Risk of endometrial cancer following estrogen replacement with and without progestins.

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.     

Hormone replacement therapy and endometrial cancer

Postmenopausal hormone replacement therapy (HRT) using unopposed estrogens significantly increases endometrial cancer risk and should not be used in non-hysterectomized women. Even low-potency estrogens (oral estriol) or low-dose unopposed estrogens significantly enhance the risk to develop endometrial cancer. This risk is markedly reduced, when in addition to estrogens, progestins are administered for at least 10 days (better 14 days) per month. In some studies, a normalization of endometrial cancer risk to that of women receiving no HRT was only found when a continuous combined estrogen/progestin replacement was used. The use of progestins for less than 10 days per month and long-cycle regimens, where a progestin is added only every 3 months cannot be recommended. For women needing HRT, estrogen dose should be selected as low as possible and reassessment of the need of HRT should be performed annually.     

A polymorphism in CYP17 and endometrial cancer risk

Among women, the A2 allele of CYP17 has been associated with elevated levels of endogenous steroid hormones; however, it does not seem to be a strong independent risk factor for breast cancer. We assessed the association between the A2 allele of CYP17 and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study cohort (cases: n = 184; controls: n = 554). We also evaluated whether endometrial cancer risk associated with CYP17 genotype was modified by established endometrial cancer risk factors. In addition, we further examined the relationship between CYP17 genotype and endogenous plasma steroid hormone levels among postmenopausal controls not using hormone replacement therapy (HRT). Women with the A2 allele of CYP17 were at decreased risk of endometrial cancer (A1/A1 genotype (reference); A1/A2 genotype: odds ratio, 0.89; 95% confidence interval, 0.62-1.27; A2/A2 genotype: odds ratio, 0.43; 95% confidence interval, 0.23-0.80; P trend, 0.02). We also observed the inverse association between the A2 allele and endometrial cancer risk to be stronger among women with a first-degree family history of endometrial and/or colorectal cancer (P for interaction, 0.05). Among 165 controls, we did not observe women with the A2 allele to have significantly elevated levels of any steroid hormone fraction. When these women were combined and analyzed with those women on whom we had previously examined the relationship between CYP17 genotype and circulating hormone levels (total n = 469), only modest associations were observed for the A2/A2 genotype and steroid hormone fractions estrone (versus A1/A1 genotype: +10.9%; P = 0.05) and estradiol (+8.5%; P = 0.17). These data suggest that the A2 allele of CYP17 decreases endometrial cancer risk, but has only weak effects on endogenous estrogen levels among postmenopausal women.     

Body mass and endometrial cancer risk by hormone replacement therapy and cancer subtype.

Epidemiologic studies unequivocally show that greater body mass increases the risk of endometrial cancer, but whether risk varies by use of postmenopausal hormone therapy (HT), location of fat deposition, or cancer subtype is still unclear. We examined these associations among 33,436 postmenopausal women in the Cancer Prevention Study II Nutrition Cohort, who completed questionnaires on diet, lifestyle, and medical history at baseline in 1992. A total of 318 cases were eligible through June 2003. Cox-proportional hazards analyses were used to estimate multivariate-adjusted rate ratios (RR). As expected, adult body mass index (BMI) was a strong predictor of risk [RR, 4.70; 95% confidence interval (CI), 3.12-7.07 for BMI 35+ versus 22.5-25.0, P trend < 0.0001]. Use of estrogen plus progestin postmenopausal HT modified the association. Among never-users, risk was significantly linear across the entire range of BMI examined (RR, 0.51; 95% CI, 0.29-0.92 for <22.5 versus 22.5-25.0; RR, 4.41; 95% CI, 2.70-7.20 for > or =35 versus 22.5-25.0, P trend < 0.0001), but among ever estrogen plus progestin users, the association was not significant (P trend = 1.0; P interaction < 0.0001). We observed no difference in risk according to tendency for central versus peripheral fat deposition. Greater BMI (> or =30 versus <25.0) increased risk of both "type I" (classic estrogen pathway, RR, 4.22; 95% CI, 3.07-5.81) and "type II" (serous, clear cell, and all other high grade) cancers (RR, 2.87; 95% CI, 1.59-5.16). The increased risk of endometrial cancer across the range of BMI in women who never used postmenopausal HT stresses the need to prevent both overweight and obesity in women.     

