Effects Of Hormone Therapy Research Articles

PD04-04: Sexual Dysfunction in Women with Early Stage Breast Cancer on Endocrine Therapy: Encouraging Results from a Prospective Study.

Abstract Background: While the side effects of endocrine therapy (ET) for early stage breast cancer (EBC) have been extensively studied, the link between ET and sexual dysfunction (SD) remains a contentious issue. Most studies have focused on documenting only the presence of problems in specific domains of endocrine symptoms (ES) (e.g. hot flushes, vaginal dryness) and sexual functioning (SF) (interest, satisfaction, arousal, lubrication) without also taking sexual distress into account. To our knowledge, there have been no prospective longitudinal studies evaluating SF and SD before the onset of ET and after treatment initiation. We report the initial 6 month results of this study of SD in women initiating ET for EBC. Methods: Hormone receptor positive EBC post-menopausal women were approached for a larger study of SF aimed at comparing the prevalence of SD across endocrine agents (tamoxifen vs aromatase inhibitor) and at evaluating the impact of anxious predisposition and ES on SD. Here we report on changes in ES, SF and SD after 6 months of ET. SF was evaluated with the Female Sexual Function Index (FSFI) while sexual distress was assessed with the Female Sexual Distress Scale. ES were measured with FACT-B ES subscale. Participants completed questionnaires prior to initiation (T0) of ET and at 6 months (T1). SD was assessed using the APA classification. Results: Between January 2009 and May 2011, 118 EBC patients entered the study and 83 have completed both assessments (mean age 62; 30% received chemotherapy). Over time, the levels of ES increased (p <0.001). Despite the worsening of ES at T1, no decline in SF was observed, this for each FSFI domain (desire, arousal, lubrication, discomfort during intercourse and satisfaction). There was no change in the percentage of women reporting 1 or more sexual problems over time (85% vs 87%, ns) nor in the percentage who were sexually distressed (32% vs 34%, ns). The prevalence of SD did not increase after 6 months of ET (T0=28% vs T1=33%, ns). There were no differences in the percentage of women who worsened (i.e., no SD at T0 but SD at T1, 12%) and those who improved (SD at T0 but no SD at T1, 7%) over time (McNemar X2, p >.5) Importantly, women classified as experiencing SD at T0 were more likely to also experience SD at T1 (OR=4.5, 95% CI=2.162 to 9.366) than women who had no SD at T0. Discussion: This is the first prospective case cohort study evaluating ES, SF and SD in women with EBC on ET. The good news for women is that although ES increased during ET (p < 0.001), this did not have a negative impact on sexual problems (85% vs 87%, ns) or SD (32% vs 34%, ns). This is encouraging news but longer follow-up of these women will provide further insight into the impact of ET on ES and SD over time (> 6 months). The impact of specific types of ET on ES, and SD will also be evaluated. Of interest, the high uptake and high completion rate (>80%) of questionnaires, indicate this is a matter of relevance and importance to women taking adjuvant ET and merits acknowledgement and sensitive discussion. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-04.

Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers

To evaluate the impact of low estrogen/progesterone receptor (ER/PR) expression and effect of endocrine therapy on survival outcomes in human epidermal growth factor receptor 2 (HER2)-negative tumors with ER/PR <10%, previously labeled as triple negative. In a retrospective review, 1257 patients were categorized according their ER/PR percentages into 3 groups, ER/PR <1% (group A), ER/PR 1% to 5% (group B), and ER/PR 6% to 10% (group C). Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. Groups A, B, and C had 897 (71.4%), 241 (19.2%), and 119 (9.4%) patients, respectively. After a median follow-up of 40 months there was no significant difference in 3-year recurrence-free survival (RFS): 64%, 67%, and 77% (P = .34) or overall survival (OS): 79%, 81%, and 88% (P = .33) for groups A, B, and C, respectively. ER/PR expression was not an independent predictor for RFS (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.86-1.39; P = .46 for group B, and HR, 0.96; 95% CI, 0.66-1.38; P = .81 for group C, compared with group A), or OS (HR, 1.11; 95% CI, 0.84-1.46; P = .46 for group B, and HR, 0.94; 95% CI, 0.63-1.42; P = .78 for group C, compared with group A). Endocrine therapy had no impact on survival outcomes (RFS: P = .10; OS: P = .45) among groups. In this cohort, a low ER/PR level (1%-5%) does not appear to have any significant impact on survival outcomes. There was a tendency for survival advantages in the ER/PR 6% to 10% is seen. Benefit of endocrine therapy in these patients is unclear.

