Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials

We conducted meta-analyses to assess the impact of menopausal hormone therapy (MHT) on the risk of incident invasive breast cancer (BC) in cohort studies (CS), case-control studies (CCS) and randomized controlled trials (RCTs) published 1989-2004. We used published data providing information upon unopposed estrogen therapy (ET), estrogen-progestin therapy (EPT) or all MHT combined. Major outcomes were MHT-associated overall risk of BC and change of risk per year used. There is a linear increase of overall risk by midterm year of case ascertainment based upon data of all study types for MHT and to a larger extent for EPT, not for ET. Effects are larger in CS than in CCS. Meta-analyses stratified by <1992 versus > or =1992 as midterm year of case ascertainment indicate larger summary risks for the latter period for all MHT analysed, in particular for EPT. Annual increases in BC risk for EPT across study types are 0-9%, for ET 0-3%. In conclusion, there is evidence that relative risks for BC risks by MHT, in particular EPT, have been increasing in recent years. Given the widespread use of MHT, and often long duration, more detailed knowledge about differential BC risks of both estrogens and progestins are necessary to minimize BC risk in symptomatic women who consider MHT.     

Menopausal estrogens and breast cancer.

1891 women given conjugated estrogens for the menopause were followed for 12 years (mean) for incidence of breast cancer. Overall, 49 cases were observed; 39.1 were expected on the basis of rates in the general population (relative risk = 1.3, P = 0.06). The relative risk increased with follow-up duration, progressing to 2.0 after 15 years (13/6.6, P = 0.01). The excess risk after 10 years was not due simply to prolonged estrogen use, since there was no clear dose-response relation to accumulated years of use. However, higher risk accrued to women using higher-dose tablets and those taking the medication on an other than daily basis. In addition, after 10 years of follow-up observation, two factors related to low risk of breast cancer, multiparity and oophorectomy, were no longer so related. Finally, estrogen use was related to an especially high risk of breast cancer among women in whom benign disease developed after they had started the drug.     

Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis

Knowledge about the impact of menopausal hormone therapy (MHT) on the risk of ovarian cancer (OvC) is insufficient, and studies are inconsistent. Mortality from OvC ranks highest among cancer sites in female reproductive organs. We performed meta-analyses to assess the impact of specified types of MHT on the risk of OvC in cohort studies (CS), case-control studies (CCS), randomized controlled trials (RCT) and cancer registry studies (CRS). We used data published 1966-2006 on estrogen therapy (ET), estrogen/progestin therapy (EPT) or MHT (unspecified regimen) identified by a structured, computerized and manual literature search. We identified 42 studies (30CCS, 7CS, 1 RCT and 4 CRS) with 12 238 cases. The risk of OvC (ever-use, annual risk) is increased 1.28-fold by ET [confidence interval (CI) 1.18-1.40] and 1.11-fold by EPT (CI 1.02-1.21) with a suggestion of greater risks with ET. There appears to be no differential impact of any therapy on histological subtypes. Risks were greater in European than North American studies for both ET and EPT. In conclusion, ET as well as EPT, are risk factors for OvC. Given the widespread use of MHT, known benefits should be weighed against the increased risk of OvC, and more studies are warranted, particularly on factors with the greatest apparent risks.     

Menopausal symptoms after cessation of hormone replacement therapy

OBJECTIVES: To determine the prevalence of recurrent menopausal symptoms among post-menopausal women who discontinued hormone replacement therapy (HRT) after the publication of the women's health initiative (WHI) study and to describe the therapeutic strategies employed to address these symptoms. METHODS: Retrospective analysis of 1000 post-menopausal women seen consecutively at an internal medicine practice from January 2004 to May 2004. RESULTS: Among 1000 post-menopausal women, 205 (21%) had discontinued HRT due to the WHI results. Menopausal symptoms were present in 91/205 (44%) women, with 52/205 (25%) having vasomotor symptoms, 51/205 (25%) urogenital complaints, and 10/205 (5%) mood-related symptoms. Out of the 91 symptomatic women, only 55 (60%) received therapy to relieve their symptoms. The most commonly employed treatments were topical estrogen in 33/91 (36%) women, complementary therapies in 18/91 (20%) women, and venlafaxine in 13/91 (14%) women. Among complementary therapies, the most frequent were black cohosh used by 8/91 (9%) women and soy by 7/91 (8%) women. CONCLUSIONS: Many post-menopausal women developed typical menopausal symptoms after discontinuation of HRT, with vasomotor and urogenital complaints being the most commonly reported. Topical estrogen, complementary therapies, and venlafaxine were the most usual treatments for menopausal symptoms. However, a large number of symptomatic women remained untreated.     

