Endocrine Therapy In Postmenopausal Patients Research Articles

Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study

Abstract Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively). Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components. Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35). The correlation between each score with the RS module scores are shown in the Table. Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32 The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31). Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence. Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-05.

First-line endocrine therapy for postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and meta-analysis

BackgroundIn establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced postmenopausal hormone receptor-positive breast cancer.MethodsWe performed a systematic review of relevant reports from randomized-controlled studies published prior to November 2016 found using medical journal search engines. The main outcomes which we evaluated were progression-free survival (PFS), objective response rate (ORR), disease control rate (CBR), and toxicity.ResultsFour controlled trials comparing aromatase inhibitors (AI) and cyclin-dependent kinase (CDK)4/6 inhibitor combination therapy to AI monotherapy, and two controlled trials comparing anastrozole to fulvestrant 500 mg were analyzed. AI/CDK4/6 inhibitor combination therapy significantly improved PFS (Risk Ratio: 0.67, 95%CI 0.60–0.73), increased ORR (Risk Difference: 0.11, 95% CI 0.07–0.16), and increased CBR (Risk Difference: 0.11, 95% CI 0.07–0.15), compared with AI monotherapy. Patients who received this combination therapy had a higher grade ≥ 3 adverse event rate more than those who received AI monotherapy (Risk Difference: 43%, 95%CI: 0.39–0.47). Fulvestrant 500 mg alone significantly improved PFS (risk ratio: 0.85, 95%CI 0.72–0.98), but ORR and CBR were similar to those of anastrozole alone.ConclusionIn the first-line treatment for advanced postmenopausal hormone receptor-positive breast cancer, a combination therapy of CDK4/6 inhibitors and AI showed significant improvement of PFS, ORR, and CBR but with significant increased toxicities compared with AI alone. Fulvestrant 500 mg monotherapy significantly prolonged PFS compared with AI monotherapy. We must wait for the results of the studies with longer follow-up period.

ISY3-4 - Issue to be solved in the near future to determine optimal sequential endocrine therapy in metastatic breast cancer

Main objective in palliative therapy for patients with metastatic breast cancer (MBC) is prolonged survival and maintenance of quality of life. In ER-positive/HER2-negative MBC, sequential endocrine therapy is one of the most important treatment strategy for patients who have hormone-responsive and no life-threatening disease. However, the optimal sequential endocrine therapy is not established. Aromatase inhibitor, selective ER modulator, selective ER down-regulator and CDK4/6 inhibitor + aromatase inhibitor are candidates as 1st line endocrine therapy for postmenopausal patients. There is also no clear guidance on subsequent treatment. From the results of several clinical trials, it may be better to sequentially use alternate drugs with different mechanism of action in sequential endocrine monotherapy. However, the advent of CDK4/6 inhibitors have resulted in a paradigm shift in the treatment of ER-positive/HER2-negative metastatic breast cancer. In this presentation, I would like to discuss about 4 issues to be solved in endocrine therapy for postmenopausal ER-positive/HER2-negative metastatic breast cancer. First, should CDK4/6 inhibitor in combination with endocrine agent be used as part of sequential endocrine therapy for all patients? Second, whether CDK4/6 inhibitor are more effective for use in 1st line therapy or subsequent treatment? Third, when using a CDK4/6 inhibitor after 1st line endocrine monotherapy, should it be changed to another endocrine agent or the same endocrine drug? Fourth, what is the optimal treatment in patients who have progressed during or after CDK4/6 inhibitor administration?

Association of Somatic Driver Alterations With Prognosis in Postmenopausal, Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown. To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2- BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016. The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors. Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002). In ER+/HER2- postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting. ClinicalTrials.gov Identifier: NCT00004205.

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial

After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Pfizer, Dutch Cancer Foundation.