Abstract 939: Mechanistic basis of tamoxifen-associated development of endocrine resistance in breast cancer

Abstract Many estrogen receptor-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with SERMs such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3ζ, is up-regulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen up-regulates 14-3-3ζ and may promote the development of endocrine resistance is not known. Our findings reveal that the tamoxifen up-regulation of 14-3-3ζ results from its ability to rapidly down-regulate a microRNA that specifically targets 14-3-3ζ. The levels of 14-3-3ζ and this microRNA were always inversely correlated, with 14-3-3ζ being elevated and the microRNA being at a low down-regulated level in tamoxifen-resistant breast cancer cells. Of note, down-regulation of the microRNA was selectively elicited by tamoxifen but not by other SERMs such as raloxifene or by the estrogen receptor down-regulator ICI182,780 (Fulvestrant). Reducing the cellular level of 14-3-3ζ by either antagomiR blockade of the tamoxifen suppression of the microRNA or by elevation of the intracellular level of the microRNA by over-expression resulted in decreased cell proliferation and colony formation, increased apoptosis, and very importantly, restoration of the growth inhibitory effectiveness of SERMs in endocrine-resistant breast cancer cells. Restoration of responsiveness to endocrine therapy was also accompanied by markedly reduced activation of HER2, EGFR, and MAPK signaling, key components in endocrine resistance. Thus, we identify tamoxifen down-regulation of a microRNA, and consequent elevation of the key survival factor 14-3-3ζ, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches that increase expression of this microRNA should be considered to down-regulate 14-3-3ζ and enhance the effectiveness of endocrine therapies. Furthermore, the observed differential effects of the two SERMs, tamoxifen and raloxifene, in regulation of this microRNA and 14-3-3ζ, may assist in understanding differences in the activities of these SERMs, as seen in the STAR breast cancer prevention trial and in other clinical trials. (Supported by a grant from The Breast Cancer Foundation to BSK and a postdoctoral fellowship from the Department of Defense (W81XWH-09-1-0398) to AB.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2011-939

Effect of Endocrine Therapies on Bone in Breast Cancer Patients

Recent data suggest that AIs are more effective than tamoxifen in the adjuvant and advanced disease settings and are now being more commonly used. Tamoxifen, as a selective estrogen receptor modulator, exerts estrogenic effects to preserve bone, whereas the AIs profoundly lower estrogen levels and cause bone loss. Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption. Objective: The aim of the study was to review the mechanistic effects of estrogen on bone and clinical data regarding bone density, bone turnover markers, and fracture rates in women with breast cancer taking tamoxifen or AIs. Evidence Acquisition and Synthesis: Data presented reflect a review of the literature and data integration from the perspective of the author’s knowledge of the field. Results: Tamoxifen increases bone density and reduces fractures in postmenopausal women with breast cancer, whereas AIs increase rate of fracture, accelerate loss of bone mineral density, and enhance levels of markers of bone formation and resorption. Bisphosphonates and denosumab counteract the effects of the AIs on bone. Guidelines for management of AI-induced bone loss are available from several sources, but a simple algorithm guides decision making most effectively. Conclusions: Endocrine therapy for postmenopausal women with breast cancer exerts substantial effects on bone, and guidelines are available to assist in the management of bone-related problems.

Abstract PD08-02: The Impact of Patient Reported Outcomes (PRO) on the Evaluation of Therapy Related Side-Effects and the Improvement of Adherence to Endocrine Treatment in Breast Cancer Patients

