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Background: The phase III DATA study (NCT00301457) investigates the efficacy of 6 versus 3 years of adjuvant anastrozole after an initial 2-3 year treatment with tamoxifen in postmenopausal women with breast cancer. A reduced bone mineral density (BMD) is associated with a lower risk of breast cancer. Bisphosphonates as adjuvant therapy in postmenopausal patients have been shown to prevent (distant) breast cancer recurrences. In this planned side-study of the DATA trial we assessed the relationship between osteoporosis and distant recurrence free survival (DRFS), and evaluated the effect of bisphosphonate use for reduced BMD in general on DRFS. Methods: Decisions on BMD measurements and bisphosphonate use in the DATA study were left to the treating physician. We registered all BMD measurements and start of bisphosphonate-use. BMD was measured by a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine/hip. We used a landmark of 3 years beyond the start of anastrozole, to create 3 different groups by BMD values based on DEXA scans made before the landmark and before a DRFS event (normal T score >-1.0, osteopenia T score Results: Of the 1860 DATA patients, 1142 (65.5% in the 6-year arm and 62.9% in the 3-year arm) had a DEXA scan within the first 3 years after randomization. A normal BMD was diagnosed in 436 (38.2%) patients, osteopenia in 565 (49.5%), and osteoporosis in 141 (12.3%). Of the latter group, 112 (80.9%) used bisphosphonates. In the total study population (n=1860), bisphosphonates were overall used over time before a DRFS event in 226 patients (24.2%) in the 6-year arm and 201 patients (21.7%) in the 3-year arm. During the study, only 46 patients used bisphosphonates without a diagnosis of osteopenia/osteoporosis. After a median follow up of 5.0 years from the landmark (interquartile range 4.3-5.7), osteoporosis (n=141) did not have a significant impact on DRFS when compared with the group without osteoporosis (normal/osteopenia (n=1001)) (HR 1.19, p=0.24 in the 6-year arm and HR=0.79, P=0.56 in the 3-year arm, P interaction=0.45). Neither when compared with only the group with a normal BMD (n=436) (HR=1.15, p=0.72 in the 6-year arm and HR=0.67, p=0.34 in the 3-year arm, P interaction=0.35). Within the group with osteoporosis, bisphosphonate use did not lead to a better DRFS (HR=1.47, P=0.72 in the 6-year arm and HR 0.65, P=0.61 in the 3-year arm, P interaction=0.55). Bisphosphonate use in general was also not associated with DRFS (HR 1.31, P=0.13 in the 6-year arm and HR 0.88, P=0.52 in the 3-year arm, P interaction=0.14). Conclusion: In this DATA sub-study, we observed no association between the presence of osteoporosis before the landmark of 3 years after the start of anastrozole and DRFS. However, as most patients with early osteoporosis also were treated with bisphosphonates this may have influenced the results. At the conference additional analyses will be presented. Citation Format: van Hellemond IE, Smorenburg CH, Peer PG, Swinkels AC, Seynaeve CM, van der Sangen MJ, Kroep JR, de Graaf H, Honkoop AH, Erdkamp FL, van den Berkmortel FW, de Roos WK, Linn SC, Imholz AL, de Boer M, Tjan-Heijnen VC. No impact of osteoporosis or bisphosphonate use for osteoporosis on breast cancer outcome: A sub-study of the DATA trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-11.