Abstract S1-03: First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer

Abstract Background. Even in view of the recent findings of the MA.17R trial, the impact of prolonged aromatase inhibitor (AI) therapy after prior tamoxifen in hormone receptor-positive early breast cancer remains insufficiently clear. Methods. In this open-label phase III study, we randomly assigned 1912 postmenopausal women with hormone receptor-positive breast cancer after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole therapy. The primary endpoint was the adapted disease-free survival (ADFS). This was defined as the DFS beyond 3 years after randomization to AI therapy because initially all patients received the same AI therapy for 3 years. ADFS events included (non-) invasive breast cancer recurrences (local, regional, distant), second primary (non-) invasive (breast) cancers, and death of any cause. The study was designed to detect an increase of the ADFS in the 6-year versus the 3-year anastrozole group corresponding with a hazard ratio (HR) of 0.60. The HRs and the corresponding 95% confidence intervals (CIs) were estimated with stratified Cox proportional-hazard models according to intention-to-treat. Results. Patients were randomized from July 2006 till August 2009. Three years after randomization 1663 patients had no DFS events, with an equal distribution between the treatment arms. The patient and tumor characteristics were well balanced. The median age at randomization was 57 years (P5 = 45 years, P95 = 76 years), the median primary tumor size was 21 mm (P5 = 10 mm, P95 = 50 mm), 67% of the patients had node-positive disease, and in 2% the tumor was HER2-positive (14% unknown); 64% of the patients had received adjuvant chemotherapy and &amp;lt;1% adjuvant trastuzumab. The median adapted follow-up was 4.1 years (P5 = 2.9 years, P95 = 5.8 years). No unexpected safety issues were seen. The 5-year ADFS was 79% in the 3-year and 83% in the 6-year anastrozole treatment group, yielding a HR for ADFS-event of 0.78 (95% CI 0.61 to 1.00; p = 0.0528). In patients with node-positive disease (N = 1117), the HR for ADFS-event was 0.71 (95% CI 0.53 to 0.96; p=0.0232), in N0 disease (N=546) 1.01 (95% CI 0.62 to 1.63; p=0.9817) and in patients with both ER and PR positive breast cancer (N = 1264) 0.68 (95% CI 0.51 to 0.90; p=0.0072). The 5-year adapted overall survival was not different between the treatment groups. Conclusion. These findings do not yet support the use of extended adjuvant AI prescription after 5 years of sequential endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer, but suggest benefit for a selected group of patients. Continued follow-up is needed to assess long-term efficacy and safety. Funding. Funded by AstraZeneca NL, ClinicalTrials.gov number, NCT00301457. Citation Format: Tjan-Heijnen VC, Van Hellemond IE, Peer PG, Swinkels AC, Smorenburg CH, Van der Sangen M, Kroep JR, De Graaf H, Honkoop AH, Erdkamp F, Van den Berkmortel FW, Kitzen JJ, De Boer M, De Roos WK, Linn SC, Imholz AL, Seynaeve C. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early 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 S1-03.

A Randomized Feasibility Study of 18F-Fluoroestradiol PET to Predict Pathologic Response to Neoadjuvant Therapy in Estrogen Receptor-Rich Postmenopausal Breast Cancer.