Abstract Background: Long term treatment regimen with significant side effects may diminish a patient's quality of life (QOL) and consequently undermine adherence. Endocrine treatment for breast cancer causes various side effects, which can lead to early discontinuation of this effective therapy. Current knowledge on patients’ quality of life (QOL) impairments caused by endocrine therapy originates from clinicians’ impressions and expert ratings. This runs the risk of underestimating the effects of endocrine therapy on patients’ quality of life. Patient reported outcome (PRO) may provide higher accuracy and may therefore essentially contribute to medication evaluation and clinical decision making. In this study, we report on the patient reported outcome (PRO) related to endocrine therapy in early breast cancer. Methods: Pre-and postmenopausal breast cancer outpatients treated with aromatase inhibitors (AIS) or tamoxifen were approached at their routine control appointment with the treating physician. We conducted a comprehensive PRO assessment comprising the following scales: FACT-B/+ES and HADS (high scores indicate high symptoms). In a short, semi-structured interview data on patients’ general medication intake behavior were collected focusing on the intake of complementary and alternative medicine (CAM) Results: We analyzed PRO data of 240 patients undergoing endocrine treatment. 66.6% received AI therapy, 71.9% were postmenopausal. We found high levels of symptom burden in this study group: 55.9% had moderate to severe bone pain, 47.8% menopausal symptoms and 49.1% loss of sex drive. Postmenopausal women in the AI group had significantly more symptoms on the endocrine subscale (mean 24.25 vs. 16.42, p=0.045), significantly more anxiety (mean 8.8 vs. 5.11, p=0.036) and depression (mean 8.75 vs. 3.86, p=0.011). In the tamoxifen group premenopausal patients scored significantly higher on all scales. Moreover, patients who used complementary substances had a significant lower physical well-being (22.70 vs. 24.39, p=0.007) and more endocrine symptoms (22.63 vs. 16.30, p=0.004). Conclusion:The results of our study show a significantly higher assessment of physical side-effects and psychosocial burden on part of the patients than implied by clinicians’ reports and expert ratings. PRO data may therefore provide a more accurate measure for symptom burden and contribute to individualized clinical decision making. It is an important tool to detect and effectively treat therapy related side effect to ultimately preserve adherence to endocrine treatment. According to our findings, it appears mandatory to incorporate PRO data in individualized clinical decision making to arrive at a more accurate assessment of symptom burden. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-02.

Abstract P5-11-16: Cognitive Effects of Endocrine Therapy in Patients with Breast Cancer

Abstract Background: Adjuvant endocrine therapy is the mainstay in the therapy of primary breast cancer. However, the impact of endocrine therapy on cognitive function in patients with breast cancer is still unclear. Numerous studies suggest a protective effect of estrogens on neurons. From these findings it has been derived that the almost complete estrogen deprivation by aromatase suppression would modify cognitive performances. The primary aim of our study was to ascertain, whether neurocognitive functioning is altered in breast cancer patients receiving various endocrine therapies. Patients and Methods: In a cross sectional study we investigated 80 post-menopausal women with breast cancer. Memory, spatial cognition, processing speed and attention were evaluated. Patients who ever received chemotherapy were not included. To compare cognitive task performance we constituted four treatment groups (see tab. 1). Tab. 1 Groups and Medication Patient characteristics were equally distributed, however, “switch” patients had received significantly more hormone replacement therapy before the onset of breast cancer than all other groups. We also evaluated mood, depression, anxiety, pre-morbid intelligence and self-perception of memory in order to receive homogenous groups. All participants were interviewed about their compliance to their medication. In this study, we used univariate statistical analyses of variance (ANOVA) and we calculated the effect-sizes of significant values. In case of lacking normal distribution we applied non-parametric statistics. Results: Women who solely received aromatase inhibitor treatment showed a significant impairment of general memory (p=0.01, d=1.15) and verbal memory (p=0.026, d=0.97) in comparison to the control group. In more than 50% of the aromatase inhibitor patients we found below-average performance concerning verbal memory compared to normative data. The aromatase inhibitor group performed significantly worse than the tamoxifen-(p=0.035, d=0.64) and the “switch-group” (p=0.03, d=0.91) with regard to attention. With respect to their spatial abilities, no significant differences in navigation and in mental rotation were noted. With regard to path integration we solely ascertained significant lower results of the aromatase inhibitor patients compared with the tamoxifen group (p=0.04). Overall, no differences were observed between the “switch”- and the tamoxifen patients. Surprisingly, most patients perceived their own memory performance as averaged. Self-perception of memory correlated with anxiety and depression but not with test scores. Conclusion: Treatment with tamoxifen alone seems to be less harmful for cognitive abilities than treatment with aromatase inhibitors alone. Patient may benefit from prior tamoxifen therapy when sequentially treated with aromatase inhibitors however this observation must be confirmed in further studies as well as the potential role of prior hormone replacement therapy and the objective adherence to therapy assessed by serum drug levels measurements. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-16.

