Therapy For Postmenopausal Breast Cancer Research Articles

Implications of Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer

Aromatase Inhibitor(AI) therapy is a crucial treatment for regulating estrogen production that combats breast cancer in postmenopausal patients. Clinical trials have emphasized its importance, as it has surpassed its prior efficacy through each succeeding generation of AI therapy and surpassed other treatment options like estrogen modulators(Tamoxifen) and Progestin therapy(Megace/Megestrol Acetate). There is a big difference between AI therapy and other therapies, though they all ultimately attempt to stop the proliferation of cancerous cells. AI therapy has been shown to be effective; however, some side effects of its use have been challenging its place in recent studies. Many physicians have noticed and questioned its use, and future research addressing these concerns needs to be executed in order to enhance the quality of life for our breast cancer patients. In this paper, an overview of the current status of breast cancer, the details of breast cancer and its development, the different types of breast cancer, the workings of AI therapy, clinical trials of Aromatase Inhibitor therapy, a comparison of different therapies, Physician input, and future implications of its effectiveness will be discussed in detail.

Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells

Estrogen receptor-positive (ER+) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice. Nevertheless, the lack of cross-resistance between AIs hints that these drugs may act through distinct mechanisms. Therefore, this work studied the different effects induced by AIs on biological processes, such as cell proliferation, death, autophagy and senescence. Moreover, their effects on the regulation of the hormonal environment were also explored. The non-steroidal AIs induce senescence, through increased YPEL3 expression, on aromatase-overexpressing breast cancer cells (MCF-7aro), whereas Exe promotes a cytoprotective autophagy, thus blocking senescence induction. In addition, in a hormone-enriched environment, the non-steroidal AIs prevent estrogen signaling, despite up-regulating the estrogen receptor alpha (ERα), while Exe down-regulates ERα and maintains its activation. In these conditions, all AIs up-regulate the androgen receptor (AR) which blocks EGR3 transcription in Exe-treated cells. On the other hand, in hormone-depleted conditions, a crosstalk between AR and ERα occurs, enhancing the estrogenic effects of Exe. This indicates that Exe modulates both ERα and AR, while Ana and Let act as pure AIs. Thus, this study highlights the potential clinical benefit of combining AR antagonists with Exe and discourages the sequential use of Exe as second-line therapy in postmenopausal breast cancer.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer

BackgroundFor postmenopausal women with hormone-receptor–positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.MethodsIn this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture.ResultsAmong the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84).ConclusionsIn postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.)

Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors.

ContextAromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer.ObjectiveWe hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.DesignCase-control study.SettingUniversity teaching hospital.ParticipantsPatients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.Main outcome measuresThe primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).ResultsAromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).ConclusionWomen who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.

Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer.

Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients' quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone-targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates.

Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98

PurposeTo evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer.MethodAIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group’s trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs).ResultsForty-six percent of the tumors had a high AIB1 expression. In line with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80–100 vs. 1–79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival (univariable: hazard ratio 1.35, 95% confidence interval 1.12–1.63. Multivariable: hazard ratio 1.29, 95% confidence interval 1.06–1.58) and overall survival (univariable: hazard ratio 1.34, 95% confidence interval 1.07–1.68. Multivariable: hazard ratio 1.25, 95% confidence interval 0.99–1.60). HER2 did not seem to modify the prognostic effect of AIB1. No difference in treatment effect between tamoxifen and letrozole in relation to AIB1 was found.ConclusionsIn a subset of the large international randomized trial BIG 1-98, we confirm AIB1 to be a strong prognostic factor in early breast cancer. Hence, although tumor AIB1 expression does not seem to be useful for the choice of tamoxifen versus an aromatase inhibitor in postmenopausal endocrine-responsive breast cancer, AIB1 is an interesting target for new anti-cancer therapies and further investigations of this biomarker is warranted.

Abstract P3-04-18: The impact of circulating androgens on the androgen receptor in aromatase inhibitor resistant breast cancer