The aim of this study was to explore the ability of 18F-fluoroestradiol (18F-FES) PET/CT imaging to predict pathologic response to neoadjuvant therapy in postmenopausal women with estrogen receptor (ER)-rich breast cancer. Methods: This was a prospective, single-center study conducted as a substudy of the neoadjuvant study of chemotherapy versus endocrine therapy in postmenopausal patients with primary breast cancer (NEOCENT) trial. Patients with ER-rich breast cancer were randomized to neoadjuvant chemotherapy (NC) or neoadjuvant endocrine therapy (NET). The baseline SUVmax of 18F-FES PET/CT was measured. The pathologic response was assessed by the Miller-Payne system as nonresponse (grades 1 and 2) and response (grades 3-5). Results: Twenty-six patients were enrolled, with pathologic response achieved in 25 (NC, 12; NET, 13). Two patients achieved pathologic complete response after NC, but the remaining 23 patients had residual disease after NC or NET. Eight of 12 patients responded to NC, and 4 of 13 to NET; the difference was marginally significant (P = 0.07). In the NC group, the 2 patients with 18F-FES-negative tumors and none of the 10 patients with 18F-FES-avid tumors achieved pathologic complete response (P = 0.02). No difference in the SUVmax between responders and nonresponders was observed in either group. However, 5 of 7 NC patients with a baseline SUVmax of less than 7.3 achieved pathologic response, whereas none of the 5 NET patients with an SUVmax of less than 7.3 were responders (P = 0.03). The SUVmax values of the NC group were negatively correlated with percentage reduction of tumor cellularity (r = -0.63, P = 0.03), whereas those of the NET group showed positive correlation (r = 0.62, P = 0.02). During the median follow-up of 74 mo (range, 44-85 mo), recurrence occurred in only 4 NET patients. In patients with an SUVmax of less than 7.3, recurrence occurred in none of the 8 NC patients and 2 of the 5 NET patients (P = 0.13). Conclusion: Postmenopausal women who are ER-positive, but 18F-FES-negative, may benefit from NC rather than NET. 18F-FES PET/CT has the potential to predict response to neoadjuvant therapy in postmenopausal women with ER-rich breast cancer.

4P - Influence of anthracycline- and/or taxane-based chemotherapy on bone metabolism of patients with primary breast cancer

Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC.Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA.Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024).Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations.Disclosure: All authors have declared no conflicts of interest. Background: Cancer therapy-induced bone loss (CTIBL) is well-known sequela of adjuvant endocrine therapy in postmenopausal patients (pts) with primary breast cancer (PBC). Pts exposed to chemotherapy (Ctx) with alkylators for lymphoma/leukemia own a high risk of premature CTIBL which as in premenopausal PBC pts may be mainly an indirect endocrine effect of Ctx. In contrast, data on direct effects of modern perioperative Ctx on bone metabolism are limited. This retrospective study was initiated to gain more detailed insights into the influence of perioperative anthracycline (A)- and/or taxane (T)-based Ctx on bone turnover of pts with pre- and postmenopausal PBC. Methods: A total of 109 pts (premenopausal: 49; postmenopausal: 60) receiving neoadjuvant or adjuvant A- and/or T-based Ctx were included. Serum markers of bone metabolism including C-telopeptide of type I collagen (ICTP) indicating the osteoclast activity, N-propeptide of type I collagen (P1NP) indicating the osteoblast activity, and bone alkaline phosphatase (BALP) were determined at baseline and prior to each subsequent Ctx cycle (C) up to C6. Changes of ICTP, P1NP, and BALP over time were analyzed by repeated-measure ANOVA. Results: A total of 600 Ctx cycles were analyzed. Baseline levels of ICTP, P1NP, and BALP were significantly higher in post- versus premenopausal pts. ICTP and BALP did not significantly change during Ctx. Both an increase of ICTP from baseline until C6 in premenopausal pts and a decrease in postmenopausal pts did not reach statistical significance. In contrast, P1NP significantly declined in postmenopausal pts from baseline to C6 (p = 0.0152). In premenopausal pts, P1NP declined from baseline to C3 and then increased until C6. These changes were highly significant (p = 0.0024). Conclusion: Our study demonstrates that A- and/or T-based Ctx for PBC exhibits direct effects on bone metabolism. In postmenopausal pts, Ctx was associated with a sustained suppression of osteoblast activity. In premenopausal pts, early osteoclast suppression completely recovered during C4-6. Whether these effects will translate into an increased risk to further develop CTIBL needs to be clarified by long-term observations. Disclosure: All authors have declared no conflicts of interest.