Effect of Endocrine Therapies on Bone in Breast Cancer Patients

Two common strategies are used to treat estrogen receptor-positive breast cancer in women: tamoxifen to inhibit estrogen action, and aromatase inhibitors (AIs) to block estrogen biosynthesis. Recent data suggest that AIs are more effective than tamoxifen in the adjuvant and advanced disease settings and are now being more commonly used. Tamoxifen, as a selective estrogen receptor modulator, exerts estrogenic effects to preserve bone, whereas the AIs profoundly lower estrogen levels and cause bone loss. Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption. The aim of the study was to review the mechanistic effects of estrogen on bone and clinical data regarding bone density, bone turnover markers, and fracture rates in women with breast cancer taking tamoxifen or AIs. Data presented reflect a review of the literature and data integration from the perspective of the author's knowledge of the field. Tamoxifen increases bone density and reduces fractures in postmenopausal women with breast cancer, whereas AIs increase rate of fracture, accelerate loss of bone mineral density, and enhance levels of markers of bone formation and resorption. Bisphosphonates and denosumab counteract the effects of the AIs on bone. Guidelines for management of AI-induced bone loss are available from several sources, but a simple algorithm guides decision making most effectively. Endocrine therapy for postmenopausal women with breast cancer exerts substantial effects on bone, and guidelines are available to assist in the management of bone-related problems.

Hormone therapy's effects on dementia a matter of timing

Hormone therapy's effects on dementia a matter of timing

Abstract 4449: Effects of endocrine therapy on mRNA- and microRNA expression profiles in prostate cancer

Abstract Introduction &amp; Objectives: The gold standard treatment for advanced prostate cancer is endocrine therapy either by castration (surgical or chemical) or with antiandrogens. Although endocrine therapy has been used for decades, the molecular consequences of androgen deprivation are poorly understood. The aim of this study was to investigate how endocrine therapy affects genome-wide gene expression and to ascertain whether chemical castration or antiandrogen use leads to unique gene expression profiles. Methods: 30 patients were randomized equally into three groups: no treatment, bicalutamide (antiandrogen) 150 mg daily, and goserelin (GnRH agonist) 3.6 mg every 4 weeks. Following the neoadjuvant treatment for 12 weeks, patients underwent radical prostatectomy. Freshly frozen specimens were collected for expression profiling of both protein (mRNA) and microRNA (miRNAs) coding genes using Illumina (probes for ∼25 000 mRNAs) and Agilent (723 miRNAs) microarrays, respectively. The amount of cancer, benign epithelium, and stroma in the specimens was assessed using H&amp;E stained slides. Statistical analyses were first done without taken into account the tissue composition of specimens. Subsequently, tailor-made in silico Bayesian modeling tool was used to predict the mRNA and miRNA expression patterns in the different cellular compartments. mRNA expression from microarray data and in silico predictions were validated with qPCR from microdissected tissue samples. Results: In unsupervised hierarchical clustering of mRNA profiles, specimens from bicalutamide and goserelin arms were clustered separately from control samples, but not separately from each other. Out of 600 significantly differently expressed mRNAs between control and treatment arms (p&amp;lt;0.05), only 56 were unique for bicalutamide treatment and 13 for goserelin treatment. Interestingly, tissue compartment analysis showed that bicalutamide affects more specifically cancer cells while goserelin has more effect to stroma and normal epithelium. In the miRNA profiles, there were only minor changes in the bicalutamide and goserelin treatment arms compared with control arm. Only 6 miRNAs were significantly differently expressed (p&amp;lt;0.05). Also, there was more variety in miRNA expression between different tissue compartments than treatment arms. Conclusions: In conclusion, androgen deprivation had more effect on mRNA than miRNA expression. Most of the differentially expressed genes behaved similarly after GnRH agonist and antiandrogen treatments. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4449.