Optimal endocrine therapy for postmenopausal, hormone-receptor positive (HR+) early breast cancer remains a point of discussion. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial showed no significant differences for disease free survival (DFS) and overall survival (OS) at 5 years between exemestane monotherapy and sequential treatment (tamoxifen followed by exemestane). We now report disease related outcomes at 10 years of follow-up (FU), and an explorative analysis to assess the predictive value of clinicopathological and immune-related biomarkers. In the TEAM trial, postmenopausal women with HR+ positive early breast cancer were randomly assigned to exemestane alone or sequential therapy. For this analysis, TEAM patients from countries that completed 10 years of FU were included. The primary endpoint was DFS at ten years, analyzed by intention to treat. Secondary outcomes were OS and cumulative incidence of relapse. An explorative per protocol analysis for relapse free survival (RFS) was performed to identify predictive pathological and immunological biomarkers, including centrally determined ER (ER-poor 0-6 vs ER-rich 7-8) and PR (0-4 vs 5-8) Allred scores, and the immunological markers CD8, FoxP3, classical HLA class 1 and HLA-G which were described earlier (Engels et al, Breast Cancer Treat Res, 2015). In total, 6120 patients were eligible for the current analysis, 3075 patients with exemestane monotherapy and 3045 patients randomized to sequential treatment. Median follow up was 9.83 years. DFS was 66.8% in the exemestane group and 66.8% in the sequential group (hazard ratio (HR) 0.96, 95% CI 0.88-1.05, p=0.389). OS was 74% in the exemestane, and 73% in the sequential group, respectively (HR 0.98, 95% CI 0.89-1.09, p=0.737). The cumulative incidence of relapse was 20% and 22% in the exemestane and sequential groups, respectively (HR 0.88, 95% CI 0.79-0.99, p=0.031). In the explorative per protocol analysis (n=4041), Allred score were available for 2996 patients; immunological markers for 1754 patients. Patients with above median numbers of FoxP3-positive T-cells showed a benefit of exemestane monotherapy for RFS (HR 0.56, 95% CI 0.42-0.75, p After ten years of follow up, both exemestane monotherapy and sequential therapy remain appropriate options for postmenopausal HR+ early breast cancer patients. Interestingly, the number of regulatory T-cells was a predictive factor for the benefit of exemestane monotherapy, which implies a role of the local immune system in endocrine therapy. Furthermore, data suggested that patients with a higher differentiation grade or ER-rich tumor derive more benefit from exemestane monotherapy. Citation Format: Blok EJ, Derks MGM, Kuppen PJK, Meershoek-Klein Kranenbarg EM, Engels CC, Liefers G-J, Putter H, Seynaeve CM, Kroep JR, Nortier JWR, Rea DW, Hasenburg A, Markopoulos CJ, Paridaens R, Bartlett JMS, van de Velde CJH. 10-year follow-up and biomarker discovery for adjuvant endocrine therapy; results of the TEAM trial [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 PD2-07.

Introduction: There are a number of commercially-available tests to stratify risk for women diagnosed with early breast cancer. While such "Generation I" tests are increasingly being used, a consensus is growing that these tests are moderately accurate in assessing risk. Moreover, Generation I tests fail to direct more personalized treatment. Therefore, there is a clear need for more informative "Generation II" tests that better assess risk, also on the long term, and provide theranostic targets. To this end, we have performed an mRNA abundance-based analysis trained in the 790 patients of the UK TEAM cohort to identify a signature of residual risk , to be validated in the remaining 3000 patients from the TEAM pathology study. Methods: RNA extracted from the tumors of respective TEAM pathology study patients were profiled using a 165-gene NanoString code set. The gene list was compiled from targets that comprise many of the existing risk assessment tests, in addition to genes known to be of importance for breast cancer pathogenesis. Signal intensities were normalized using the R statistical environment; 336 different combinations of preprocessing methods were assessed and the most optimal method selected using unbiased criteria. A10-fold cross-validation approach, in combination with a network-based patient risk score calculation formula, was used to derive a 95-gene signature. Briefly, genes were first filtered based on a Cox regression p-value threshold of 0.25; the sum of the weighted mRNA abundance levels of the result genes was calculated for each patient as the risk score. Patient-wise risk scores were then used in a multivariate Cox proportional hazards model along with clinical covariates such as age, grade, HER2 status and nodal status, using DRFS truncated to 10 years as an end-point. Results: Univariate survival analysis revealed a number of significantly prognostic candidates. The resulting 95-gene signature identified in the training set, stratified patients into high and low risk with an HRhigh of 2.74 (p Conclusions: The impact of test-guided therapy using multi-parametric tests is increasingly being felt in the clinic, and is reshaping modern health-care economics. A successful Generation II multi-parametric test will better discriminate those that are truly at high risk for recurrence following endocrine therapy and indicate potential therapeutic options for intervention for those who would not benefit from current modalities. Citation Format: Bayani J, Yao CQ, Quintayo MA, Haider S, Brookes CL, Yan F, van de Velde CJH, Hasenburg A, Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Boutros PC, Rea DW, Bartlett JMS. Defining a signature of residual risk following endocrine treatment in the tamoxifen and exemestane adjuvant multinational (TEAM) trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-29.

