Positive Postmenopausal Breast Cancer Patients Research Articles

Changes in intestinal microbiota in postmenopausal oestrogen receptor-positive breast cancer patients treated with (neo)adjuvant chemotherapy

This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.

Assessment of cardiotoxicity in hormone positive postmenopausal breast cancer patients receiving aromatase inhibitors

Background: Aromatase inhibitors (AIs) represent an effective endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients with early stage or metastatic disease.Objective: Assessment of Cardiotoxicity in Hormone positive Postmenopausal Breast Cancer Patients receiving AIs (upfront orswitch therapy).Methods: This cross sectional study included 123 postmenopausal breast cancer patients presented to the Clinical Oncology Department, Ain Shams University (Cairo, Egypt) in the interval from August 2016 to June 2017 with hormone receptor positive receiving Aromatase Inhibitors, To assess cardiotoxicity in these patients, they were subjected to blood pressure and lipid profile measurement, electrocardiography (ECG), and electrocardiography (ECHO) and classified into patients had Nolvadex then A.I (arm 1) and others had upfront A.I (arm 2).Results: The age of patients ranged from 41 years to 85 years with mean age of 61 years. Seventy one patients (57.7%) showed cardiotoxicity as assessed by ECHO. They showed significant correlation with rising age above 62 years, IHD, history of HTN and DM (p value: .001, .001, .017 and 0.035 respectively). However, correlation between cardiotoxity and blood pressure changes, lipid profile changes and ECG findings and ECHO changes in switch therapy and upfront A.I were not statistically significant (p value = .275, .116, .081 and .761 respectively).Conclusion: Assessment of cardiotoxicity in hormone positive postmenopausal breast cancer patients receiving Aromatase Inhibitors showed evidence of cardiotoxicity in half the patients (57.7%) as detected by ECHO only. They showed statistically non significant correlations either recievied switch therapy or upfront A.I.

Letrozole and Anastrozole in Early Breast Cancer Post-menopausal Patients in Oncology Department at Suez Canal University Hospital

Background:There are limited data in the literature comparing the efficacy of aromatase inhibitors in postmenopausal hormonal receptor positive early breast cancer patients. Aim: To compare the efficacy of letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients. Patients and Methods: A retrospective study with a mean follow-up period of 64 months (about 5 years) for 74 files of early invasive postmenopausal breast cancer hormonal receptor positive patients; 39 received letrozole and 35 received anastrozole, considering TTP as primary end point, and OS as second end points. Results: Letrozole is not superior to anastrozole during the first 55 months of treatment (80% PFS at 5th year), and 80% OS benefit at 6th year.. Overweight patients had better (90% PFS at 5th year) than obese patients (60% PFS at 5th year). Conclusion: Letrozole is not superior to anastrozole in efficacy in early invasive hormonal receptor positive breast cancer postmenopausal patients during the first 5 years of treatment; however, Letrozole 2nd line after tamoxifen is superior to anastrozole 2nd line after tamoxifen in treating obese patients with early invasive hormone receptor positive breast cancer.

Cell Cycle Regulation in Treatment of Breast Cancer.

Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first-generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies. Here we will review the mechanisms of cell cycle regulation and targeting key cell cycle regulators (such as CDKs) in breast cancer treatment. Particularly, we will discuss the mechanism of CDK inhibitors in disrupting cell cycle progression, the use of selective CDK4/6 inhibitors in treatment of advanced, hormone receptor (HR)-positive postmenopausal breast cancer patients, and other clinical trials that aim to extend the utilization of these agents.