Molecular mechanisms of regulation of estrogen receptor a expression level in breast cancer

Estrogen receptor alpha (ERalpha) plays an important role in breast cancer development and progression and thus becomes a useful molecular target for breast cancer therapy. ERalpha is differentially expressed in breast cancer patients. Moreover, ERalpha expression levels may change at different stages of breast cancer even for the same patient. ERalpha expression is closely associated with the effect of endocrine therapy and prognosis. The mechanisms underlying ERalpha expression are complicated, because ERalpha expression is regulated at different levels, including chromatin, transcriptional, post- transcriptional, translational, and post-translational levels. Many proteins modulate the transcription of ERalpha gene at the chromatin and transcriptional levels through direct or indirect interaction with the ERa promoter. Some microRNAs decrease ERalpha levels possibly by induction of the degradation of ERalpha mRNA and/or repression of the mRNA translation. At the post-translational level, many proteins regulate ERalpha protein levels through ubiquitin-proteosome pathway. This review focuses on molecular mechanisms of regulation of ERalpha expression at different levels.

Exploring the Impact of the Hormonal Milieu on Cognitive Functioning

An area receiving increasing empirical attention in the past several years is cognitive functioning among cancer survivors exposed to adjuvant systemic therapies. This increased focus can be attributed to the recognition that a sizeable minority of those patients undergoing adjuvant chemotherapy report and/or demonstrate some degree of cognitive compromise—colloquially called chemobrain or chemofog. However, to date, there has been considerably less research on the possible cognitive effects of endocrine therapies for cancer treatment or risk reduction/prevention. Medications such as tamoxifen and raloxifene or the aromatase inhibitors—drugs that modify the hormonal milieu in those women with hormone receptor– positive tumors—may independently, or with chemotherapy, be associated with cognitive complaints. Given the importance of estrogen, the main target for these drugs, for normal brain function and its relationship to several neurological processes, it makes sense to better understand the potential cognitive sequelae of these medications. In this issue of the Journal of Clinical Oncology, Legault and colleagues report their findings comparing the impact of two selective estrogen receptor modulators (SERM)—tamoxifen and raloxifene—on the cognitive function of postmenopausal women at increased risk for breast cancer. The Cognitive Aging Study of Tamoxifen and Raloxifene (Co-STAR) study enrolled nearly 1,500 healthy women older than 65 years (excluding any with suspected dementia) who had been randomly assigned to one of two groups, either oral tamoxifen 20 mg/d or oral raloxifene 60 mg/d, as part of the STAR trial. The majority of women were enrolled in Co-STAR after having initiated their STAR trial medication, although a small number of women (n 273) had cognitive functioning assessment before starting SERM therapy. In this article, they report results from those women observed for at least 3 years who completed a focused, brief, neurocognitive battery at three assessment points roughly 12 months apart. Although the investigators had hypothesized that raloxifene would confer cognitive benefits compared with tamoxifen, they found little difference in cognitive performance between the tamoxifen and raloxifene groups and suggested that these two SERMs have a similar impact on cognitive functioning in this particular cohort of older women deemed at elevated risk for breast cancer. There are several important strengths of the Co-STAR study conducted by Legault and colleagues. For example, they undertook the challenging task of assessing cognitive function in a large scale, multisite, longitudinal study, paying close attention to the important issue of practice effects (ie, that repeated exposure to the same or similar tests often leads to higher performance after the initial assessment). They also attempted to measure meaningful domains of cognition that have been previously implicated in cognitive aging and also with chemobrain sufferers—learning and memory and executive functioning (ie, working memory and verbal fluency). A large sample size, a sound analytic strategy, and the investigators’ careful attention to potential confounds such as depression and affective style all lend weight to their conclusion that those women who received tamoxifen did not differ in neuropsychological performance from those that received raloxifene. Scores on the majority of neuropsychological tasks either stayed stable or improved over time (as would be expected based on practice effects). The one task on which a clinically significant decline in performance was noted was on a verbal learning and memory task that had been significantly modified including what the authors describe as the introduction of a more difficult form. However, the applicability of these findings beyond this population, for example to patients with breast cancer, is unclear. As the authors note, there may be group differences in lifetime and current estrogen exposure that may leave some groups primed to benefit from SERM administration (eg, those with osteoporosis) or, conversely, groups that are more likely to experience cognitive compromise. In terms of groups more vulnerable to cognitive compromise, this article does not address (and wasn’t intended to) an issue of considerable importance to the Journal of Clinical Oncology readership, which is whether SERM exposure during adjuvant systemic chemotherapy might be more likely to cause cognitive changes in women with breast cancer. Certainly the limited data available in the breast cancer studies that have examined adjuvant tamoxifen therapy does not suggest a neuroprotective effect of SERM exposure. Our group at University of California, Los Angeles has reported, in a cross-sectional study of long-term breast cancer survivors, that patients exposed to both tamoxifen and chemotherapy were more likely to experience cognitive compromise several years after treatment than were those who received no adjuvant therapy or who received chemotherapy alone and that this group is more likely to show altered neurophysiology, as assessed by brain positron emission tomography. A recent study of premenopausal breast cancer patients who did not receive any chemotherapy, but who had been taking tamoxifen for an average of 2.3 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L