CYP17 and CYP19 genetic polymorphisms in endometrial cancer: association with intratumoral aromatase activity

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Allelic polymorphisms of the genes involved in steroidogenesis/steroid metabolism may contribute to EC susceptibility. It is important to know endocrine mechanisms by which such susceptibility is acquired. Here, we compared CYP19 (aromatase) and CYP17 (17alpha-hydroxylase/17,20-lyase) gene polymorphisms correspondingly in 136 and 165 EC patients and in 116 and 188 non-affected women primarily of postmenopausal age. In these expanded studies we confirmed our previous observations that genotypes with longest alleles of CYP19 (A6 or A7) are over-represented (64.7+/-4.0 vs. 49.1+/-4.6%, P = 0.04, and 11.0+/-2.7 vs. 1.7+/-1.2%, P = 0.01)) and A2/A2 CYP17 genotype is under-represented (12.1+/-2.5 vs. 25.0+/-3.2%, P = 0.001) in patients as compared to controls. Additionally, aromatase activity was studied by tritiated water release assay in tumor tissues of 32 EC patients. In carriers of A2/A2 CYP17 genotype this activity was significantly lower than in carriers of A1/A1 genotype or in combined group of A1/A1 and A1/A2 CYP17 carriers (P = 0.04 in both cases). On the other side, intratumoral aromatase activity demonstrated tendency to higher values in carriers of longest CYP19 alleles (A6A6 and A6A7) than in carriers of all other CYP19 allele variants (P = 0.066). Thus, specific set of genetic polymorphisms (carrying of CYP17 A1 allele and combination of longest A6 or A7 CYP19 alleles) may predispose to the induction of higher rate of local estrogen biosynthesis in malignant endometrium, that in its turn may support growth of the latter. Further studies are warranted to connect revealed regularities with the type I or II of EC.     

Hormone replacement therapy for survivors of breast and endometrial cancer

Indirect evidence suggests that endogenous and exogenous estrogen does not influence the outcome of patients treated for breast or endometrial cancer. However, many reports have affirmed beneficial effects of hormone replacement therapy (HRT) in preventing multiple disease states and improving the quality of life of individual patients. Every practitioner of urogynecology understands the benefits of local and systemic therapy to women who suffer from urinary incontinence and/or loss of pelvic floor support. Thus, it seems appropriate to suggest that survivors of breast or endometrial cancer who request information on HRT for relief of their menopausal symptoms and for other benefits, of which patients are becoming increasingly aware, deserve a comprehensive explanation.     

Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use

Tamoxifen is a selective estrogen receptor modulator that is used to treat and to prevent breast cancer; however, its use is associated with an increased risk of endometrial cancer. Tamoxifen is metabolized by various cytochrome P450 (CYP) enzymes, but predominantly by CYP3A4. In this study, we examined whether a genetic variant of the CYP3A4 gene, CYP3A4*1B, influences endometrial cancer risk--alone and when associated with tamoxifen exposure. We conducted a case-control study on 566 endometrial cancer cases and 964 ethnically matched controls. The variant CYP3A4 allele was present in 6% of the controls and 9% of the endometrial cancer patients (OR = 1.6, 95% CI = 1.1-2.3, P = 0.02). The allele was more common in women with endometrial cancer who had been treated with tamoxifen for breast cancer (16%). Women who carried the CYP3A4*1B allele had approximately 3-fold increase in the risk of developing endometrial cancer following tamoxifen treatment, compared with women who did not take tamoxifen (P = 0.004). These findings suggest that a subgroup of breast cancer patients who carry the CYP3A4*1B allele and take tamoxifen may be at increased risk of developing endometrial cancer.     

