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Purpose: To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting., Patients and Methods: We enrolled all postmenopausal patients diagnosed with stage I-III estrogen receptor positive breast cancer during the years 2007-2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure., Results: We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92-14.28] and 13.40 [95% CI 12.36-14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50-1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48-1.02])., Conclusions: Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Purpose: It has been hypothesized that selenium (Se) can prevent cancer, and that Se deficiency may be associated with an increased risk of breast cancer. However, findings from epidemiological studies have been inconsistent. The objective of this study was to assess the association between Se intake and risk of breast cancer in the Women's Health Initiative (WHI)., Methods: This study included 145,033 postmenopausal women 50-79 years who completed baseline questionnaires between October 1993 and December 1998, which addressed dietary and supplemental Se intake and breast cancer risk factors. The association between baseline Se intake and incident breast cancer was examined in Cox proportional hazards analysis., Results: During a mean follow-up of 15.5 years, 9487 cases of invasive breast cancer were identified. Total Se (highest versus lowest quartile: HR 1.00, 95% CI 0.92-1.09, P trend  = 0.66), dietary Se (highest versus lowest quartile: HR 0.99, 95% CI 0.89-1.08, P trend  = 0.61), and supplemental Se (yes versus no: HR 0.99, 95% CI 0.95-1.03) were not associated with breast cancer incidence., Conclusions: This study indicates that Se intake is not associated with incident breast cancer among postmenopausal women in the United States. Further studies are needed to confirm our findings by using biomarkers such as toenail Se to reduce the potential for misclassification of Se status.

Purpose: The incidence and predictors of diabetes (DM) in patients with breast cancer (BC) were evaluated. We compared DM incidence and physician access in BC patients to matched controls., Methods: We identified women with stage I-III BC diagnosed from 2005 to 2013 in the SEER-Medicare database, with ≥ 2 years of follow-up after diagnosis, without previous DM claims. Incident DM was determined by ≥ 1 DM claims after BC diagnosis. Multivariable analysis was used to identify factors associated with incident DM. Age- and race-matched non-cancer controls were obtained from a 5% random sample and assigned an index date. Physician and PCP visits per-patient-per-year were compared between cases and controls in the two-year period prior to and after the index date., Results: Among 14,506 eligible BC patients, 3234 (22.3%) developed DM versus 16.5% of controls. Among BC patients, factors associated with incident DM included race (Black OR 1.63 95% CI 1.39-1.93, Hispanic OR 3.03 95% CI 1.92-4.81; vs. Caucasians), SES (Quintile 0 vs. Quintile 4 OR 1.55 95% CI 1.33-1.78), and receipt of chemotherapy (vs. none OR 1.19 95% CI 1.08-1.31). Among cases and controls, respectively, median physician visits per-patient-per-year were 19 and 17 prior to the index date, and 46 and 19 after the index date; median PCP visits were 2 for both groups in both periods., Conclusion: About 22% of BC patients developed DM, more than controls in the same period. While there were differences in healthcare access, there weren't differences in PCP access between groups. This represents an opportunity for better comorbidity management in BC patients.

Background: The role of female sex hormones in the pathogenesis of malignant melanoma (MM) remains controversial. Although melanocytes appear to be hormonally responsive, the effect of estrogen on MM cells is less clear. Available clinical data does not consistently demonstrate that increased endogenous hormones from pregnancy or increased exogenous hormones from oral contraceptive pills and hormone replacement affect MM prevalence and outcome., Objective: We sought to examine potential associations between in vitro fertilization (IVF) and melanoma., Methods: A literature review was conducted. Primary outcomes were reported as associations between IVF and melanoma risk compared with the general population. Secondary outcomes included associations stratified by type of IVF regimen and subgroup, such as parous versus nulliparous patients., Results: Eleven studies met our inclusion criteria. Five studies found no increased risk for MM among IVF users compared with the general population. Two studies found an increase in MM in clomiphene users, and 4 studies found an increase in MM among patients who were gravid or parous either before or after IVF., Conclusion: The reviewed studies do not reveal consistent patterns of association between IVF and MM among all infertile women. However, the data indicates a potential increased risk for MM in ever-parous patients treated with IVF. High-quality studies including a large number of MM cases that control for well-established MM risk factors are needed to adequately assess the relationship between IVF and MM, particularly among ever-parous women., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I 2  = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables., (© 2016 UICC.)