Current status of hormone therapy and breast cancer

This editorial comments on two similar reviews of the literature on breast cancer and post-menopausal hormone therapies (HTs), puts the results in clinical perspective and suggests where they direct future research and clinical management. Although epidemiological studies have suggested increased breast cancer risk for all menopausal HT regimens, unopposed oral estrogen regimens have not been associated with any increased risk in recent randomized placebo controlled trials (RCTs). Added progestogen after 5 years of combined HT in RCTs increases the risk of breast cancer by four cases per 10,000 per annum. As yet there is no evidence of different risk by progestogen type, dose or route. Theoretically local intrauterine progestogen may not give the same risk, but long-term trials are required. The commentary addresses the responsibility of the media in presenting levels of risk to the public, moving towards safer regimens, safer therapies, appropriate patient choice and, in particular, correct timing of HT where it is prescribed around menopause. This is in contrast to many of the trials when HT was administered after the potential climacteric window of therapeutic opportunity. The current main indication for HT remains for menopausal symptom control where it improves quality of life. HT may be required for many years. The informed woman should decide on HT based on her personal benefits and risks, which should include all aspects of her health.     

Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation

OBJECTIVES: Hormone therapy (HT) is associated with a modest, but significantly increased risk for arterial and venous thromboembolism. We have compared the effects of estrogen, tibolone, and raloxifene on relevant markers of coagulation activation and investigated whether there is a dose-response relationship of oral HT. METHODS: Randomized, open-label, comparative study of 202 healthy women who were assigned to receive treatment for 12 weeks with either low-dose hormone therapy containing 1 mg 17beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17beta-estradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). RESULTS: The groups were comparable with regard to demographic characteristics and laboratory variables at baseline. D-dimer increased markedly in the conventional-dose HT group, but remained unchanged in the low-dose HT group. Tibolone was associated with a medium increase, whereas raloxifene was associated with a decrease in D-dimer levels. Changes in prothrombin fragment 1 + 2 showed a similar pattern for all four groups, whereas no significant differences in changes of thrombin-antithrombin complex were observed. CONCLUSIONS: Our data suggest that low-dose HT is associated with less activation of coagulation than conventional-dose HT. This finding may be of clinical importance since randomized clinical trials showing increased risk of thrombosis have utilized conventional-dose HT.     

Stereotactic body radiotherapy (SBRT) and concomitant systemic therapy in oligoprogressive breast cancer patients

Clinical & Experimental Metastasis - Breast cancer is a heterogenous disease with a deep tailoring level. Evidence is accumulating on the role of stereotactic body radiotherapy (SBRT) in the...     

Menopausal hormone therapy decisions: insights from a multi-attribute model

A multi-attribute utility (MAU) decision model for menopausal hormone replacement therapy (HRT) was developed using structured interviews (n=40) to identify decision factors, and a telephone survey (n=97) to ascertain utility scores. Utility scores for individual factors and composite scores reflecting the HRT decision were compared according to HRT use. Composite utility scores (range of -1.0 to 1.0, with higher values supporting HRT use) were 0.55, -0.27, and -0.19 for the 48 HRT users, 23 former users, and 26 never users, respectively (P<0.0001). Among HRT current users, the main factors supporting use were concerns about heart disease, osteoporosis, and symptoms of menopause. Among former users, side effects weighed heavily against use, and among never users breast cancer concerns weighed heavily against use. Linear regression methods were used to identify the utilities most predictive of current HRT use. The decision model provided insight regarding how personal expectations and values influence HRT use.     