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. CONCLUSIONS: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.     

Risk of second breast cancer according to estrogen receptor status and family history

A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48–0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19–3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81–14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57–21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58–118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.     

Risk of cancer in women receiving hormone replacement therapy

Cancer risk following treatment with non-contraceptive estrogens was studied in a population-based cohort of 23,244 women. Complete follow-up for an average of 6.7 years revealed 1,087 incident cancers versus 962.5 expected (relative risk/RR/ = 1.13; 95% confidence interval 1.10-1.20). We confirmed the recent findings of a more detailed analysis of the same cohort, based on a 1-year shorter follow-up period, namely: a markedly increased risk of endometrial cancer (RR = 1.8; 1.5-2.1), notably in women receiving potent estrogens, i.e., conjugated estrogens or estradiol (RR = 2.0; 1.6-2.4), and a slightly increased risk of breast cancer (RR = 1.1; 1.0-1.2). A slightly decreased risk of invasive cervical cancer (RR = 0.8; 0.5-1.2) is most likely due to more frequent smear taking than in the background population. There was no increase in the risk of cancer of ovary (RR = 1.0; 0.8-1.2), pancreas (RR = 0.8; 0.5-1.2), large bowel (RR = 1.0; 0.8-1.2) or kidney (RR = 1.0; 0.7-1.4). The risk of developing cancer in liver or biliary tract was lower than expected (RR = 0.4; 0.2-0.7), particularly in women who had used potent estrogens (RR = 0.3; 0.1-0.6), an unexpected finding which warrants further studies. Increased risks of malignant melanoma (RR = 1.5; 1.0-2.1) and lung cancer (RR = 1.3; 0.9-1.7) need cautious interpretation because of their low magnitude, the absence of a biological gradient when subgroups were analyzed and the slightly higher prevalence of smokers in the cohort than in the background population.     

The CYP1B1_1358_GG genotype is associated with estrogen receptor-negative breast cancer

Cytochrome P450 1B1 (CYP1B1) is a major enzyme in the initial catabolic step of estradiol (E2) metabolism and belongs to the multitude of genes regulated by the estrogen receptor alpha (ERalpha). The common non-synonymous polymorphisms CYP1B1_1358_A>G and CYP1B1_1294_C>G increase CYP1B1 enzymatic activity. Given a relationship between CYP1B1 and breast tumor E2 level as well as E2 level and breast tumor ERalpha expression it is of interest to know whether CYP1B1 polymorphisms have an impact on the ERalpha status of breast cancer. We genotyped the GENICA population-based breast cancer case-control collection (1,021 cases, 1,015 controls) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and investigated in cases the association between genotypes and tumor ERalpha status (739 ERalpha positive cases; 212 ERalpha negative cases) by logistic regression. We observed a significant association between the homozygous variant CYP1B1_1358_GG genotype and negative ERalpha status (P = 0.005; OR 2.82, 95% CI: 1.37-5.82) with a highly significant Ptrend for CYP1B1_1358_A>G and negative ERalpha status (P = 0.003). We also observed an association of CYP1B1_1358_GG and negative PR status (P = 0.015; OR 2.36, 95% CI: 1.18-4.70) and a Ptrend of 0.111 for CYP1B1_1358_A>G and negative progesterone receptor (PR) status. We conclude that the CYP1B1_1358_A>G polymorphism has an impact on ERalpha status in breast cancer in that the CYP1B1_1358_GG genotype known to encode higher CYP1B1 activity is associated with ERalpha negativity.     

Breast cancer risk: effects of estrogen replacement therapy and body mass.