PG 11.02 Endocrine therapy for post-menopausal patients: type and duration

PG 11.02 Endocrine therapy for post-menopausal patients: type and duration

Abstract P6-07-11: Health economic impact of breast cancer index (BCI) for late disease management in patients with estrogen receptor-positive, node-negative breast cancer

Abstract Background Several recent randomized, prospective clinical trials (MA.17, ATLAS, aTTom) have demonstrated the clinical benefit of extending endocrine therapy beyond 5 years to address the persistent risk of recurrence in patients with ER+ breast cancer. Breast Cancer Index (BCI) is a gene expression-based test that predicts overall (10y) risk of recurrence in patients with ER+, LN- breast cancer, and also informs late (post-5 year) disease management by providing information on risk of late (≥5y) recurrence, and likelihood of benefit from extended (≥5y) endocrine therapy. Previously, BCI was shown to be cost saving across a 10-year disease horizon. The current study specifically assessed the health economic benefit of BCI for late disease management, evaluating the impact of identifying patients at risk of late recurrence and those that may benefit from extended endocrine therapy. Methods A fact-based economic model was developed which projected the cost and effectiveness of BCI from a US third-party payer perspective in a hypothetical population of patients with ER+, LN- breast cancer who are disease free at 5 years post-diagnosis compared to standard clinical practice. Patients flowed through the model based on patterns of care and BCI data. Costs associated with endocrine therapy, toxicity, follow-up, and recurrence were modeled over 5 yrs. Model inputs were based primarily on published literature, and supplemented by interviews with disease experts and payers. Sensitivity analyses were performed around key inputs to estimate effects on the model. Results Use of BCI is projected to be cost saving in this population of patients that are disease-free at 5 years post-diagnosis, with a net cost savings of $691 per patient tested after accounting for BCI cost. Gross cost savings were projected to be achieved through reduced recurrence in patients receiving extended endocrine therapy based on BCI ($4,102), and reduced recurrence in previously non-compliant patients ($39). BCI was cost saving for both pre- and post-menopausal women. Sensitivity analyses demonstrated that results were most sensitive to current use of extended endocrine therapy in postmenopausal patients, future use of extended endocrine therapy in BCI (H/I) high patients, and the percentage of patients characterized as BCI (H/I) high. Conclusions BCI is projected to be cost saving in a population of ER+, LN-, breast cancer patients who are recurrence free at 5 years post-diagnosis. Cost savings are achieved through projected impact on extended endocrine therapy use and endocrine therapy compliance, and provide additional cost savings beyond impact on chemotherapy utilization. These findings require validation in additional cohorts, including studies of real-world clinical practice. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-11.

Age-Specific Nonpersistence of Endocrine Therapy in Postmenopausal Patients Diagnosed with Hormone Receptor–Positive Breast Cancer: A TEAM Study Analysis

Early discontinuation of adjuvant endocrine therapy may affect the outcome of treatment in breast cancer patients. The aim of this study was to assess age-specific persistence and age-specific survival outcome based on persistence status. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational trial were included. Nonpersistence was defined as discontinuing the assigned endocrine treatment within 1 year of follow-up because of adverse events, intercurrent illness, patient refusal, or other reasons. Endpoints were the breast cancer-specific and overall survival times. Analyses were stratified by age at diagnosis (<65 years, 65-74 years, ≥75 years). Overall, 3,142 postmenopausal breast cancer patients were included: 1,682 were aged <65 years, 951 were aged 65-74 years, and 509 were aged ≥75 years. Older age was associated with a higher proportion of nonpersistence within 1 year of follow-up. In patients aged <65 years, nonpersistent patients had lower breast cancer-specific and overall survival probabilities. In patients aged 65-74 years and patients aged ≥75 years, the survival times of persistent and nonpersistent patients were similar. Nonpersistence within 1 year of follow-up was associated with lower breast cancer-specific and overall survival probabilities in patients aged <65 years, but it was not associated with survival outcomes in patients aged 65-74 years or in patients aged ≥75 years. These results suggest that extrapolation of outcomes from a young to an elderly breast cancer population may be insufficient and urge age-specific breast cancer studies.

P5-17-05: 24 Months Follow-Up Results from PACT (Patient's Anastrozole Compliance to Therapy Programme), a Non-Interventional Study Evaluating the Influence of a Standardized Information Service on Compliance in Postmenopausal Women with Early Breast Cancer.