Hormone receptor-positive early breast cancer: controversies in the use of adjuvant chemotherapy

Current adjuvant treatments for operable breast cancer include chemotherapy, endocrine therapy in hormone receptor-positive tumors, and trastuzumab for HER2-positive tumors. Metanalyses of randomized trials show that in patients with hormone receptor-positive breast cancer, the effects of endocrine therapy and chemotherapy on survival are non-mutually exclusive. Most of these patients are therefore considered candidates to combined treatment. Recently, however, the endocrine responsiveness of tumors has been redefined on clinical, histopathological, and molecular bases. An emerging concept is that as endocrine responsiveness increases, chemoresponsiveness decreases. In the adjuvant setting, therapeutic choices are often based on small projected improvements in clinical outcomes. As a consequence, the role of chemotherapy and traditional management algorithms in patients with hormone receptor positive is being challenged. This review will address the current controversy regarding the role of adjuvant chemotherapy, including the newer anthracycline and taxane-based programs, in these patients.

Effect of endocrine therapy with tamoxifen on hormone receptor status in patients with breast cancer

e11598 Background: Endocrine therapy (ET) of patients with hormone receptor (HR)-positive breast cancer (BC) is thought to adversely affect the HR status of the tumor with time. In order to evaluate this, a study was undertaken comparing the HR status of patients with estrogen receptor (ER)-positive BC prior to adjuvant tamoxifen (Tam) therapy and after progression. Methods: A retrospective analysis of all BC patients presented to the unit between 1999 to 2004 with an initial stage I-III ER-positive BC, who received Tam between 6 and 60 month and went on to develop progressive disease in the form of local recurrence or distant metastasis. Progression was confirmed by tumor biopsy and analysis of the HR status. All patients were evaluated for ER and progesterone receptor (PR) status using immunohistochemistry as well as tumor grading prior to Tam therapy and after relapse. Results: 67 eligible patients with ER-positive BC were recorded. All patient and tumor characteristics, including age, tumor size, histology and adjuvant therapy were similar as published elsewhere. 82% were initially PR-positive. The mean duration of Tam administration of 20mg po was 40.7±19.9 month. The mean duration to progression was calculated at 54.9±34.6 month. After relapse, 70.1% of tumors retained a positive ER status and only 53% showed positive PR expression. Using the nonparametric McNemar's test, a highly significant reduction (p&lt; 0.001) of both HR was the result of Tam administration. Conclusions: our data suggests that progression under ET shows a trend towards loss of HR status (ER as well as PR). Therefore, this data is a useful tool for the clinician in evaluating the effectiveness of further ET in patients with progressive BC without having been able to confirm the present HR status through biopsy. Furthermore, as opposed to common belief, the reduction in positive ER tumors showed no correlation with tumor grading. No significant financial relationships to disclose.

Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.

Down-Regulation of Phosphatidylinositol 3′-Kinase/AKT/Molecular Target of Rapamycin Metabolic Pathway by Primary Letrozole-Based Therapy in Human Breast Cancer

The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.

Adjuvant Hormonal Therapy for Premenopausal Women With Breast Cancer

Endocrine therapy is a required element of the management of premenopausal women with early-stage steroid hormone receptor-positive breast cancer. There is uncertainty about how best to implement that therapy using the strategies of tamoxifen and estrogen deprivation as well as how to integrate these approaches with chemotherapy. Other research focuses on identification of improved markers for endocrine response or resistance and on the special side effects of endocrine therapy in young women.