Neuroendocrine carcinoma of the breast is an extremely rare tumor. A standard treatment has yet to be established because only a few cases have been reported in literature. The authors report five cases observed from January 2007 to December 2014 and a review of literature. Four patients underwent quadrantectomy and in two cases axillary nodal dissection and only one to mastectomy with axillary nodal dissection. Tumor size was from T1 to T2 with N0 to N1, according TNM classification. Pathological specimens were stained with hematoxylin and eosin and an immunohistochemical panel of antibodies (Neuron-specific enolase, Chromogranin, Synaptophysin, Estrogen and Progesterone receptors, c-erb and Ki-67). All cases showed markers positivity to Neuron-specific enolase, Chromogranin, Synaptophysin and Estrogen and Progesterone receptors were found. Ki-67 was higher than 40% in four patients. Adjuvant chemotherapy was administrated in patients with Ki-67>10%; every patients were treated with radiotherapy and with hormonal therapy too. Although Neuroendocrine breast tumor is considered a distinct entity, the best treatment seems to be correlate to the size of tumor and to the lymph node status and to Ki-67 index like the common breast cancer., Key Words: Diagnosis, Neuroendocrine breast carcinoma.

Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of fertile age. It is associated with several risk factors and long-term health consequences. Chronic anovulation combined with relative estrogen excess and consequent prolonged stimulatory effect on the endometrium can lead to the pathogenesis of hormonal dependant carcinoma. PCOS is thus traditionally reported to be associated with increased risk of endometrial, as well as breast and ovarian cancers. This article provides a critical literature review of the relationship between PCOS and the incidence of estrogen-dependant gynecological tumours, and it then discusses whether the commonly cited risk factor association can be substantiated by high quality studies which comply with the requirements of "evidence-based medicine."

Pulmonary lymphangioleiomyomatosis is an uncommon disease of unknown etiology characterized by the proliferation of abnormal smooth muscle cells in the lungs, leading to parenchymal destruction and progressive respiratory failure. The natural history of this disease remains poorly understood, primarily seen in women of childbearing age. The diagnosis can be difficult because symptoms are nonspecific and very similar to other respiratory diseases like asthma, emphysema and bronchitis. Lymphangioleiomyomatosis may not be diagnosed until a pneumothorax, chylothorax, interstitial lung disease or angiomyolipomas are discovered. The recent advances in genetic and molecular research provide new hope to discover the intricate mechanism of disease and evaluate new therapies. Internists, primary care physicians and pulmonologists should be aware of this condition in order to avoid delay in the diagnosis and institute appropriate therapy. The clinical features, pathophysiology, molecular genetics and medical treatment will be reviewed.

The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We have recently shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype. It is necessary to establish risk factors capable of predicting the risk of ER-positive breast cancer that will enable the efficient selection of candidates for preventive therapy. We analyzed genetic factors, including 14 single nucleotide polymorphisms (SNPs), environmental risk factors (body mass index, age at menarche, pregnancy, age at first birth, breastfeeding, family history of breast cancer, age at menopause, use of hormone replacement therapy, alcohol intake, and smoking), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 [IGF1] and IGF binding protein 3 [IGFBP3]), and mammographic density in 913 women with breast cancer and 278 disease-free controls. To identify important risk factors, risk prediction models for ER-positive breast cancer in both pre- and postmenopausal women were created by logistic regression analysis. In premenopausal women, one SNP (CYP19A1-rs10046), age, pregnancy, breastfeeding, alcohol intake, serum levels of prolactin, testosterone, and IGFBP3 were considered to be risk predictors. In postmenopausal women, one SNP (TP53-rs1042522), age, body mass index, age at menopause, serum levels of testosterone, and IGF1 were identified as risk predictors. Risk factors may differ between women of different menopausal status, and inclusion of common genetic variants and serum hormone measurements as well as environmental factors might improve risk assessment models. Further validation studies will clarify appropriate risk groups for preventive therapy., (© 2011 Japanese Cancer Association.)