Abstract Aromatase Inhibitor (AI) therapy is the gold standard first line therapy for post-menopausal breast cancer. Following AI treatment the conversion of circulating androgens into estrone can be diminished by >99%, completely altering the tumour steroid microenvironment. Estrogens have been extensively studied in terms of the role of sex steroids as causative agents of breast cancer but interestingly, a case–control study nested within the European Prospective Investigation into Cancer and Nutrition reported that elevated levels of both serum androgens and estrogens are associated with increased breast cancer risk (E2 RR: 2.28 and androstenedione RR: 1.94). Also clinical studies have reported increases in the serum levels of androstenedione (4AD) in patients that recur on AI therapy. In order to begin to address the role of circulating androgens and the androgen receptor (AR) in AI resistant breast cancer, RNA sequencing was performed on AI resistant (MCF7-aro-LetR) cells cultured with 4AD in the presence of letrozole. Gene expression analysis was performed using the cBioPortal software found that PI3K signalling pathways were upregulated in response to 4AD treatment as well as the upregulation of pathways involved in exocytosis and hormone secretion. We found elevated levels of PI3K and AR in endocrine resistant breast cancer compared to sensitive cell lines and that our AI resistant LetR cells showed significant reduction in cell growth in response to the combined pan class PI3K inhibitor BEZ235 and anti-AR treatment. Clinically, we evaluated the potential role of PI3K signalling in AI resistance a breast cancer patient TMA (n=488) was stained immunohistochemically for phospho-AKT and AR. The protective effect conferred by high AR expression in the total patient population (p=0.02) and tamoxifen treated population (p=0.05) was lost in the AI treated population (p=0.49). For p-AKT staining, patients that were positive for p-AKT significantly associate with the more aggressive luminal B classification yet exhibit an inverse association with luminal A subtype. Kaplan Meier analysis revealed that AR is associated with a more favourable outcome in p-AKT negative patients but that this is lost in the context of elevated p-AKT. Furthermore, interrogation of the breast invasive carcinoma TCGA dataset (n=963) revealed that patients with upregulated AR mRNA and wildtype PI3K exhibited more invasive disease compared with those harbouring a PI3K mutation (p=0.02) (n=56). Further investigations into the AR interacting partners will help elucidate potential mechanisms of action and the role of androgens and AR in facilitating breast cancer tumourigenesis. Citation Format: Creevey L, Ali A, Bleach R, Hill ADK, Young L, McIlroy M. The impact of circulating androgens on the androgen receptor in aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-18.

The effects of the standardized extracts of Ginkgo biloba on steroidogenesis pathways and aromatase activity in H295R human adrenocortical carcinoma cells.

ObjectivesAromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761) induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. MethodsCortisol, aldosterone, testosterone, and 17β-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21) and the hydroxysteroid dehydrogenases (3β-HSD2 and 17β-HSD1/4). Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. ResultsH295R cells exposed to EGb761 (10 and 100 μg/mL) showed a significant decrease in 17β-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and 17β-HSD1) related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/ Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. ConclusionsThese results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and 17β-HSD1, and lead to a decrease in 17β-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer.

Abstract 3981: Tamoxifen inhibited cell migration and increased chemosensitivity by reversal of EMT in ER-negative breast cancer cells

Abstract BACKGROUND: Tamoxifen (TAM) is the mainstay endocrine drug used as adjuvant therapy for postmenopausal breast cancer (PMBC) patients. Although the efficacy of tamoxifen has been attributed to the induction of cell cycle arrest and apoptosis by inhibition of ER signaling pathway, recent evidence indicates that tamoxifen also possesses ER-independent antitumor activity in breast cancer treatment. However,the mechanism is not clear. Therefore, the present study is aimed to investigate the anti-tumor mechanism of tamoxifen on ER negative breast cancer. METHODS: The cell morphology changes were observed by using electron microscopy. Proteins expression was tested by western blot. miRNAs expression was examined by Real-Time PCR. And cells migration ability was observed by trans-well assay. Mice experiments were carried by using nude mice. Inhibition of protein expression was done by RNA interfering experiments. RESULTS: Our results showed an interesting morphology change of ER negative breast cancer cells. After treated with TAM, the morphology ER negative MDA-MB-231 and MCF-7/ADR breast cancer cells were reversed from mesenchymal type to epithelial type accompanied by down regulation of Vimentin and up-regulation of E-cadherin. Meanwhile cells migration ability was also significantly decreased. But ER positive MCF-7 breast cancer cells didn't show any changes after exposure to TAM. Mice experiments demonstrated that TAM significantly suppressed lung metastasis rate of ER negative breast cancer cells. In addition, TAM enhanced adriamycin effect on ER negative but not ER positive breast cancers cells. To explore the mechanisms, we screened miRNAs changes by miRNA array analysis, and found that miR-200c is obviously up-regulated. Through Biological information analysis, CPG island is found exist in the promoter region of miR-200c. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5Aza-dC) also increased miR-200c expression. Further investigation demonstrated that DNA (cytosine-5)- methyltransferase DNMT 1 and 3A were down-regualted by TAM. And inhibition of DNMT 1 and 3A by RNAi increased miRNA-200c. These results indicated that TAM inhibited cells migration and enhanced adriamycin sensitivity of ER negative breast cancer cells by reversing their EMT-like property. And the EMT reversal effect resulted from up-regulation of miR-200c. Down-regualtion of DNMT 1 and 3A and CPG island demethylation of miRNA-200c contributed to up-regulation of miR-200c. CONCLUSIONS: Tamoxifen inhibited cells migration and increased chemosensitivity by reversal of EMT in ER negative breast cancer cells. Our findings described a novel mechanism to explain how TAM effect on ER negative breast cancer cells. Citation Format: Xiujuan Qu, Qian Wang, Yan Wang, Ye Zhang, Yuee Teng, Yunpeng Liu. Tamoxifen inhibited cell migration and increased chemosensitivity by reversal of EMT in ER-negative breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3981. doi:10.1158/1538-7445.AM2015-3981