Abstract Introduction: According to recent retrospective studies, compliance to adjuvant endocrine therapy for early breast cancer (EBC) may drop to below 70% after one year and to as low as 50% by year 4. PACT aimed to increase treatment adherence in postmenopausal women taking an adjuvant aromatase inhibitor via a standardized information service (educational arm). Yet, after 12 months, there was no difference in compliance between the standard and educational arm (reported at this meeting 2010). Methods: PACT is a prospective, randomised, two-arm parallel-group study in Germany, sponsored by AstraZeneca (NCT00555867). Postmenopausal women on anastrozole for hormone-receptor positive (HR+) EBC were randomized to routine clinical care alone or to receive additional standardized information (educational arm) at nine times over the first 12 months of adjuvant therapy. Primary endpoints were compliance and persistence rates in the educational versus routine arm after 12 months. Secondary endpoints included longer follow-up, reasons for non-compliance, influence of baseline characteristics, and clinical outcome parameters (DSF, OS). Compliance was evaluated via patient questionnaires, prescription data and physician recall. Per protocol compliance was analysed only for patients with full documentation both by patients and physicians. Persistence was defined as the duration of time from initiation to discontinuation of therapy (Cramer et al 2007) and measured by prescription data. Results: PACT enrolled 4,923 female patients at 109 breast centres and 1,361 registered specialist practices from all regions in Germany. 4,397 patients were evaluable for baseline characteristics. 2,707 patients were evaluable for the primary endpoint (full documentation on tablet intake both by patients and physicians). No difference in compliance could be shown between the standard (88.2%) and the educational arm (88.3%) at 12 months (p=0.92, Fisher's exact test). Persistence rates were 40.3% for the standard arm and 43.0% for the educational arm, respectively (p=0.17, Fisher's exact test). At 24 months, data from 1539 patients was available for analysis compliance per protocol. Compliance rates were 88.7% (educational arm) and 87% (standard arm; p=0.29). Persistence again much lower at 41.1% and 42.1% (p=0.68). Variables influencing compliance were regular attendance to follow-up visits, participation in a cancer rehabilitation program, number of co-morbidities and current employment status. Persistence was influenced by factors such as tumour stage, joint pain and cancer rehab program participation. Conclusion: The addition of standardized information materials to standard clinical care did not lead to a significant increase in compliance or persistence rates at 12 or 24 months. With 4,923 women included, the PACT study represents the largest prospective study to evaluate the influence of educational material as well as baseline demographic and histopathological characteristics on the compliance and persistence to adjuvant endocrine therapy in postmenopausal patients with HR+ EBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-17-05.

P2-12-01: Immunohistochemical (IHC) BAG1 Expression Improves the Estimation of Residual Risk (RR) by IHC4 in Postmenopausal Patients Treated with Anastrozole or Tamoxifen: A TransATAC Study.