Breast cancer risk is strongly related to several reproductive and hormonal factors, but the nature of the effects of endogenous oestrogens has been difficult to establish. Data are now available from several large prospective studies with biobanks of stored serum, enabling better characterization of the associations of endogenous oestrogens, and other endogenous hormones, with breast cancer risk. In postmenopausal women, relatively high serum concentrations of oestradiol are associated with a more than twofold increase in the risk for breast cancer, and this probably explains the increase in risk in obese postmenopausal women. In premenopausal women the data available on oestrogens are more limited and difficult to interpret due to the large variations in endogenous oestrogens during the menstrual cycle, but are compatible with a positive association between oestradiol and breast cancer risk. There is also evidence that breast cancer risk is positively associated with androgens, prolactin and insulin-like growth factor-I. Further data are required, with better assays and repeat measures, to provide more accurate estimates of risk and to clarify the role of oestrogens in premenopausal women and the roles of other endogenous hormones., (Copyright © 2011. Published by Elsevier Inc.)

Background: Endometrial cancer is the most common gynaecological cancer in the western world, the incidence increasing in the United Kingdom by over 40% since 1993. Two types of endometrial cancer exist - oestrogen-dependent type 1 with good prognosis and non-oestrogen-dependent type 2 with poor prognosis. The histopathological distribution of the increase in endometrial cancer is unknown. This study investigates the observed incidence trends of the two types, the age, stage, and socioeconomic distribution of this increase and survival outcome., Methods: Data were analysed from 6867 women with endometrial cancer registered between 1994 and 2006, at a UK population-based cancer registry., Results: Increased endometrial cancer incidence is confined to type 1 cancers with a significant increase in age standardised incidence rate (ASR) from 12.0 per 100,000 (confidence interval (CI) 10.7-13.2) in 1994 to 16.3 per 100,000 (CI 14.9-17.7), P<0.001 in 2006, while ASR of type 2 cancer changed from 2.5 per 100,000 (CI 2.0-3.1) in 1994 to 2.2 per 100,000 (CI 1.7-2.7) in 2006, which was not statistically significant P>0.05. Increase in type 1 cancer is most marked in age groups 60-69 years (P<0.001) and 70-79 years (P<0.001) and distributed equally among socioeconomic quintiles. While outcome for type 1 cancer has improved, 1-year survival in type 2 cancer is unchanged from 73.1% in 1994 to 74.3%, P=0.089 and 5-year survival decreased from 55.1% to 40.9%, P=0.001., Conclusion: Increased incidence in endometrial cancer is confined to type 1 cancers, seen most in the 60-79 age groups and across all socioeconomic quintiles. Survival in type 2 cancer has decreased significantly. Urgent research is needed to investigate prevention strategies in type 1 and improve therapy in type 2 cancers.

Objective: The influence of the relationship between pre- and post-menopausal stage of patients with breast cancer (BC) and the risk of sentinel lymph node (SLN) metastasis as well as the influence of oestrogen receptor (ER) status within each one of these groups were analyzed., Methods: A BC database with 1,388 patients was analysed. Three age groups were studied: A, elderly postmenopausal, 200 patients, ≥ 70 years old; B, younger postmenopausal, 89 patients, 55-69 years old; C, premenopausal, 85 patients, <55 years old. In each group 2 subgroups were analyzed: positive ER and negative ER tumours. Data analysed: SLN-positive patients, non-sentinel node (NSN)-positive patients, non-surgical detections (NSD) and non disease-free (NDF) patients after a follow-up of 52 months., Statistical Analysis: chi-squared test, significance: P ≤ 0.05., Results: SLN metastasis was significantly (P<0.025) more common in premenopausal than in postmenopausal patients, and within those, mainly in negative ER tumours. Positive-NSN increases slightly in premenopausal patients (exclusively in negative ER tumours). NDF patients are similar in the 3 groups and in all of them it is much more frequent in negative ER tumours., Conclusion: SLN metastasis varies significantly according to hormonal state and not according to age, being more frequent in premenopausal patients and mainly in ER negative tumours., (Copyright © 2010 Elsevier España, S.L. y SEMNIM. All rights reserved.)

Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake and risk of postmenopausal breast cancer stratified by estrogen and progesterone receptor status. This study was embedded within the Netherlands Cohort Study on diet and cancer, which was initiated in 1986 enrolling 62,573 women aged 55-69 years at baseline. After 13.3 years of follow-up, 2225 incident breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status. No association was observed for overall breast cancer or receptor-negative breast cancer risk, irrespective of smoking status. A statistically non-significantly increased risk of ER positive, PR positive and joint receptor-positive breast cancer was found in never-smoking women. The multivariable-adjusted hazard ratios were 1.31 (95% CI: 0.87-1.97, P (trend) = 0.26) for ER+, 1.47 (0.86-2.51, P (trend) = 0.14) for PR+, and 1.43 (0.83-2.46, P (trend) = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 microg/day) to women in the lowest (median 9.5 microg/day). This study showed some indications of a positive association between dietary acrylamide intake and receptor-positive breast cancer risk in postmenopausal never-smoking women. Further studies are needed to confirm or refute our observations.

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer., (2010 AACR.)

Following local therapy for ductal carcinoma in situ (DCIS), tamoxifen reduces the risk of ipsilateral and contralateral breast cancer by 30%-50%. Studies of tamoxifen in women with resected DCIS have not shown any effect on overall or cancer-specific survival. The adverse event profile of tamoxifen is well characterized, and individual risks and benefits should be assessed to guide decision making. We review the results of the phase III trials of tamoxifen in DCIS as well as the emerging risk reduction therapies.

The p53 tumor suppressor gene has a central role in the defense against cancer, including breast cancer, and contains a polymorphic variant (Arg/Pro) at codon 72 that has been shown to have different biological properties regarding apoptosis and cell cycle arrest. Earlier studies have shown allele specific loss of heterozygosity (LOH) at this particular site and we aimed to investigate its biological relevance in codon 72 heterozygous breast cancer patients (i.e., survival and age of disease onset). 199 postmenopausal cases were analyzed for LOH using MegaBACE(1000) and statistics was performed using Statistical Package for Social Sciences. LOH was found in totally 124 (62.3%) patients and the Pro allele (n = 103) was significantly more often deleted compared to the Arg allele (n = 21) (P = 0.001). Patients with LOH of the Arg allele were diagnosed at an earlier age (mean age 62.5 years) than those with loss of the Pro allele (mean age 69.2 years) (P = 0.011). LOH of the Arg allele was also associated with worse survival (P = 0.05). LOH in comparison to ROH correlated significantly with increased S-phase fraction. Tumor size, stage or number of positive lymph nodes was not related to LOH. Our results and earlier findings suggest a selective loss of the Pro allele during carcinogenesis that might confer a growth advantage for cancer cells. On the other hand, it appears to be more harmful for patients to loose the Arg allele since we found that loss of this allele was associated with earlier onset and worse prognosis.