Abstract P3-05-21: Investigation into the oncogenic potential of the androgen receptor in aromatase inhibitor resistant breast cancer

Abstract The heterogenous nature of breast cancer, exemplified by a wide range of subtype classifications, has been well documented. The identification of the novel molecular apocrine breast tumours (ER-, PR-ve, HER2-ve, AR+), with a gene expression profile reflective of ER+ luminal breast cancer, has led to the proposition of an alternative role for the androgen receptor as a pseudo ER. This proposition was borne out of global expression profiling and AR recruitment of molecular apocrine cells, demonstrating that more than 50% of AR binding to the genome mirrors the pattern of ER binding suggesting that in the absence of ER, AR can mimic ER in its DNA binding capabilities. Aromatase Inhibitor (AI) therapy is the gold standard first line therapy for postmenopausal breast cancer. AIs function by abrogating the activity of the enzyme Cyp 19 (aromatase), which is responsible for converting circulating androgens to estrogen. By preventing this conversion step, this eradicates the main steroid driving breast cancer growth and in turn results in a more androgenic environment. We hypothesise that AR may also act as a pseudo ER in our AI resistant (MCF7-letrozole resistant) cells. Preliminary data demonstrates that AR is recruited to some but not all classical ER target genes as well as some AR target genes in MCF7-LetR cells, therefore highlighting the potential of AR to act as an oncogene in this setting. Analysis of AR protein expression also demonstrates higher levels of AR in AI resistant cells versus sensitive cells. In the evaluation of the responsiveness of a range of breast cancer cell lines to the AR antagonist Bicalutamide, it was noted that our AI resistant cells demonstrated responsiveness to Bicalutamide treatment. RNA sequencing experiments following AR knockdown in AI resistant cells also provide crucial information as to the key genes differentially regulated by AR. Given that resistance to AI therapy is an emerging clinical issue, further elucidation of the potential mechanisms of AI resistance and potential AR targets is highly warranted. Citation Format: Leonie Young, Laura Creevey, Azlena Ali, Arnold DK Hill, Marie McIlroy. Investigation into the oncogenic potential of the androgen receptor in aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-21.

Estrogen-dependent sushi domain containing 3 regulates cytoskeleton organization and migration in breast cancer cells.

Aromatase inhibitors (AI) are the standard endocrine therapy for postmenopausal breast cancer; however, currently used biomarkers, i.e., estrogen receptor-alpha/progesterone receptor (ERα/PR), predict only slightly more than half of the potential responders to AI treatment. To identify novel markers of AI responsiveness, a genome-wide microarray analysis was performed using primary breast tumor samples from 50 postmenopausal women (PMW) who later developed metastatic breast cancer. Sushi domain containing 3 (SUSD3) was significantly differentially expressed gene, with 3.38-fold higher mRNA levels in AI-responsive breast tumors versus non-responders (p<0.001). SUSD3 was highly expressed in ERα-positive breast tumors and treatment with estradiol increased SUSD3 expression in ERα-positive breast cancer cells. Treatment with an antiestrogen or ERα knockdown abolished basal and estradiol-dependent SUSD3 expression. Recruitment of ERα upstream of the transcription start site of SUSD3 was demonstrated by chromatin immunoprecipitation (ChIP)-PCR. Flow cytometric analysis of SUSD3 knockdown cells revealed blunted estradiol effects on progression into S and M phases. SUSD3 was localized to the plasma membrane of breast cancer cells. SUSD3 knockdown decreased the appearance of actin-rich protrusions, stress fibers and large basal focal adhesions, while increasing the presence of cortical actin concomitant with a decrease in Rho and FAK activity. SUSD3-deficient cells demonstrated diminished cell spreading, cell-cell adhesion, and motility. In conclusion, SUSD3 is a novel promoter of estrogen-dependent cell proliferation and regulator of cell-cell and cell-substrate interactions and migration in breast cancer. It may serve as a novel predictor of response to endocrine therapy and potential therapeutic target.