PI3KCA mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy

PI3K/AKT/mTOR pathway alterations are frequent in patients with infiltrating breast cancer (IBC). Their clinical and pathological relevance has been insufficiently documented. We evaluated PI3KCA for mutations and the expression of PTEN, AKT, mTOR and p70S6K by immunohistochemistry in 246 IBC patients treated with hormone therapy (median follow-up, 97 months). A PI3KCA mutation was observed in 50 out of 229 informative cases (21.8 %), PTEN loss in 107 out of 210 (51 %), moderate/high level of expression of AKT in 133 out of 188 (71 %), moderate/high level of expression of mTOR in 173 out of 218 (79 %) and moderate/high level of expression of p70S6K in 111 out of 192 cases (58 %). PI3KCA mutation was associated with the absence of Her2/neu amplification/overexpression and a low level of MIB1/Ki-67 labelling. The expression of p70S6K was associated with a high level of mTOR immunoreactivity, and high PTEN expression was associated with high AKT expression level. Univariate analysis showed that PI3KCA mutation status was not associated with clinical outcome in the series as a whole or in the node-negative subgroup. However, in the node-positive subgroup, exon 9 PI3KCA mutation was associated with unfavourable overall survival (OS), although its impact on the final model in multivariate analysis seemed to be limited. Of the other markers, only high p70S6K expression was associated with a significantly prolonged OS. PI3KCA mutation status is of limited prognostic relevance in oestrogen receptor-positive breast cancer patients treated with hormone therapy.     

Menopausal hormone therapy use in 17 European countries during the last decade

Introduction

The first ‘Women's Health Initiative’ (WHI) randomised controlled trial assessed use of continuous combined menopausal hormone therapy (cc-MHT). It was prematurely stopped because of an increased invasive breast cancer (BC), coronary heart disease (CHD), stroke and pulmonary embolism risk. Consequently, scientific societies recommended use of MHT at the lowest effective dose for the shortest duration. As a result, a sharp decline in MHT use occurred worldwide.

Aim

To report in a uniform way the change in MHT use in European countries. To evaluate whether the variability of the MHT changes were related to some medical indicators.

Materials and methods

IMS Health provided MHT sales data for the years 2002 till 2010 for 17 countries. We tested several hypotheses to explain the heterogeneity of MHT use changes.

Results and discussion

In 2002, the estimated MHT rate in women 45–69 years old varied considerably between countries ranging from less than 5% to more than 25%. In all countries a profound decrease occurred between 2002 and 2010, ranging from 50% to 77%. By the end of 2010, the MHT uptake was lower than 10% in all countries except in Finland. MHT use change was not correlated to MHT use and prevailing BC incidence at baseline, nor to the number of gynaecologists per 100,000 women or to the level of information about MHT.

Conclusion

The global MHT use experienced a sharp decrease in all the analysed countries, although some variability exists. The decrease was unrelated to the assessed parameters.     

Progestogens in postmenopausal hormone therapy and the risk of breast cancer

Hormone therapy is the treatment of choice for the alleviation of menopausal symptoms and the treatment of urogenital atrophy. In women with an intact uterus a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer. There is a wide variety of marketed progestogens which differ in their pharmacological properties according to their structure. Convincing evidence from both clinical trials and epidemiological studies indicates that combined estrogen–progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy. Concerning the different types of progestogens, data from large observational studies suggest that natural progesterone and dydrogesterone are associated with a lower risk of breast cancer compared with the other progestins. Observational studies, furthermore, indicate that sequential estrogen–progestogen regimens may lead to a lower risk elevation compared to continuous regimens. The effect of tibolone on breast cancer is unclear. Concluding, both the type of the progestogen and the mode of HT administration may have an impact on breast cancer risk.     

Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer

Our objective was to investigate the efficacy and safety of capecitabine maintenance therapy (CMT) after capecitabine-based combination chemotherapy in patients with metastatic breast cancer. The clinical data of 139 metastatic breast cancer patients treated from March 2008 to May 2012 with capecitabine-based combination chemotherapy were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, we used CMT for 50 patients, while 37 patients were treated with a different (non-CMT) maintenance therapy. We compared time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety of the two groups, and a sub-group analysis was performed according to pathological characteristics. Sixty-four percent of the patients received a median of six cycles of a docetaxel+capecitabine combination chemotherapy regimen (range 1-45); the median TTP (MTTP) for the complete treatment was 9.43 months (95%CI=8.38-10.48 months) for the CMT group and 4.5 months (95%CI=4.22-4.78 months; P=0.004) for the non-CMT group. The MTTPs for the maintenance therapies administered after the initial capecitabine combined chemotherapy were 4.11 months (95%CI=3.34-4.87 months) for the CMT group and 2.0 months (95%CI=1.63-2.38 months) for the non-CMT group. Gastrointestinal side effects, decreased white blood cells and palmar-plantar erythrodysesthesia were the main adverse reactions experienced with the combination chemotherapies, CMT and non-CMT treatments. No significant differences in the incidence of adverse reactions were detected in the CMT and non-CMT patients. After initial disease control was achieved with the capecitabine-based combination chemotherapy, CMT can significantly prolong TTP rates with a favorable safety profile.     