Earlier, estrogens were considered simply the most important hormones involved in female physiology and reproduction. Nowadays it has become familiar that they have pivotal roles in gene regulation of cell differentiation and proliferation. There are many contradictions concerning the associations of female sexual steroids and cancer. Cancers of the highly estrogen dependent organs are in the forefront of tumors as they are regarded as hormone associated ones. However, re-evaluation of earlier results supporting the carcinogenic capacity of estrogen exhibited many shortcomings and controversies. Recently, the clinical studies on hormone replacement therapy in postmenopausal women justified beneficial anticancer effects in several organs even in the female breast. The newly revealed association between estrogen deficiency and oral cancer risk also means a contradiction of the traditional concept of estrogen-induced cancer. Distinction between cancers of moderately and highly estrogen dependent tumors can be based on their different epidemiological features. The vast majority of the so-called smoking associated malignancies of the moderately estrogen dependent organs occur typically in the late postmenopausal life of women when the ovarian estrogen production is fairly decreased. However cancers of the highly estrogen dependent organs such as breast, endometrium and ovary exhibit both premenopausal and postmenopausal occurrence. In spite of the different epidemiological data of these two groups of cancers the mechanism of gene regulation disorder in the background of tumor initiation cannot act through quite opposite pathways. This suggests that in moderately estrogen sensitive organs a serious, in the highly estrogen dependent sites even a mild estrogen deficiency is enough to provoke gene regulation disorders. The new findings both on smoking associated and hormone related cancers might lead to the same conversion; not estrogen but rather its deficiency may provoke cancer initiation.

Peculiarities of the incidence and spread of main non-infectious diseases (MNID) are in one or another way connected with the conception of "normal" and "successful" aging. The age-related increase in the frequency of MNID, associated with estrogen deficiency or excess, can be explained by the presence of estrogen effect switching phenomenon. The increase in the genotoxic effect of estrogens, isolated or combined with the weakening of the hormonal effect, can worsen the clinical course of MNID (including malignant tumors of hormone-dependent tissues). The effects of two other endocrine-genotoxic switchings (the joker function of glucose and adipogenotoxicosis) may realize in the same direction. The three mentioned phenomena form the so called basic triad, separate elements of which can interact. Endocrine-genotoxic switchings and their inductors are targets for prophylactic measures and, possibly, therapeutic ones. Both approaches may be divided into several groups with different points of application, whereas their ultimate goal is optimal balance between hormonal and DNA-damaging effects of estrogens, glucose, and adipose tissue-associated factors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.

A novel mechanistic hypothesis is proposed which suggests that hyperhomocysteinemia is a risk factor for the development of estrogen-induced hormonal cancer in humans. Mechanistically, hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of intracellular S-adenosyl-L-homocysteine, a strong non-competitive inhibitor of the catechol-O-methyltransferase-mediated methylation metabolism of endogenous and exogenous catechol estrogens (mainly 2-hydroxyestradiol and 4-hydroxyestradiol). While a strong inhibition of the methylation metabolism of 2-hydroxyestradiol would decrease the formation of 2-methoxyestradiol (an antitumorigenic endogenous metabolite of 17beta-estradiol), an inhibition of the methylation of 4-hydroxyestradiol would lead to accumulation of this hormonally-active and strongly procarcinogenic catechol estrogen metabolite. Both of these effects resulting from inhibition of the methylation metabolism of catechol estrogens would facilitate the development of estrogen-induced hormonal cancer in the target organs. This hypothesis also predicts that adequate dietary intake of folate, vitamin B6, and vitamin B12 may reduce hyperhomocysteinemia-associated risk for hormonal cancer. Experimental studies are warranted to determine the relations of hyperhomocysteinemia with the altered circulating or tissue levels of 4-hydroxyestradiol and 2-methoxyestradiol and also with the altered risk for estrogen-induced hormonal cancer.

Breast cancer is a major cause of female morbidity and mortality worldwide. In this review, we discuss the hormonal and genetic risk factors associated with breast cancer development and describe the currently available models for predicting an individual woman's risk. We highlight three more sophisticated surrogate markers of life-time oestrogen exposure (plasma oestradiol, mammographic breast density, bone mineral density) and propose that these may be used to improve estimates of a woman's absolute risk.