Co-expressed type of ER and HER2 protein as a predictive factor in determining resistance to antiestrogen therapy in patients with ER-positive and HER2-positive breast cancer

The purpose of this study was to analyze whether inter-site variation types on estrogen receptor (ER) and HER2 expression may be a predictive factor for evaluating the effectiveness of endocrine therapy in patients with ER-positive and HER2-positive breast cancer. A total of 366 consecutive women with invasive breast cancer who had undergone curative surgical treatment between 1996 and 2001 were included in this study. ER status was evaluated using the Allred score and HER-2 status was evaluated according to the HercepTest. In ER-positive and HER2-positive tumors, the expression of ER and HER2 was described as the co-expressed type or the differently expressed type using double staining with ER and HER2. Of the 366 patients, 249 (68.1%) were positive for ER and 74 (20.2%) were positive for HER2. ER-positive and HER2-negative tumors were found in 221 patients (60.4%), ER-negative and HER2-negative in 71 (19.4%), ER-negative and HER-2-positive in 46 (12.6%), and ER-positive and HER2-positive in 28 (7.7%). HER2 status was inversely correlated (p<0.01) with ER status. In ER-positive tumors, an inverse correlation between ER and HER2 was also observed. The co-expressed type was found in 10 patients, and the differently expressed type was found in 18. There was no difference in tumor size and nodal involvement between the two types. There was no significant difference in disease-free survival between patients with the co-expressed type tumor and the differently expressed type tumor. In patients with the differently expressed type tumor, those who received antiestrogen therapy showed a significantly better disease-free survival rate than those who did not receive antiestrogen therapy. As for patients with the co-expressed type of tumor, no significant difference in disease-free survival was observed between patients with and without antiestrogen treatment. The present study suggests that the co-expressed type of tumour might be a resistant factor to antiestrogen therapy in ER-positive and HER2-positive breast cancer.

Co-expressed type of ER and HER2 protein as a predictive factor in determining resistance to antiestrogen therapy in patients with ER-positive and HER2-positive breast cancer

900 Background: The purpose of this study is to analyze whether or not inter-site variation types on ER and HER2 expression may be a predictive factor for evaluating effectiveness of endocrine therapy in patients with ER-positive and HER2-positive breast cancer. Methods: A total of 366 consecutive women with invasive breast cancer who had undergone curative surgical treatment between 1996 and 2001 were included in this study. ER status was evaluated using the Allred score and HER2 according to the HercepTest. In ER-positive and HER2-positive tumors, expression of ER and HER2 was described as the co-expressed type or the differently expressed type using double staining with ER and HER2 antibody. Results: Of the 366 patients, 249 (68.1%) were positive for ER and 74 (20.2%) were positive for HER2. ER-positive and HER2-negative tumors were found in 221 patients (60.4%), ER-negative and HER2-negative in 71 (19.4%), ER-negative and HER2-positive in 46 (12.6%), and ER-positive and HER2-positive in 28 (7.7%). HER...

Aromatase inhibitors—Socio-economical issues

Novel, third-generation aromatase inhibitors are currently implemented for treatment of postmenopausal breast cancer in the metastatic and adjuvant setting and, potentially, for breast cancer prevention. Introduction of novel therapeutic strategies to large patient groups may add significant costs to health care budgets, forcing institutions to focus entirely on costs or the cost-utility of implementing such novel strategies. Breast cancer is the most frequent cancer in the female population in western societies, and its incidence is currently increasing in other parts of the world as well. Due to the proven efficacy and limited side effects of endocrine therapy in the adjuvant setting, the indications for use have been successively broadened. Currently, the majority of postmenopausal women treated for an estrogen-receptor positive breast cancer will be offered adjuvant endocrine therapy; thus, a general change of practice may cause significant implications to healthcare costs. This may relate to direct drug costs as well as indirect costs related to prevention of side effects, like additional use of bisphosphonates to prevent enhanced bone loss. The aim of this paper is to overview these considerations and put them into perspective by simple illustrations taken from current cost estimates.

Side effects of endocrine therapy in patients with breast cancer

Side effects of endocrine therapy in patients with breast cancer