Abstract Aim: To determine whether the incorporation of BAG1 staining improves the estimate of RR after endocrine therapy in postmenopausal patients with ER+ve tumours treated with endocrine therapy. Background: BAG1 encodes a protein (BCL2-associated athanogene 1) that binds to BCL2 and enhances its anti-apoptotic effects. BAG1 is included as a separate subgroup in the 21-gene OncotypeDx Recurrence Score (RS) that is used to assess RR after endocrine therapy in primary ER+ breast cancer. IHC4 is a 4-panel set of IHC markers (ER, PgR, HER2, Ki67) that was shown to provide as much prognostic accuracy as RS in the translational arm of the ATAC trial (TransATAC) of anastrozole versus tamoxifen alone or combined and subsequently independently validated (Cuzick et al, JCO, 2011, in press). Addition of extra markers such as BAG1 to IHC4 may improve the accuracy of the IHC4 and provide extra discriminatory power for oncologists. Methods: Samples in triplicate TMAs from the TransATAC cohort were stained for BAG1 using the Genetex 3.10G3E2 antibody after validation using siRNA knockdown. Staining was scored separately as nuclear or cytoplasmic and categorized by intensity as 0, 1, 2 or 3. BAG1 IHC values were assessed for their correlation with BAG1 mRNA levels. The statistical analysis plan was pre-specified and tested possible additional information from BAG1 expression to the IHC4 in patients not treated with chemotherapy by change in the likelihood ratio chi-square (ΔLR-X2). Results were included only if there was also complete data for ER, PgR, Ki67 and HER2. Primary analysis was on the HER2−ve node-negative (N-neg) population; secondary analysis was on all N-neg patients. Follow-up was to 10 years and the primary end-point was time to distant recurrence (TTDR). Results: Data on both nuclear and cytoplasmic BAG1 as well as the other 4 IHC parameters was available on 961 cases of which 855 were HER2−ve. There was a significant correlation between cytoplasmic and nuclear BAG1 (p=0.23, p&amp;lt;0.0001) but the nuclear staining correlated better with mRNA levels and was therefore considered further. Weak but significant correlations were also seen with ER, PgR and tumour grade. In the univariate analysis nuclear BAG1 was significantly associated with worse TTDR in HER2−ve and all N-neg cases (X2=7.91, p=0.005 and X2=10.63, p=0.001 respectively). Nuclear BAG1 also contributed significantly in multivariate analyses in the 2 populations firstly when added to the clinical model (X2=4.99, p=0.02 and X2=5.93, p=0.015 respectively) and secondly when subtracted from clinical plus the IHC4 parameters (X2=5.55, p=0.02 and X2=4.50, p=0.03 respectively). Conclusions: Nuclear BAG1 expression has significant value for estimating RR that is independent of standard clinical and IHC parameters and it improves the prediction of TTDR in the TransATAC population beyond that with the validated IHC4 score. Unlike IHC4 markers, BAG1 is not commonly measured in pathology work-up of breast cancers. The clinical utility of its addition to IHC4 will be tested by measuring its discrimination of high and low risk patients in clinical practice. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-01.

Exemestane versus anastrozole as front‐line endocrine therapy in postmenopausal patients with hormone receptor‐positive, advanced breast cancer

Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer. Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored. In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥ 2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported. In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting.

Abstract P5-11-05: Influence of Demographic and Histopathological Characteristics on Compliance and Persistence in 4.923 Postmenopausal Women with Early Breast Cancer (EBC) - Results of the Patient's Anastrozole Compliance to Therapy Programme (PACT)

Abstract Introduction: According to recent retrospective studies, compliance to adjuvant endocrine therapy for early breast cancer (EBC) may drop below 70% after one year and to as low as 50% by year 4. The PACT-study aims investigate the effect of standardized information materials (brochures and motivational letters) to standard clinical care. Here we present the results for the primary endpoints compliance and persistence rates at 12 months as well as the influence of demographic and histopathological characteristics on compliance and persistence. Methods: PACT is a prospective, randomised, parallel-group study with 60 months of follow-up (NCT00555867, sponsored by AstraZeneca Germany). Postmenopausal women on anastrozole (ANA) for hormone-receptor positive (HR+) EBC were randomized to routine clinical care alone or additional standardized information (educational arm) for the first 12 months of adjuvant therapy. Primary endpoints are compliance and persistence rates in the educational versus routine arm after 12 months. Secondary endpoints include influence of baseline demographic and histopathol. characteristics on compliance and persistence as well as influence of compliance on clinical outcome parameters (DFS, OS). Compliance is evaluated via patient questionnaires, prescription data and physician recall and was defined as intake of at least 80% of the total medication (292 ANA tablets in 12 months). Persistence is defined as“duration of time from initiation to discontinuation of therapy” (Cramer 2007). A patient was defined as persistent if the documentation supported the intake of ANA during the full first 12-months. Results: PACT enrolled 4,923 patients at 109 breast centres and 1,361 registered specialist practices from Germany. 4,397 patients were evaluable for baseline characteristics. 2,707 patients had a visit documented at 12 months (≥9 to 18 months) and were evaluable for the primary endpoint. No difference in compliance could be shown between the standard (88.2%) and educational arm (88.3%) at 12 months (p=0.95, Fisher's exact test). In a modified analysis classifying patients not attending for a follow-up visit after 12 months as non-compliant, the compliance rate in both arms was sign. lower with 53.9% in the standard and 55.1% in the educational arm, yet no significant intergroup difference (p=0.43). Persistence rates were 40.3% for the standard and 43.0% for the educational arm (p=0.17). Influence of baseline demographic and histopathological characteristics on compliance and persistence are currently under review and will be presented at the meeting. Conclusion: The addition of standardized information materials to standard clinical care did not lead to increased compliance or persistence rates at 12 months. Data on the influence of baseline demographic and histopathological characteristics on compliance and persistence will be presented. PACT represents the largest prospective study to evaluate the influence of educational materials and baseline demographic and histopathol. characteristics on compliance and persistence to adjuvant endocrine therapy in postmenopausal patients with HR+ EBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-05.