A case-control study was carried out in Mexico City during 1995-1997 among women with epithelial ovarian cancer (84 cases) and endometrial cancer (85 cases). The control group consisted of 668 healthy women, matched according to age categories. In a multivariate analysis, the reproductive risk factors for ovarian and endometrial cancer are similar. The risk of ovarian cancer was inversely related to the number of full-term pregnancies; the odds ratio (OR) was 0.17 and the 95% confidence interval (CI) was 0.05-0.54 when comparing nulliparous women versus those with more than seven pregnancies. For endometrial cancer, a similar association was observed (OR, 0.11; 95% CI, 0.04-0.34). The use of oral contraceptive hormones was inversely associated with both ovarian (OR, 0.36; 95% CI, 0.15-0.83) and endometrial cancer risk (OR, 0.36; 95% CI, 0.14-0.90). In women with a history of more than 8.7 years without ovulation, the risk of ovarian cancer decreased four times (OR, 0.23; 95% CI, 0.10-0.50), and that of endometrial cancer decreased more than five times (OR, 0.17; 95% CI, 0.08-0.35). These two neoplasms are clearly typified as hormone dependent, and it is possible to establish that "ovulation" and "exfoliative" mechanisms jointly determine the level of risk for both ovarian and endometrial cancer.

Effects of smoking on breast cancer risk remains controversial. Tar products have been claimed to increase risk, antioestrogenic effects to reduce risk. Another possibility is that associations to smoking have been confounded by diet. The increasing incidence of breast cancer from 1960 to 1994 in Sweden is parallel to that of lung cancer and the increasing proportion of female smokers. The incidence of endometrial and colon cancer was in premenopausal women negatively and in postmenopausal women positively related to the incidence of breast cancer. Possible explanations and hypotheses to the different co-variance between breast cancer and lung, endometrial and colon cancer in pre- and postmenopausal women are discussed from the perspectives of smoking, sex hormones and diet. It is concluded that the strong and specific positive relationship between breast and lung cancer in premenopausal women is compatible with the hypothesis that aromatic hydrocarbons may be involved in the causation of disease.

We sought to determine the strength of the evidence suggesting that estrogen and postmenopausal replacement hormones play a role in the development of breast cancer. We reviewed the existing English language literature in MEDLINE on hormones and breast cancer, including reports on cell proliferation and endogenous hormone levels, as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer in women. A factor that increases the probability that cancer will develop in an individual has been defined as a cancer cause. The Hill criteria for demonstrating a link between environmental factors and disease were used to review the evidence for a causal relationship between female hormones and breast cancer. We found evidence of a causal relationship between these hormones and breast cancer, based on the following criteria: consistency, dose-response pattern, biologic plausibility, temporality, strength of association, and coherence. The magnitude of the increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year. The positive relationship between endogenous hormone levels in postmenopausal women and risk of breast cancer supports a biologic mechanism for the relationship between use of hormones and increased risk of this disease. The finding that the increase in risk of breast cancer associated with increasing duration of hormone use does not vary substantially across studies offers further evidence for a causal relationship. We conclude that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous estrogens, and breast cancer incidence in postmenopausal women. Hormones may act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate the proliferation of malignant cells. Strategies that do not cause breast cancer are urgently needed for the relief of menopausal symptoms and the long-term prevention of osteoporosis and heart disease.

Increased bone mineral density (BMD), as a marker of higher integrated estrogen exposure over time, could be an important risk factor for postmenopausal breast cancer. In the Study of Osteoporotic Fractures 8065 non-black women age 65 years and older were followed for an average of 3.2 years. There were 121 incident breast cancer cases. The age adjusted incidence rate/1000 person years of breast cancer was substantially higher among women with high BMD at several measured bone sites. There was approximately a 2-fold higher risk of breast cancer for women in the upper as compared to the lower 25th percentile of BMD. Considerable controversy exists about the association of hormone replacement therapy (HRT) and increased risk of breast cancer. In this paper we modeled the effects of selection for HRT, presuming that women with lower BMD would be more likely to be on HRT, then estimated the observed versus potential risk of breast cancer among HRT users as compared to nonusers. The model suggests that the potential risk of breast cancer associated with HRT could be greatly underestimated and that postmenopausal women with high BMD who are placed on HRT could have a substantially increased risk of breast cancer. This model of increased risk of breast cancer associated with BMD and HRT needs to be evaluated within clinical trials and larger observational studies that include measures of BMD.

