi: 10.1093/aje/152.10.950. [DOI] [PubMed] [Google Scholar]
- 5.Rockhill B, Colditz GA, Rosner B. Bias in breast cancer analyses due to error in age at menopause. Am J Epidemiol. 2000;151:404–8. doi: 10.1093/oxfordjournals.aje.a010220. [DOI] [PubMed] [Google Scholar]
- 6.Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. Journal of the National Cancer Institute. 2000;92:328–32. doi: 10.1093/jnci/92.4.328. [DOI] [PubMed] [Google Scholar]
- 7.Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485–91. doi: 10.1001/jama.283.4.485. [DOI] [PubMed] [Google Scholar]
- 8.Weiss LK, Burkman RT, Cushing-Haugen K, et al. Hormone replacement therapy regimens and breast cancer risk. Obstet Gynecol. 2002;100:1148–58. doi: 10.1016/s0029-7844(02)02502-4. [DOI] [PubMed] [Google Scholar]
- 9.Olsson HL, Ingvar C, Bladstrom A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer. 2003;97:1387–92. doi: 10.1002/cncr.11205. [DOI] [PubMed] [Google Scholar]
- 10.Ursin G, Tseng CC, Paganini-Hill A, et al. Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer? Journal of clinical oncology. 2002;20:699–706. doi: 10.1200/JCO.2002.20.3.699. [DOI] [PubMed] [Google Scholar]
- 11.Colditz GA. Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin Cancer Res. 2005;11:909s–17s. [PubMed] [Google Scholar]
- 12.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321–33. doi: 10.1001/jama.288.3.321. [DOI] [PubMed] [Google Scholar]
- 13.Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243–53. doi: 10.1001/jama.289.24.3243. [DOI] [PubMed] [Google Scholar]
- 14.Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy. Annual trends and resposne to recent evidence. JAMA. 2004;291:47–53. doi: 10.1001/jama.291.1.47. [DOI] [PubMed] [Google Scholar]
- 15.Stefanick ML. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med. 2005;118(Suppl 12B):64–73. doi: 10.1016/j.amjmed.2005.09.059. [DOI] [PubMed] [Google Scholar]
- 16.Hing E, Brett KM. Changes in U.S. prescribing patterns of menopausal hormone therapy, 2001-2003. Obstet Gynecol. 2006;108:33–40. doi: 10.1097/01.AOG.0000220502.77153.5a. [DOI] [PubMed] [Google Scholar]
- 17.Coombs NJ, Cronin KA, Taylor RJ, Freedman AN, Boyages J. The impact of changes in hormone therapy on breast cancer incidence in the US population. Cancer Causes Control. 2009 doi: 10.1007/s10552-009-9437-5. [DOI] [PubMed] [Google Scholar]
- 18.MacLennan AH, Gill TK, Broadbent JL, Taylor AW. Continuing decline in hormone therapy use: population trends over 17 years. Climacteric. 2009;12:122–30. doi: 10.1080/13697130802666251. [DOI] [PubMed] [Google Scholar]
- 19.Verkooijen HM, Bouchardy C, Vinh-Hung V, Rapiti E, Hartman M. The incidence of breast cancer and changes in the use of hormone replacement therapy: a review of the evidence. Maturitas. 2009;64:80–5. doi: 10.1016/j.maturitas.2009.07.015. [DOI] [PubMed] [Google Scholar]
- 20.Hausauer AK, Keegan TH, Chang ET, Glaser SL, Howe H, Clarke CA. Recent trends in breast cancer incidence in US white women by county-level urban/rural and poverty status. BMC Med. 2009;7:31. doi: 10.1186/1741-7015-7-31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Birkhauser MH, Reinecke I. Current trends in hormone replacement therapy: perceptions and usage. Climacteric. 2008;11:192–200. doi: 10.1080/13697130802060455. [DOI] [PubMed] [Google Scholar]
- 22.Daling JR, Malone KE, Doody DR, et al. Relation of regimens of combined hormone replacement therapy to lobular, ductal and other histologic types of breast carcinoma. Cancer. 2002;95:2455–64. doi: 10.1002/cncr.10984. [DOI] [PubMed] [Google Scholar]
- 23.Stahlberg C, Pedersen AT, Lynge E, et al. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer. 2004;109:721–7. doi: 10.1002/ijc.20016. [DOI] [PubMed] [Google Scholar]
- 24.Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–27. doi: 10.1016/s0140-6736(03)14065-2. [DOI] [PubMed] [Google Scholar]
- 25.Reeves GK, Beral V, Green J, Gathani T, Bull D. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol. 2006;7:910–8. doi: 10.1016/S1470-2045(06)70911-1. [DOI] [PubMed] [Google Scholar]