BACKGROUND: Epidemiologic studies have focused on the association between breast cancer risk and a variety of lifestyle and exogenous factors. PURPOSE: The purpose of this study was to clarify the effects of alcohol consumption, cigarette smoking, oral contraceptive (OC) use, estrogen replacement therapy (ERT), and body mass on risk of breast cancer. METHODS: These variables were examined in a case-control study of 604 patients with newly diagnosed breast cancer and 520 control subjects who did not have breast cancer and were frequency matched for age, hospital, and time of diagnosis. These case patients and control subjects were part of an ongoing study of breast cancer by the American Health Foundation and were selected for interview from hospitals in the New York City area from January 1987 through December 1989. The data were analyzed by computation of odds ratios (ORs) for potential risk factors, with adjustment for age at diagnosis and other potential confounding variables and with stratification by menopausal status. RESULTS: We observed positive effects of ERT and high body mass on the risk of postmenopausal breast cancer, particularly when each factor was examined in the absence of the other factor. In lean postmenopausal women, the adjusted summary OR associated with ERT was significantly elevated (OR = 2.0; 95% confidence interval [CI] = 1.1-3.5; P < .01), and there was a statistically significant dose response of breast cancer risk with ERT duration (adjusted ORs = 2.0 for < 5 years and 2.2 for > or = 5 years; positive trend, P < .02). Reciprocally, in women who did not receive ERT, high body mass (Quetelet index > 27) was a significant risk factor for postmenopausal breast cancer (OR = 2.1; 95% CI = 1.3-3.3; P < .02), and the linear trend in risk with increasing body mass was significant (positive trend, P < .02). The strongest effect of body mass occurred in women who were lean at age 18 and gained enough weight to place them in the upper tertile of body mass at the time of diagnosis (OR = 2.6; 95% CI = 1.5-4.6; P < .01). There was no evidence of significant positive associations between breast cancer risk and cigarette smoking, alcohol consumption, or OC use in any subgroup of these women. CONCLUSIONS: Our results support the hypothesis that excess adipose deposition heightens breast cancer risk in the postmenopausal years. Furthermore, they underscore the need for continuing investigation of the effects of exogenous estrogens on the development of this malignancy, particularly in lean postmenopausal women.     

Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy.

We investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with higher endogenous hormone levels, influences the use of hormone replacement therapy (HRT). The study included 749 postmenopausal women ages 44-75 years at baseline randomly selected from a larger multiethnic cohort. African-American, Japanese, Latina, and white women were included in the study. Women who carry the CYP17 A2/A2 genotype were about half as likely as women with the A1/A1 genotype to be current HRT users (odds ratio = 0.52; 95% confidence interval, 0.31-0.86). This association was present in all four racial/ethnic groups and for women above and below the median weight of 150 pounds. These findings suggest that the actual risk of breast cancer associated with HRT use may be higher than previously reported.     

CYP17A1 T-34C polymorphism is not associated with endometrial cancer risk

The association between CYP17A1 T-34C polymorphism and endometrial cancer risk has been inconsistent and underpowered. To clarify the effect of CYP17A1 T-34C polymorphism on the risk of endometrial cancer, a meta-analysis of all available studies relating CYP17A1 T-34C polymorphism to the risk of endometrial cancer was conducted. The authors searched PubMed, EMBASE, Scopus, and VisionCite databases updated on March 2013. Data were extracted by two independent authors and pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated. Finally, seven studies with 1,570 endometrial cancer cases and 2,474 controls were included in the meta-analysis. There was no statistically significant association between CYP17A1 T-34C polymorphism and endometrial cancer under heterogeneous codominant model (OR?=?0.91, 95 %CI?=?0.68–1.21). Although CYP17A1 T-34C polymorphism was marginally associated with endometrial cancer risk under homogeneous codominant model (OR?=?0.69, 95 %CI?=?0.49–0.99), the significant association was not stable after sensitivity analysis. We concluded that CYP17A1 T-34C polymorphism might not be one risk factor in the carcinogenesis of endometrial cancer. Further large and well-designed studies are needed to confirm this association.