Catherine Schairer

The Risk of Breast Cancer after Estrogen and Estrogen–Progestin Replacement

To examine the risk of breast cancer after noncontraceptive treatment with estrogen, we conducted a prospective study of 23,244 women 35 years of age or older who had had estrogen prescriptions filled in the Uppsala region of Sweden. During the follow-up period (mean, 5.7 years) breast cancer developed in 253 women. Compared with other women in the same region, the women in the estrogen cohort had an overall relative risk of breast cancer of 1.1 (95 percent confidence interval, 1.0 to 1.3). The relative risk increased with the duration of estrogen treatment (P = 0.002), reaching 1.7 after nine years (95 percent confidence interval, 1.1 to 2.7). Estradiol (used in 56 percent of the treatment periods in the cohort) was associated with a 1.8-fold increase in risk after more than six years of treatment (95 percent confidence interval, 0.7 to 4.6). No increase in risk was found after the use of conjugated estrogens (used in 22 percent of the treatment periods) or other types, mainly estriols (used in 22 percent of the treatment periods). Although the numbers of women were smaller, the risk of breast cancer was highest among the women who took estrogen and progestin in combination for extended periods. The relative risk was 4.4 (95 percent confidence interval, 0.9 to 22.4) in women who used only this combination for more than six years. Among women who had previously used estrogens alone, the relative risk after three years or more of use of the combination regimen was 2.3 (95 percent confidence interval, 0.7 to 7.8). We conclude that in this cohort, long-term perimenopausal treatment with estrogens (or at least estradiol compounds) seems to be associated with a slightly increased risk of breast cancer, which is not prevented and may even be increased by the addition of progestins.

Cancer incidence and mortality in women receiving estrogen and estrogen‐progestin replacement therapy—long‐term follow‐up of a Swedish cohort

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow‐up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen‐progestin combined brand was associated with an increasing relative risk of breast cancer with follow‐up time, the SIR reaching 1.4 (95% CI 1.1–1.8) after 10 years of follow‐up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6–5.9) in women prescribed estrogens alone, whereas those given an estrogen‐progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol‐progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow‐up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow‐up time. We conclude that hormone replacement increases the endometrial‐cancer risk after unopposed estrogens and the breast‐cancer risk—notably after estrogen‐progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.

Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PURPOSE Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Menstrual Factors and Risk of Breast Cancer

A case control study of 2,908 breast cancer cases and 3,180 controls, derived from a nationwide screening program, enabled evaluation of the relationship of breast cancer risk to a variety of menstrual factors. Risk was significantly inversely related to age at menarche, with women who first menstruated at age 15 or later having a 23% lower risk than those with menarche prior to the age of 12. There was a higher relative risk (1.3) for premenopausal than menopausal women. In contrast to previous studies, there was only a slight increase in risk associated with a late age at natural menopause, possibly owing to errors in recall. Bilateral oophorectomy at an early age exerted a protective influence on breast cancer risk, with effects manifested approximately 10 to 15 years after oophorectomy. Women who had both ovaries removed prior to the age of 40 had a 45% reduced risk compared to women with a natural menopause at ages 50 to 54. In addition, bilateral oophorectomy at an early age was associated with a lowered risk relative to natural menopause at a comparable age, which may reflect the more pronounced and sudden decline in endogenous hormones associated with the surgery. Although these results were based on patient reports regarding the types of surgical menopause experienced, validation against medical records showed close correspondence regarding the number of ovaries removed.

Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults

IMPORTANCE Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. OBJECTIVE To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015. EXPOSURES Leisure-time physical activity of a moderate to vigorous intensity. MAIN OUTCOMES AND MEASURES Incident cancer during follow-up. RESULTS A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. CONCLUSIONS AND RELEVANCE Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

Obesity and Thyroid Cancer Risk among U.S. Men and Women: A Pooled Analysis of Five Prospective Studies

Background: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain. Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex. Results: Over follow-up (mean = 10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08–1.24); HR in men, 1.21 (95% CI, 0.97–1.49)]. There was no significant heterogeneity between studies (both P > 0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5–24.9 kg/m2) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03–1.35)]. Conclusion: BMI was positively associated with thyroid cancer risk in both men and women. Impact: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. Cancer Epidemiol Biomarkers Prev; 20(3); 464–72. ©2011 AACR.