The Letrozole Phase 1 Metabolite Carbinol as a Novel Probe Drug for UGT2B7

Carbinol [4,4'-(hydroxymethylene)dibenzonitrile] is the main phase 1 metabolite of letrozole, a nonsteroidal aromatase inhibitor used for endocrine therapy in postmenopausal breast cancer. We elucidated the contribution of UDP-glucuronosyltransferase (UGT) isoforms on the glucuronidation of carbinol. Identification of UGT isoforms was performed using a panel of recombinant human UGT enzymes. Kinetic studies were done in recombinant human UGT2B7 and pooled human liver microsomes (HLMs). A liquid chromatography-tandem mass spectrometry method was used for detection of metabolites. To assess the impact of UGT2B7*2, we determined the carbinol glucuronidation activity using HLM as well as UGT2B7 protein expression in 148 human livers. Moreover, we analyzed the plasma concentrations of 60 letrozole-treated breast cancer patients. We identified UGT2B7 as the predominant UGT isoform involved in carbinol glucuronidation. In HLMs and recombinant UGT2B7, we determined K(m) values (9.99 and 9.56 µM) and V(max) values (3430 and 2399 pmol/min per milligram of protein), respectively. In the set of 148 human livers, carbinol glucuronidation activity significantly correlated with UGT2B7 protein as determined by Western blotting (r(s) = 0.5088, P < 0.0001). Neither carbinol glucuronidation activity (*1/*1: n = 25, 2434 ± 1018; *1/*2: n = 80, 2356 ± 1372; *2/*2: n = 43, 2251 ± 1421 pmol/min per milligram of protein) nor UGT2B7 protein expression was altered by the UGT2B7*2 genotype. No impact of UGT2B7*2 on plasma levels of carbinol and carbinol-gluc [bis(4-cyanophenyl)methyl hexopyranosiduronic acid] in 60 letrozole-treated patients was found. Taken together, these findings suggest carbinol as a novel in vitro probe substrate for UGT2B7. In vitro and in vivo data suggest a lack of influence of the UGT2B7*2 polymorphism on carbinol glucuronidation.

Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial

In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

421 ER Allred Score Predicts Outcome of Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer – a TEAM Study Analysis

421 ER Allred Score Predicts Outcome of Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer – a TEAM Study Analysis

Adaptive Changes Result in Activation of Alternate Signaling Pathways and Acquisition of Resistance to Aromatase Inhibitors

Hormone therapy is an effective approach for the treatment of breast cancer. Although the antiestrogen tamoxifen has had a major impact on the treatment of the disease, aromatase inhibitors (AIs), which reduce estrogen synthesis, have recently proved to be more effective. These agents are now used as first-line therapy for postmenopausal breast cancer. Nevertheless, despite the efficacy of these agents, resistance to treatment eventually may occur in some patients. In an effort to overcome this resistance and extend the benefits of AIs, investigators have studied the mechanisms involved in resistance to AIs. Adaptive changes that result in activation of alternate signaling pathways in AI-resistant tumors have been identified in xenograft and cell line models. Expression of estrogen receptor α and aromatase was shown to be decreased in tumors after long-term treatment with AIs. In contrast, increased expression was observed in tyrosine kinase receptors such as Her-2 and insulin-like growth factor receptor, as well as in downstream signaling proteins such as mitogen-activated protein kinase. Functional activation of the mitogen-activated protein kinase pathway and dependency on growth factor receptor signaling have been observed in AI-resistant cells and tumors.

Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and Validation

PurposePrevious studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.MethodsWe created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates.ResultsThe 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results.ConclusionsOur modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.

Abstract P1-11-11: Correlation between ER/PgR/Her-2/Ki67 Expression and Response to Neoadjuvant Endocrine Therapy for HR Positive Post-Menopausal Breast Cancer