Abstract P5-11-12: Quality of Life in the PACT-Programme (Patient's Anastrozole Compliance to Therapy Programme): Influence of a Standardized Information Service on Patient Satisfaction and Health Related Quality of Life in Postmenopausal Women with Early Breast Cancer (EBC)

Abstract Introduction: In recent years, patient reported outcomes have become increasingly a focus in clinical investigations. Health related quality of life (HRQoL) is now regularly evaluated in clinical trials, yet data on HRQoL in postmenopausal women receiving adjuvant aromatase inhibitor treatment for early breast cancer (EBC) is limited. Here, we present the 12 months results on HRQoL and patient satisfaction from PACT, a program which aims to increase awareness, motivation and adherence to adjuvant anastrozole therapy in routine clinical practice by adding regular standardized information (brochures and motivational letters) to standard clinical care. Methods: PACT is a prospective, randomised, two-arm parallel-group study with 60 months follow-up (NCT00555867, sponsored by AstraZeneca Germany). Postmenopausal women on anastrozole for hormone-receptor positive (HR+) EBC were randomized to routine clinical care alone or additional regular standardized information (educational arm) for the first year of adjuvant endocrine therapy. Primary endpoint was the compliance rate in the educational vs. routine arm after 12 months. Secondary endpoints include HRQoL and patient satisfaction, evaluated via EORTC IN-PATSAT32, QLQ-C30, and QLQ-BR23. The present analysis focuses on differences in HRQoL and patient satisfaction between the standard and educational arm and between compliant and non-compliant patients at 12 months after treatment initiation. Results: 4,923 patients were enrolled into PACT by Nov. 2008. Of these, 2,707 were evaluable for analysis of the primary endpoint compliance and the secondary endpoints patient satisfaction and HRQoL. Analysis of HRQoL and patient satisfaction scores showed no differences between the standard and the educational arm at 12 months. When comparing compliant vs. non-compliant patients, however, compliant patients reached significantly higher (=better) patient satisfaction scores in all domains. In addition, compliant patients achieved significantly higher (=better) scores in the HRQoL domains of physical functioning (p=0.04), emotional functioning (p=0.018), cognitive functioning (p=0.004), social functioning (p=0.005), and sexual enjoyment (p=0.047), as well as lower (=better) scores in the domains of fatigue (p=0.01), systemic therapy (p=0.003), and arm symptoms (p=0.03). After correction for multiple testing, statistically significant differences favouring compliant patients were retained in the areas of information provision and availability (p=0.0008 and p=0.0005, respectively). Conclusion: In postmenopausal patients with HR+ EBC assigned to adjuvant endocrine treatment with an aromatase inhibitor (anastrozole), HRQoL and patient satisfaction were not affected by the intervention. However, analysis of compliant vs. non-compliant patients revealed improved scores for patient satisfaction in multivariate analysis favouring compliant patients at 12 months after treatment initiation. PACT represents an important project in health outcomes research regarding adjuvant endocrine therapy in postmenopausal patients with HR+ EBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-12.

Neoadjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive early breast cancer: a new concept

Patients with resectable, nonmetastatic (stage I-IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer.

Bone and Men's Health. Effects of aromatase inhibitors on human osteoblasts

Aromatase inhibitors (AIs) have been widely employed as an adjuvant endocrine therapy in postmenopausal patients with estrogen receptor (ER) positive breast carcinoma in place of tamoxifen. AIs work on suppressing both systemic and local estrogen biosynthesis in an almost complete manner resulting in estrogen depletion and subsequently inhibition of estrogen dependent carcinoma cell proliferation. Despite marked therapeutic effects in these patients, potential side effects related to long term and marked estrogen depletion should be considered for the benefits of these patients. Among these possible side effects, bone loss and/or increased rates of pathological fractures may be considered one of the most serious complications in terms of effecting activities of daily life of the patients. AIs can be classified into two types, steroidal and non-steroidal in terms of their structure and modes of actions. The former is also characterized to display androgenic actions. Estrogens are well-known to exert their effects primarily through osteoblasts in human bone tissues. Therefore, in this review, we will summarize in vitro effects of AIs, especially androgenic effects of steroidal AIs upon human osteoblasts in order to further understand their effects on human skeletal systems.

Outcome of Primary Endocrine Therapy in Postmenopausal Patients with Endocrine-responsive Breast Cancer

Purpose: The purpose of this study was to investigate the efficacy and toxicity of primary endocrine therapy in postmenopausal elderly patients with endocrine-responsive breast cancer.Patients and Methods: The study included 11 postmenopausal patients with breast cancer aged 70 years and over who started primary endocrine therapy between April 2004 and November 2007. Treatment consisted of 1 mg/day anastrozole or 25 mg/day exemestane and was continued until progressive disease was noted. In patients who had progressive disease, another aromatase inhibitor or tamoxifen was administered.Results: The drugs used as primary therapy were anastrozole and exemestane in 7 and 4 patients, respectively. Seven patients had a performance status of 0 to 1 and 4 had 3 to 4. The best clinical response was a complete remission in 2 patients, in addition to partial remission in 4, stable disease in 4 (including 2 patients with long-term stabilization), and disease progression in 1, with a response rate of 55% and a clinical benefit rate of 73%. The average duration of primary treatment was 15.5 months, and 2 patients died during the study (one from cerebral hemorrhage and the other from breast cancer). With regard to safety, a fracture of the right fourth finger was observed in 1 patient.Conclusion: Primary endocrine therapy with aromatase inhibitors resulted in a high response rate and a long-term clinical benefit, along with a superior tolerability. Therefore, this therapy can be effective in extremely elderly patients with endocrine-responsive breast cancer.

Target and reality of adjuvant endocrine therapy in postmenopausal patients with invasive breast cancer

Previous research evaluating the use of adjuvant endocrine therapy among postmenopausal breast cancer patients showed with 15–50% wide ranges of non-adherence rates. We evaluated this issue by analysing an unselected study group comprising of 325 postmenopausal women, diagnosed from 1997 to 2003 with hormonal receptor-positive invasive breast cancer. The different clinical situations that led to the discontinuation of adjuvant endocrine therapy were clearly defined and differentiated: non-adherence was not simply the act of stopping medication, but rather the manifestation of an intentional behaviour of the patient. Of the 287 patients who initiated endocrine therapy, 191 (66.6%) fully completed this treatment. Thirty-one patients (10.8%) showed non-adherence to therapy. Patients who had follow-up with a general practitioner, rather than in an oncologic unit, were more likely to be non-adherent (P=0.0088). Of 25 patients who changed medication due to therapy-related adverse effects, 20 (80%) patients fully completed the therapy after drug change. In adjuvant endocrine therapy, a lowering of the non-adherence rate to 10.8%, the lowest reported in the literature, is realistic when patients are cared for by a specialised oncologic unit focusing on the individual needs of the patients.