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2%) compared to exemestane-treated patients (-1.0%) (p=0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p=0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Comparison of the efficacy of adjuvant letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients.

e11554 Background: In the adjuvant hormonal treatment of postmenopausal breast cancer patients, most of the trials have showed the superiority of aromatase inhibitors over tamoxifen. However, there are limited data in the literature comparing the efficacy of aromatase inhibitors in postmenopausal women. Thus, the aim of this study is to compare the efficacy of letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients. Methods: Newly diagnosed breast cancer patients from 2001 to 2012 in our clinic were retrospectively analyzed. A total 566 hormone receptor-positive postmenopausal breast cancer patients were analyzed. The patients were divided into two group; anastrozole group (n=235) and letrozole patients (n=331). Kaplan–Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). The log-rank test was used to examine the statistical significance of the differences observed between the groups. Results: The mean age was 59.2±8.5 in anastrozole group, and 60.1±8.4 in letrozole arm (P = 0.19). The mean BMI was 29.4±5.1 kg/m2 and 29.3±5.3 kg/m2 of anastrozole and letrozole arm, respectively (P =0.84). The median follow-up time for this analysis was 25.1 months. The histology of the primary tumor and type of surgery was similar and not statistically significant in both groups. Also in both arms the incidence of lymphovascular invasion, perineural invasion, HER2 positivity and histological grade were similar and not statistically significant. There were no apparent differences in baseline nodal status (P = 0.43), tumor size (P = 0.58) and tumor stage (P = 0.15) between two treatment arms. In anastrozole arm DFS rate was 93.7%, 81.3% and 66.0% whereas in letrozole arm DFS rate was 90.6%, 78.7% and 68.5% in the first, third and fifth years respectively. Median OS could not be obtained due to low events in both groups. Three year survival rate in anastrozole group was 98.8%, whereas in letrozole arm was 96.7% (P=0.84). Conclusions: In this retrospective study, the efficacy of letrozole and anastrozole was similar in hormone-receptor positive postmenopausal breast cancer patients.

Abstract PD01-03: Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment

Abstract BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients. METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1–3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interaction between these markers and treatment. RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12–0.47, p < 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48–2.21, p = 0.95), p for interaction 0.003. CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-03.

Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the TEAM pathology study.

516 Background: Some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy, and might benefit additionally from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk, and may inform treatment decisions. We tested the efficacy of this panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM patients were collected and TMAs constructed. The cohort was 47% node positive and 36% were also treated with adjuvant chemotherapy. Triplicate 0.6mm2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, and distant relapse free (DRFS) and disease free survival (DFS) analysed. Results: In multivariate regression analyses, corrected for conventional clinicopathological markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in ER positive node negative patients (N=1226) not receiving chemotherapy (p=0.004). Further analyses in all patients not exposed to chemotherapy, irrespective of nodal status (N=2559) and in the entire cohort (N=3837) showed Mammostrat scores provide additional information on DRFS in these groups (p=0.001 and p<0.0001 respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. Conclusions: The Mammostrat score predicts DRFS for both exemestane and tamoxifen-exemestane treated patients irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data following treatment provides further evidence for its’ utility in risk stratification of ER positive postmenopausal breast cancer patients.

Endocrine therapy after aromatase inhibitor therapy in breast cancer

Aromatase inhibitor (AI) therapy has become a gold standard of endocrine therapy for all stages of estrogen receptor (ER)-positive postmenopausal breast cancer patients in many countries. However, ...

CYP2D6 Polymorphisms as Predictors of Outcome in Breast Cancer Patients Treated with Tamoxifen: Expanded Polymorphism Coverage Improves Risk Stratification