Evidence of a healthy estrogen user survivor effect.

We examined the relation between menopausal estrogen use and all-cause and cause-specific mortality in a cohort of over 49,000 women followed between 1979 and 1989 in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-Up Study. We found a lower all-cause mortality rate among women who took estrogens [rate ratio (RR) = 0.7; 95% confidence interval (CI) = 0.7–0.8], particularly current users (RR = 0.3; 95% CI = 0.2–0.4), than among women who never took them. Additional analyses, however, revealed that women who had recently stopped taking estrogens had a higher all-cause mortality rate than women who had never taken them (RR = 1.4; 95% CI = 1.2–1.7). Women who had recently stopped taking estrogens also had higher mortality rates from circulatory disease (RR = 1.3; 95% CI = 1.0–1.8) and cancer (RR = 1.6; 95% CI = 1.2–2.2) than women who never took them. The most likely explanation for these results is that women stop taking estrogens when they develop symptoms of serious illness. As a consequence of this “healthy estrogen user survivor effect,” nonexperimental studies are susceptible to overestimating the benefits of menopausal estrogen use, particularly current use, on mortality.

Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States).

This study examines the relationship between menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer, focusing on whether associations differ according to whether the tumors arein situ or invasive. Data are from a prospective study conducted 1980–89 on 49,017 selected participants in the Breast Cancer Detection Demonstration Project, a five-year screening program conducted between 1973 and 1980 in the United States. Overall, the rate ratio for estrogen-only use compared with no-hormone use was 1.0, and that for the estrogen-progestin combination was 1.2 (95 percent confidence interval [CI]=1.0–1.6). However, the associations differed according to whether the tumors werein situ or invasive. The rate ratios ofin situ breast cancer associated with use of estrogens alone and the combination regimen were 1.4 (CI=1.0–2.0) and 2.3 (CI=1.3–3.9), respectively. Duration of estrogen-only use also was associated with risk ofin situ tumors, with users for 10 or more years at twice the risk of nonusers (P-value for trend test =0.02). Duration of use was not associated with risk of in vaisve cancer. Our results are consistent with the hypothesis that hormone replacement therapy is related to earlier-stage breast cancer; however, the possibility that the results reflect increased breast cancer surveillance among those taking hormones cannot be ruled out.

Breast cancer risk associated with gynecologic surgery and indications for such surgery

Risk of breast cancer was assessed in relationship to gynecologic operations using data from a record‐linkage study involving 15,844 women in the Uppsala Health Care Region of Sweden, who underwent surgery between 1965 and 1983. Data abstracted from medical records for the breast cancer cases and a random sample of the cohort allowed examination of risk associated with these operations in regard to menopausal status and indications for the operations. Among women who were pre‐menopausal at the time of operation, a bilateral oophorectomy before the age of 50 years was associated with a 50% reduction in the risk of breast cancer compared with the background population, a reduction in risk evident within 10 years of the operation. A bilateral oophorectomy after the age of 50 years in pre‐menopausal women or after a natural menopause was not associated with any reduction in risk. There were no reductions in risk associated with a unilateral oophorectomy or hysterectomy among women who were pre‐menopausal at the time of operation. In fact, hysterectomy alone was associated with a slight increase in breast cancer risk when the operation was due to myomas, abnormal bleeding, and, possibly, severe forms of endometriosis but not to other reasons. Risk did not vary substantially by indications for oophorectomy, including benign ovarian neoplasms and functional ovarian cysts, though endometriosis was associated with a non‐significant increase in breast cancer risk. Int. J. Cancer, 70:150–154, 1997.