Postmenopausal hormone therapy before and after breast cancer: clinical experiences

Conventional oestrogen-based hormone therapy (HT) increases the incidence of breast pain and tenderness, mammographic density and the risk of breast cancer. Combined oestrogen plus progestogen therapy (EPT) increases the risk of breast cancer to a greater degree than oestrogen alone (ET). Attention must therefore be focused on identifying women at risk of breast cancer or on producing a HT that has fewer breast side effects. Randomised controlled trials have shown that while EPT induces breast tenderness or pain in up to 50% of women and increases mammographic density in up to 70% during the first year of treatment, only about as many as one-tenth women report breast tenderness or pain with tibolone and increases in mammographic density are rare, occurring with a similar incidence as seen in untreated controls. Many women with breast cancer suffer vasomotor symptoms rather than risk recurrence with conventional HT. However, in a small randomised controlled trial in women with early breast cancer undergoing adjuvant tamoxifen treatment, tibolone reduced hot flushes, night sweats and improved quality of life compared with placebo.     

Menopausal hormone therapy does not play a major role in left ventricular hypertrophy

Objectives

Left ventricular hypertrophy (LVH) is a precursor of morbidity and mortality in women. Use of menopausal hormone therapy (MHT) might be associated with decreased left ventricular mass (LVM) and lower risk of LVH, although results of previous observational and clinical studies are inconclusive. Therefore, we analyzed the association between MHT use and either LVM indexed to height^2.7 (LVMI) or LVH determined echocardiographically.

Methods

Data from women aged ≥ 45 years recruited for the population-based Study of Health in Pomerania were used for cross-sectional (n = 975) and longitudinal (n = 675; 361 women without LVH at baseline) analyses. Information on ever (past and current) and never use of MHT were obtained. Linear (LVMI) or logistic (LVH) regression analyses were performed while controlling for potential confounders.

Results

Crude and age-adjusted analyses suggested an association between ever use of MHT and lower odds for LVH. This association was no longer significant in fully adjusted models. Compared to women who never used MHT, the odds ratios of LVH for ever MHT users were 0.97 [95%-confidence interval (95%-CI) 0.71–1.30] in cross-sectional and 0.70 (95%-CI 0.44–1.11) in longitudinal fully adjusted analyses. Similarly, results with an alternative classification of MHT use (never, past, and current) indicated no significant associations with LVH after full adjustment.

Conclusions

This study provides little evidence of an association between MHT use and LVH. Differences in lifestyle or health-related factors between never and MHT users could provide an explanation, in part, for the presumptive protective benefit of MHT on LVH.     

Steroid hormone receptors in breast cancer

The significance of hormone receptor (estrogen(ER)- and progesterone receptor (PgR) assay was described with special reference to the treatment of advanced and early breast cancer. Fifty to sixty percent of ER-positive breast cancer responds to endocrine treatment, while only about 10% of ER-negative cancer do. Advanced breast cancer patients with ER-positive tumors survive longer than those with ER-negative tumors, mainly because of better response to therapy. The clinical benefit of assaying the hormone receptors in primary breast cancer was discussed, particularly concerning with the relapse-free and overall survivals of the patients after primary operation. The findings suggest the possibility of selecting operable breast cancer patients for the most appropriate adjuvant using ER and PgR.     

Anti-neutrophil antibodies (anti-MPO-ANCAs) are associated with poor prognosis in breast cancer patients

Anti-neutrophil antibodies are capable of activating neutrophils in sterile environments, releasing extracellular traps containing myeloperoxidase (MPO) and anti-MPO antibodies (MPO-ANCAs or anti-MPO-ANCAs), which have been implicated in the pathogenesis of several diseases. The present study evaluated systemic and tumor tissue levels of anti-MPO-ANCAs breast cancer patients, and its relation to clinicopathological characteristics. Anti-MPO-ANCAs were measured in serum and tissue samples of 150 patients by enzyme-linked immunoassay. Samples were pooled according to clinicopathological characteristics of patients. Higher anti-MPO-ANCAs levels were detected in groups presenting negative clinicopathological characteristics, such as high histological grade tumors and risk factors such as body mass index, menopausal status and early onset at diagnosis. The present data highlights anti-MPO-ANCAs as associated to poor prognosis in breast cancer, a role beyond its actually discussed role in autoimmunity and vasculitis.