This study aimed to validate matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)/Taqman copy number assay (CNA) CYP2D6 genotyping by AmpliChip CYP450 Test for the prediction of tamoxifen metabolizer phenotypes in breast cancer, and to investigate the influence of CYP2D6 variant coverage on genotype-phenotype relationships and tamoxifen outcome. Hormone receptor-positive postmenopausal breast cancer patients (n = 492) treated with adjuvant tamoxifen, previously analyzed by MALDI-TOF MS/CNA, were reanalyzed by AmpliChip CYP450 Test and validated by independent methods. Cox proportional hazard ratios (HR) were calculated for recurrence of poor (PM) relative to extensive metabolizer (EM) phenotypes with increasing numbers of CYP2D6 variants. Kaplan-Meier distributions were calculated for different phenotype classifications. Concordance was 99.2% to 99.5% for CNA and 99.8% to 100% per CYP2D6 allele (*3, *4, *5, *9, *10, and *41). The prevalence of predicted phenotypes was 1.2% for ultrarapid metabolizer (UM), 37.2% for EM without variant, 43.5% for heterozygous EM, 9.7% for intermediate metabolizer (IM), and 8.3% for PM. Approximately, one third of patients were misclassified based on a *4 analysis only, but inclusion of all reduced-function alleles increased the PM-associated HR from 1.33 (P = 0.58) to 2.87 (P = 0.006). Kaplan-Meier analyses showed highest and lowest clinical benefit for UM and PM with respect to both the AmpliChip-based and a redefined phenotype assignment. The latter revealed significant allele-dose-dependent associations (P = 0.011) and largest effect size (HR(PM_EM) = 2.77; 95% confidence interval, 1.31-5.89). MALDI-TOF MS/CNA is suitable for accurate CYP2D6 genotyping. For tamoxifen pharmacogenetics, broad CYP2D6 allele coverage is recommended to reduce phenotype misclassification. Classification based on refined EM and reduced-function metabolizers is advisable. AACR.

Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients

Aromatase inhibitors (AIs) are considered the gold standard for endocrine therapy of estrogen receptor (ER) positive postmenopausal breast cancer patients. The therapy may enhance therapeutic response and stabilize disease but resistance and disease progression inevitably occur in the patients. These are considered at least partly due to an emergence of alternative intratumoral estrogen production pathways. Therefore, in this study we evaluated effects of exemestane (EXE) upon the enzymes involved in intratumoral estrogen production including estrogen sulfatase (STS), 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), and estrogen sulfotransferase (EST) and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). 116 postmenopausal patients with invasive ductal carcinoma, stage II/IIIa, were enrolled in JFMC34-0601 clinical trials between March, 2006 and January, 2008. EXE of 25 mg/day was administered according to the protocol. Pre- and posttreatment specimens of 49 cases were available for this study. Status of STS, EST, 17beta-HSD1, ER, progesterone receptor (PgR), human epidermal growth factor receptor type 2 (Her2), and Ki67 in pre- and post-specimens were evaluated. Specimens examined before the therapy demonstrated following features; ER+ (100%), PgR+ (85.7%), and Her2+ (77.6%). After treatment, the number of Ki67, PgR, and ER positive carcinoma cells demonstrated significant decrement in clinical response (CliR) and pathological response (PaR) groups. Significant increment of 17beta-HSD1 and STS immunoreactivity was detected in all groups examined except for STS in PaR. EST showed significant increment in nonresponsive groups. Alterations of Ki67 of carcinoma cells before and after therapy were subclassified into three groups according to its degrees. Significant alterations of intratumoral enzymes, especially 17beta-HSD1 and STS, were correlated with Ki67 reduction after neoadjuvant EXE therapy. This is the first study demonstrating significant increment of STS and 17beta-HSD1 following AI neoadjuvant therapy of postmenopausal ER positive breast carcinoma patients. This increment may represent the compensatory response of breast carcinoma tissues to estrogen depletion.

Heat Shock Protein 90 Inhibitors: New Mode of Therapy to Overcome Endocrine Resistance

Aromatase inhibitors are important drugs to treat estrogen receptor alpha (ERalpha)-positive postmenopausal breast cancer patients. However, development of resistance to aromatase inhibitors has been observed. We examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of aromatase inhibitor-resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. Aromatase inhibitor-responsive MCF-7aro and aromatase inhibitor-resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G(2) cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERalpha, the ERalpha transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Collectively, results from this study provide data to support that HSP90 inhibitors may be an effective therapy to treat aromatase inhibitor-resistant breast cancers and that improved efficacy can be achieved by combined use of a HSP90 inhibitor and an AKT inhibitor.

Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phase II trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-17)

A multicenter phase II study was conducted to analyze the clinical activity of the steroidal aromatase inhibitor exemestane in the neoadjuvant treatment of post-menopausal women with strongly ER- and/or PgR- positive operable breast cancer. From September 2000 to December 2003, 80 women were recruited for treatment with exemestane 25 mg once daily for 4 months. The primary end-point was the clinical response rate according the WHO criteria; the secondary end-points included toxicity and the number of patients who qualified for breast conserving surgery at the end of treatment, comparability of evaluation methods for response, potential alterations of hormone receptor and Her2/neu status during treatment. On an intention to evaluate analysis, according to the prespecified criteria the overall clinical objective response rate was 34%, the pCR rate was 3% and the rate of breast conserving surgery was 76%. When sonographic and mammographic longitudinal measurements were included in patients with missing palpation data, response rates were 38% and 41%, respectively. The tumor response was independent of the Her2/neu status which remained unchanged during treatment. In contrast, while the ER expression remained unaltered, downregulation of the PgR was observed. The treatment was well tolerated with no grade 3 and 4 toxicities except gastrointestinal (one grade 3 case) and hot flushes (two grade 3 cases). This study shows that exemestane is effective and safe as a preoperative therapy in post-menopausal patients with strongly hormone receptor-positive breast cancer.

Adjuvant cyclic Tamoxifen and Megestrol acetate treatment in postmenopausal breast cancer patients – Longterm follow-up

To evaluate possible differences in effect on recurrence-free survival (RFS) and overall survival (OS) in node positive postmenopausal breast cancer patients receiving Tamoxifen or cyclic Tam and Megestrol acetate as adjuvant treatment. Between 1989 and 1994, 489 patients with pT(1-2)pN+ hormone receptor positive or unknown tumours were included in a randomized national multicenter study to receive either Tam alone or cyclic Tam (8 weeks) and MA (8 weeks) for 2 years. Final follow-up was completed as of June 2002. Time from start of treatment to first recurrence and novel primary breast tumour, overall survival and cancer specific survival were estimated. No differences in RFS, OS or cancer specific survival were observed between the two treatment groups. Adjuvant treatment used as standard Tam alone, compared to Tam and MA, as employed in this group of patients gave similar outcomes. Side effects that led to cessation of study medication were observed in both arms.

The site of first relapse in postmenopausal high-risk node positive operable breast cancer patients

772 Background: Adjuvant therapy of “high risk” node positive postmenopausal breast cancer patients (BC pts), specially in group of 65 years and older, is still controversial, concerning the use of systemic chemotherapy (CT). Methods: The analysis was retrospective and included 72 postmenopausal operable BC pts, with N+ (≥4 axillary lymph nodes), treated in Clinical Center of Montenegro. ER and/or PR status was unknown, or it was ER+ and/or PR+. The treatment consisted of radical mastectomy or breast conserving surgery, followed with adjuvant tamoxifen (alone or in combination with CMF or anthracycline based chemotherapy), with or without radiotherapy. Results: Median age of pts were 62 years (range 47–79).19/72 pts were treated with adjuvant tamoxifen alone. Combination tamoxifen and chemotherapy (concomitant or sequential tamoxifen after CT) were applied in 53 pts. Metastatic disease had been registered in 28 pts (39%). In the group of patients 65 yrs and younger 18/40(45%), pts relapsed, the most frequently in liver 6/18. Pts 65 years and older had 10/32 (31%) relapses. Soft tissue (5/10) and bone metastases (4/10) were the most frequently observed first site of relapse, but no relapses were noticed in the liver. Conclusions: Our results suggest that the operable BC may differ biologically between two age groups, at least in the most frequently first relapse sites. No significant financial relationships to disclose.

Current status of endocrine therapy for breast cancer.

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.