Until a few years ago, every treated breast cancer was an absolute contraindication to hormonal replacement therapy (HRT). However, the very high five-year survival rate in stage I breast cancer observed today brings more and more apparently healthy early postmenopausal women who have been treated for breast cancer in the past and who are suffering from heavy vasomotor symptoms due to estrogen deficiency to gynecological consultation. Usually well informed, the same group of women starts to worry about an increased risk of postmenopausal osteoporosis and of cardiovascular diseases. What attitude should be adopted today? Our approach should be differentiated and respect the staging, the estrogen-receptor status, and the presence or absence of axillary lymph-node metastasis of every patient. In estrogen receptor-negative women, there is no contraindication to continuous combined HRT by a fixed estrogen-progestin combination. In estrogen receptor-positive and lymph-node-negative patients, treatment by a nonaromatizable progestin, such as medrogestone or medroxyprogesterone acetate (MPA), can be introduced to relieve the patient from her postmenopausal syndrome. After 2-3 years of a favorable evolution of the treated cancer, the substitution might be shifted to a fixed-combined continuous HRT. Because estrogen receptor-positive and lymph-node-positive patients today are usually receiving adjuvant treatment with tamoxifen, they profit already from prophylaxis for postmenopausal osteoporosis and, very likely, from decreased cardiovascular risk. If women out of this group continue to suffer from heavy vasomotor symptoms, MPA might be added. However, it must be stressed that every administration of sexual steroids to women who have been treated for breast cancer has to be started only in full agreement with the treating oncologist concerned with the case and only after having obtained the informed consent of the patient. The new ethical dilemma will be our attitude to quality of life in relation to life prolongation.

There are 470 million women aged 50 years and older living in the world today, in other words, older than the average age of natural menopause throughout recorded history. Only 50 years ago, even in developed countries, the average women did not live to be 50 years of age. The result of this increased survival is that more and more women are living for longer and longer periods of time after their menopause. What are the implications of prolonged life after the menopause? Most of the current interest in the menopause is prompted by its possible relation to chronic diseases, most notably reproductive cancers, osteoporosis, and heart disease. All of these conditions are more common in women after the menopause, and two of them are directly influenced by the use of replacement estrogen. Thus, estrogen replacement reduces the risk of osteoporotic fractures by about 50%, and unopposed estrogen doubles or triples the risk of endometrial cancer. The risk of these conditions without treatment differs in different countries and populations, and consequently the benefit of hormone replacement will differ. The largest potential benefit of estrogen replacement therapy is the prevention of heart disease. In countries with a relatively high risk of heart disease, observational studies suggest that estrogen reduces this risk by 50%. In other areas, where heart disease in women is much less common, the use of estrogen to prevent heart disease in otherwise healthy women is inappropriate given the uncertain relation of long-term estrogen therapy to the risk of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated how histopathological features, such as structural atypism (SAT), nuclear anaplasia (NAN) and Gleason's pattern, influence the prognosis of patients receiving endocrine therapy. Patients with SAT 3 or NAN 3 clearly had a lower survival rate and a shorter survival period than those with other grades of SAT or NAN and this tendency was more prominent in the high stage than low stage. Patients with a higher grade of SAT or NAN had a poorer prognosis as well, when only cancer-related death was considered in the calculation of survival and survival period. The results described above suggest that the grade of SAT and NAN is one of most influential factors for prognosis. In the analysis for the prognosis of patients according to grade of mean value of SAT + NAN, there were differences in prognosis among mean value of SAT + NAN 2-4, 5 and 6. This indicated that the combined grading system would provide more information to the prediction of prognosis. Patients with Gleason's primary (or secondary) pattern 1 and 2, or 3 and 4 had a better survival than those with pattern 5 in the analysis when only cancer-related death was considered. This was coincident with the result that the survival rate for each Gleason's sum 2-3, 4-5, 6, 7-8 and 9-10 was different. Consequently, Gleason's pattern influenced the rate of cancer-related deaths, and this pattern may be another important factor for predicting the prognosis.