- 26.Pike MC, Wu AH, Spicer DV, Lee S, Pearce CL. Estrogens, progestins, and risk of breast cancer. Ernst Schering Found Symp Proc. 2007:127–50. doi: 10.1007/2789_2007_059. [DOI] [PubMed] [Google Scholar]
- 27.Brinton LA, Richesson D, Leitzmann MF, et al. Menopausal Hormone Therapy and Breast Cancer Risk in the NIH-AARP Diet and Health Study Cohort. Cancer Epidemiol Biomarkers Prev. 2008;17:3150–60. doi: 10.1158/1055-9965.EPI-08-0435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study. American journal of epidemiology. 2008;167:1407–15. doi: 10.1093/aje/kwn090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Chen WY, Hankinson SE, Schnitt SJ, Rosner BA, Holmes MD, Colditz GA. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer. 2004;101:1490–500. doi: 10.1002/cncr.20499. [DOI] [PubMed] [Google Scholar]
- 30.Chen WY, Colditz GA. Risk factors and hormone-receptor status: epidemiology, risk-prediction models and treatment implications for breast cancer. Nat Clin Pract Oncol. 2007;4:415–23. doi: 10.1038/ncponc0851. [DOI] [PubMed] [Google Scholar]
- 31.Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007;109:1721–8. doi: 10.1002/cncr.22618. [DOI] [PubMed] [Google Scholar]
- 32.Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008;52:108–18. doi: 10.1111/j.1365-2559.2007.02889.x. [DOI] [PubMed] [Google Scholar]
- 33.Rakha EA, Ellis IO. Triple-negative/basal-like breast cancer: review. Pathology. 2009;41:40–7. doi: 10.1080/00313020802563510. [DOI] [PubMed] [Google Scholar]
- 34.Bernstein L, Allen M, Anton-Culver H, et al. High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States). Cancer Causes Control. 2002;13:625–35. doi: 10.1023/a:1019552126105. [DOI] [PubMed] [Google Scholar]
- 35.Rothman K, Greenland S. Modern Epidemiology. 2nd ed. Lippincott Williams & Wilkins; Philadelphia: 1998. [Google Scholar]
- 36.Chlebowski RT, Kuller LH, Prentice RL, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360:573–87. doi: 10.1056/NEJMoa0807684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Hosmer D, Lemeshow S, May S. Applied Survival Analysis: Regression Modeling of Time to Event Data. 2nd ed. John Wiley & Sons, Inc.; New Jersey: 2008. [Google Scholar]
- 38.Bakken K, Alsaker E, Eggen AE, Lund E. Hormone replacement therapy and incidence of hormone-dependent cancers in the Norwegian Women and Cancer study. Int J Cancer. 2004;112:130–4. doi: 10.1002/ijc.20389. [DOI] [PubMed] [Google Scholar]
- 39.Hofvind S, Moller B, Thoresen S, Ursin G. Use of hormone therapy and risk of breast cancer detected at screening and between mammographic screens. Int J Cancer. 2006;118:3112–7. doi: 10.1002/ijc.21742. [DOI] [PubMed] [Google Scholar]
- 40.Lee SA, Ross RK, Pike MC. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer. 2005;92:2049–58. doi: 10.1038/sj.bjc.6602617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol. 2004;190:1141–67. doi: 10.1016/j.ajog.2003.09.033. [DOI] [PubMed] [Google Scholar]
- 42.Newcomb PA, Titus-Ernstoff L, Egan KM, et al. Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:593–600. [PubMed] [Google Scholar]
- 43.Cleland WH, Mendelson CR, Simpson ER. Effects of aging and obesity on aromatase activity of human adipose cells. J Clin Endocrinol Metab. 1985;60:174–7. doi: 10.1210/jcem-60-1-174. [DOI] [PubMed] [Google Scholar]
- 44.Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003;289:3254–63. doi: 10.1001/jama.289.24.3254. [DOI] [PubMed] [Google Scholar]
- 45.Phipps AI, Malone KE, Porter PL, Daling JR, Li CI. Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer. Cancer. 2008;113:1521–6. doi: 10.1002/cncr.23786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–34. doi: 10.1158/1078-0432.CCR-06-1109. [DOI] [PubMed] [Google Scholar]
- 47.Li CI, Malone KE, Porter PL, et al. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev. 2008;17:43–50. doi: 10.1158/1055-9965.EPI-07-0558. [DOI] [PubMed] [Google Scholar]
- 48.Li CI, Daling JR, Malone KE, et al. Relationship between established breast cancer risk factors and risk of seven different histologic types of invasive breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:946–54. doi: 10.1158/1055-9965.EPI-05-0881. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.