Abstract Background: Endocrine therapy was standard adjuvant treatment for hormone receptor positive breast cancer. However, there were factors other than receptor status could influence endocrine responsiveness. Neoadjuvant therapy was an excellent platform for predictive factors research, but the standard for evaluating the efficacy of neoadjuvant endocrine therapy was controversy. The aim of this study was to investigate the correlation among the results of different response evaluation system, and the relationships between ER/PgR/Her-2/Ki67 expression and the responses to neoadjuvant endocrine therapy for postmenopausal breast cancer. Methods: Data of consecutive 133 core needle biopsy (CNB) confirmed hormone receptor strongly positive (more than 50% tumor cell stained ER or PgR) postmenopausal breast cancer treated with neoadjuvant endocrine therapy were analysis retrospectively. All pts. were planned to receive endocrine therapy alone as their adjuvant treatment and prescribed Anastrozole 1 mg per day for 16 weeks before surgery. Clinical response were evaluated by using documented ultrasound records,pathological response was evaluated by one senior pathologist with Miller &amp; Payne classification. Cell cycle complete response was defined as post-treatment Ki67 ≥1%. The new slides of pre-treatment and surgical specimens were made for ER/PgR (ER\PR DakoCytomation)/Her-2 (Her-2 Dako HercepTest TM)/Ki67 (Ki67 Ventana) immunohistochemical staining through Benchmark XT Staining Instrument (Ventana Medical Systems. Inc. Arizona. USA) and classified by using image analysis system Ariol (Applied Imaging Inc., San-Jose, California, USA). Results: Clinical response were CR:0.8% PR:33.1% SD:66.1%, pathological response were G5:3% G4+G3:47.4% G2+G1:49.6%, Ki67 change were &amp;lt;1%: 22.8% decrease but &amp;gt;1%:45.1% no decrease: 32.1%. The correlation and consistency among the response evaluated differently were poor [table 1]. The per-treatment ER/PR/Her-2/Ki67 showed low degree of correlation with responses [table 2]. Pre-treatment ER≥90% and PR≥90% and Her-2 coudln't predict better response. The correlation and consistency among response evaluated in different system Conclusion: The correlation and consistency among the results of response to neoadjuvant endocrine therapy evaluated by different system were poor. ER/PgR/Her-2/Ki67 showed low degree of correlation to responses. It's difficult to predict response to Arimidex neoadjuvant endocrine therapy by using ER/PgR/Her-2/Ki67 expression. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-11.

Abstract P4-02-14: Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and a Validation

Abstract Purpose Previous studies have suggested that postmenopausal breast cancer women with wild-type CYP2D6 might actually have similar or superior recurrence free survival outcomes when they take tamoxifen rather than an aromatase inhibitor (AI). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. Methods We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive-metabolizer (EM) patients using annual hazard ratio (HR) data from BIG 1-98 trial. Then we replicated the model by evaluating 9-year event-free survival (EFS) using HR data from ATAC trial. We also employed two-way sensitivity analyses to explore the impacts of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates. Results The 5-year DFS of tamoxifen-treated EMs was 83.3%, similar to that for genotypically unselected patients receiving an AI (83.7%). In the validation study, we further demonstrated that EMs could get comparable survival benefit from tamoxifen relative to an AI (9-year-EFS, 81.4% vs. 83.2%). Two-way sensitivity analyses showed the robustness of results. Conclusions Our modeling analyses indicate that among EMs, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to scrutinize the value of CYP2D6 genotype in the selection of endocrine therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-14.

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.

Rheumatic Disorders and Functional Disability With Aromatase Inhibitor Therapy

Background Aromatase inhibitor therapy is often effective for breast cancer, yet it can be accompanied by musculoskeletal pain and stiffness. This prevalence assessment aimed to characterize a rheumatologist's view of frequency and clinical features, including associated disability, within a breast cancer clinic panel of 77 patients. Patients and Methods The "aromatase inhibitor arthralgia" frequency was estimated at 50%, including both those with new and worsened discomfort. Substantial functional disability was associated, whether measured by individual functional disability (frequencies ranging from 39% to 61%) or composite score of 7 functional disability areas (median score 5 compared with median 0 in the comparison group; P = .00003). Results The frequency of clinical hand osteoarthritis appeared somewhat increased in the aromatase inhibitor arthralgia group (28% vs. 14%; not statistically significant). Yet the distribution of aromatase inhibitor—related symptoms and functional disabilities appeared to parallel those joint regions commonly affected by osteoarthritis. Using clinical criteria to assess 5 common rheumatic disorders (hand osteoarthritis, trigger finger, carpal tunnel syndrome, Raynaud's phenomenon, and sicca syndrome), the aromatase inhibitor arthralgia group tended to have more common rheumatic disorders ( P < .05), consistent with nociceptive mechanisms making latent disorders symptomatic. Conclusion Aromatase inhibitor therapy for postmenopausal breast cancer might be associated with common musculoskeletal symptoms and with substantial functional disability and should prompt patient education. In view of the potential relevance of estrogen deprivation to osteoarthritis onset and severity, future studies of natural history should include systematic assessment of osteoarthritis frequency and severity.