The general trend on the treatment for prostatic carcinoma has been changing from endocrine therapy alone to an alternative type according to stage. We evaluated clinically the favorable and unfavorable outcome of endocrine therapy in Japan, so that others will be appropriately evaluated. In a cooperative study made by members of five universities, 572 patients with clinically or histologically reconfirmed prostatic carcinoma were entered in this retrospective study. We studied the true influence of prognostic factors on the prognosis of 497 patients with prostatic carcinoma who had received endocrine therapy, employing multivariate analyses, such as quantification method II, multiple regression analysis and Cox's proportional hazard model. Twelve factors were considered in the study; "age", "stage", "histological findings (structural atypism = SAT, nuclear anaplasia = NAN, Gleason's primary and secondary pattern)", "pretreatment level of total acid (ACP) and of alkaline phosphatase (ALP)", "castration performed or not performed", "doses of estrogen", "type of response of local prostatic tumor and of ACP to endocrine therapy". Analysis of the "importance" of a prognostic factor by a partial correlation determined by quantification method II, revealed "stage" to have the greatest "importance" on prognosis throughout the entire period. "Response of local prostatic tumor", "response of ACP" and "Gleason's primary pattern" tended to be important factors for prognosis, in particular, in the first half period, and "age" and "Gleason's secondary pattern" were important in the latter half. Multiple regression analysis revealed the "stage", once again to be the most influential factor on the prognosis for the entire observation period. Also "response of local prostatic tumor", "SAT" and "Gleason's primary pattern" affected the patients' prognosis in the first half of the observation period. In the latter half, "age" became more of an influential factor than "histological findings". Analysis with Cox's proportional hazard model revealed that "response of ACP", "stage", "age", "Gleason's primary and secondary pattern", and "response of local prostatic tumor" were definitely the more influential prognostic factors, of which chi-square values (or t values) were statistically significant. Comparison of the significant factors in each multivariate analysis revealed that common influential prognostic factors, such as "age", "stage", "histological findings (mainly Gleason's primary and secondary pattern)", "response of local prostatic tumor" and "response of ACP" were coincident to the clinical impression. The clarification of these factors would be clinically beneficial when treating patients with endocrine therapy.

Of 572 patients with prostatic carcinoma, 497 received endocrine therapy as the initial treatment. These patients were surveyed in a cooperative research study by members from five universities. Prognosis, causes of death and side effects of estrogen therapy were studied. The prognosis of patients who had received endocrine therapy became worse, as the stage progressed. The prognosis of those who had received a combination of estrogen therapy with castration tended to be better than that of those who had received estrogen therapy alone. Similarly, the prognosis of those who had received a combination of progesterone therapy with castration tended to be better than that of those who had had progesterone therapy alone. No relationship was found between estrogen doses (low, medium and high) and prognosis, although a precise comparison among the three could not be made because of the smaller number of patents with low doses. A high dose of estrogen may not always be the indication, rather a medium dose such as 300 mg diethylstilbestrol diphosphate may be clinically appropriate. The cause of death could be identified in 303 patients who had received endocrine therapy. Cancer-related death was the most frequent (63.7%), and cardio- or cerebrovascular death accounted for only 14.2% of the cases. When this analysis was confined to the patients who had received estrogen therapy, estrogen administration seemed to be the cause of cardio- or cerebrovascular death of 16.1% of the patients. Daily dosing of estrogen was not definitely related to the incidence, or the interval to cardio- or cerebrovascular death. However, among the patients who had died of cardio- or cerebrovascular disease, 50% of the patients who had received a medium or high dose of estrogen tended to die within two years after treatment, while 50% of those who had received a low dose died within three years.