Approximately 75% of all breast cancer patients is treated with endocrine therapy, based on stratification using estrogen receptor (ER) and progesterone receptor. To date, these classical biomarkers are the only ones available to predict the response to (neo)adjuvant endocrine therapy. Response to endocrine therapy depends on the presence of an active tumor-driving ER signalling pathway and, in the case of treatment with aromatase inhibitors (AI), also on aromatase-induced estradiol as the pathway activating ligand. Conventional nuclear staining for ER is not necessarily indicative of an estradiol-activated ER signalling pathway. We evaluated a recently described diagnostic computational model (Verhaegh, Cancer Research 2014) which identifies ER pathway activity based on tissue-derived target gene mRNA levels, for its clinical utility to predict neoadjuvant AI response in ER positive breast cancer patients. Tumour tissue from pre-treatment biopsies and post-treatment resection material was collected from patients with early breast cancer (>2 cm and >50% ER expression) participating in the TEAM-IIA trial, which were treated with neoadjuvant exemestane for 3 to 6 months. Using Laser Capture Microdissection (LCM), tumour cells were isolated and the probability of ER pathway activity was assessed with RT-qPCR. In total, 77 FFPE samples were analysed (51 biopsies + 26 paired resection cases). In a preliminary analysis, results were correlated with clinical response based on palpation and mammography. ER pathway activity significantly decreased during therapy (0.45 vs 0.27, two sided t-test p=0.001). Based on mammography, baseline ER activity in biopsy predicted therapy outcome after 3 months, with a higher probability of ER activity in responders, n=7, compared to non-responders, n=12, (0.73 vs 0.44, one sided t-test p=0.003). When therapy was continued up to 6 months, no correlation was found suggesting that other factors influence overall outcome of neo-adjuvant therapy. Baseline ER-pathway activity significantly predicted progressive disease by palpation at the end of therapy (mean treatment duration of 174 days, range 86-288 days) with a mean ER-pathway activity at biopsy of 0.53 vs 0.16 (p=0.01). The significant difference in baseline activity with progressive disease indicates that low ER pathway activity could be used to predict low response rates. This is supported by the observation that all progressive disease cases at end of therapy had low baseline ER activity. Furthermore, baseline activity particularly predicted early radiological response based on mammography. These preliminary results indicate that our ER pathway activity model could be able to predict response to endocrine neoadjuvant therapy. Further evaluation will be performed in order to assess the influence of post-treatment activity and other markers for response (Ki-67). *First and second author contributed equally to this work. Citation Format: Blok EJ, Alves de Inda M, Charehbili A, den Biezen E, Fruytier S, van Brussel A, Seynaeve CM, Kroep JR, Verhaegh W, van de Velde CJH, van de Stolpe A, Kuppen PJK. ER pathway activity as a predictive biomarker for neoadjuvant endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-65.

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 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.

There is now significant evidence emerging from the pivotal trials of AIs versus Tamoxifen (AIOG) demonstrating the value of meta-analysis of key clinical questions. The "Trans-AIOG" group has been tasked with the exploration of key molecular/biomarker questions that are pertinent to meta-analyses of biomarkers (past/present/future) in AIOG trials. HER2 has been long proposed as a marker of endocrine "resistance". Data from three trials, before the era of HER-directed therapy, suggest a potential role for HER2 to select patients for treatment with upfront AIs. However the individual trials lack power to test treatment-by-HER2 interaction due to sample size and low HER2+ve rates. A meta-analysis of the predictive value of HER2 status, specifically within the first 3 years of endocrine therapy, has the potential to inform patient selection for upfront or sequential strategies with AIs. The pre-existing standardization of methodology for HER2 (IHC/FISH) facilitates analysis of existing data from BIG-1-98, TEAM and ATAC for this key marker. Analysis plan: Following a prospectively-designed analysis plan, patient-level data from 3 randomized phase III trials (ATAC, BIG 1-98, TEAM) comparing AIs to tamoxifen during the first 2-3 years of adjuvant treatment were collected at the CRCTU (Birmingham UK), accounting for both the established time-dependency of relapse in HER2+ve, anti-endocrine treated patients and to address the clinical question of "upfront" vs "sequential" strategies for AIs. For each trial, covariate-adjusted Cox models estimated HER2-by-treatment (AI vs Tam) interaction on distant recurrence-free interval-censored at 2-2.75 years follow-up. A meta-analysis of the HER2-by-treatment interaction terms and of treatment effects according to HER2 status was performed. Results: 12129 patients with centrally-confirmed ER and HER2 status, 1092 (9%) HER2+ve, with 473 (4%; 111 among HER2+ve) distant recurrences were analyzed. The meta-analysis estimated a pooled HER2-by-treatment interaction of 1.61 (95% CI 1.01,2.57), reflecting treatment effect hazard ratio(AI/Tam) of HR=1.13 (0.75,1.71) among HER2+ve and HR=0.70 (0.56,0.87) among HER2-ve. There was heterogeneity among interaction terms (I-squared=59%, p=.09) that resulted from treatment effect heterogeneity among HER2+ve subgroup (I2=71%, p=.03), not the HER2-ve subgroup (I2=0%). The results for disease-free survival were similar. Conclusion: An individual patient data meta-analysis across 3 trials (ATAC, BIG 1-98, TEAM) conducted prior to standard use of HER2-directed adjuvant therapy demonstrated a marginally-significant interaction between HER2 status and treatment with AIs vs Tamoxifen in the 2-2.75 years prior to potential "switching" between Tamoxifen and AIs. Patients with HER2-ve cancers experienced improved outcomes when treated with AIs vs Tamoxifen whilst patients with HER+ve cancers fared no better, or slightly worse, during AI treatment. However, the small number of HER2+ve cancers and events even in this meta-analysis may explain a large degree of heterogeneity in the treatment effects within the HER2+ve subgroups across the 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded. Citation Format: Bartlett JMS, Ahmed I, Regan MM, Sestak I, Mallon EA, Dell'Orto P, Thürlimann BJK, Seynaeve C, Putter H, Brookes CL, Forbes JF, Colleoni MA, Bayani J, van de Velde CJH, Viale G, Cuzick J, Dowsett M, Rea DW, On Behalf of the Translational Aromatase Inhibitor Overview Group (Trans-AIOG). HER2 status as predictive marker for AI vs Tam benefit: A TRANS-AIOG meta-analysis of 12129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S4-06.

Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m2, IV, q 4 wks) or capecitabine (Cape) (1000 mg/m2 PO bid, days 1–14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0–1 vs 2–3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65–86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0–1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42–1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49–1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1–2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3–4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21–4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31–4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-05.

Background Mutations in ESR1, the gene encoding the estrogen receptor, have been linked to endocrine resistance in metastatic breast cancer (MBC). It is thought that these mutations are selected during endocrine treatment (ET), but direct evidence that these ESR1 mutations (mESR1) emerge during treatment with endocrine agents is scant. We set out to evaluate mESR1 in circulating tumor cells (CTCs) and matched plasma cell-free DNA (cfDNA) of MBC patients before start of 1st line ET and at progression. Materials & Methods CellSearch-enriched CTCs (≥ 5 CTC/7.5 mL) of 37 MBC patients before start of 1st line ET (baseline cohort; BL) and 38 MBC patients who had progressed on any line of ET for metastatic disease (progressive disease cohort; PD) were evaluated. 52% of the PD patients received one line of ET and 48% more lines, of which 92% contained an aromatase inhibitor. In addition, 10 CellSearch-enriched fractions from healthy blood donors (HBDs) and 46 matched plasma samples (7xHBD, 15xBL, 24xPD) were included. DNA was isolated using the AllPrep kit and cfDNA with the QIAamp CNA kit (Qiagen). Hotspot mutations for ESR1 (D538G, Y537S, Y537C and Y537N) were evaluated with mutation-specific Taqman assays by chip-based digital PCR (QuantStudio 3D). mESR1 status was assessed after target-specific ESR1 amplification capturing all 4 mutations, with thresholds for positivity based on the highest variant allele frequencies in HBDs. Results Of all the CTC samples in the BL cohort, 1 patient had mutated Y537N copies, while this mutation was not detected in the matched cfDNA. This patient had received adjuvant treatment with tamoxifen. Also none of the other 14 BL cfDNA samples analyzed harbored mESR1. Three PD patients (8%) were positive for mESR1 in their CTCs (2x D538G and 1x Y537S). These D538G variants identified in CTCs were also detected in the corresponding cfDNA of these patients; for the Y537S mutation no matched cfDNA was available. Seven additional mESR1 carriers were identified in the other 22 matched cfDNA PD samples, resulting in 38% mESR1 positivity of the PD plasma samples (7x D538G, 1x Y537C and 1x Y537C). Conclusion Sensitivity for detecting mESR1 in CTC fractions (identified in 8% of the PD patients) was lower than for cfDNA samples. Using cfDNA for mESR1 detection, we found an higher prevalence of mESR1 variants in samples obtained at progression to ET (38%) compared to baseline (0%). These findings further substantiate the role of mESR1 in endocrine resistance. Citation Format: Sieuwerts AM, Beije N, Kraan J, Van M, Onstenk W, Vitale SR, van der Vlugt – Daane M, Hamberg P, Dirix LY, Brouwers A, de Jongh FE, Jager A, Seynaeve CM, Jansen MPHM, Foekens JA, Martens JWM, Sleijfer S. ESR1 mutations in circulating tumor cell versus circulating cell-free DNA of metastatic breast cancer patients before first-line endocrine therapy and at progression [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 P1-02-02.

Background: Recent evidence confirms the importance of both biological and pathological risk markers in predicting early relapse for breast cancer patients treated with endocrine therapy. Most studies use a two step process integrating biological markers into a “biological predictor (e.g. Oncotype Dx, “IHC4” etc) followed by assessment of the predictive value of such tests in the context of pathological markers (grade, nodal status etc). We have taken a one step process integrating both biological and pathological markers into a single model to assess key factors for predicting outcome at 2.75 years and 5 years of endocrine therapy; to inform choices between switching, upfront and extended adjuvant treatment with AIs. Patients & Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. Quantitative analysis ER, PgR, Ki67, HER1, HER2, and HER3 was performed centrally. A prognostic model, integrating data from biological and pathological markers was created to assess risk (disease-free survival) after 2.75 and 5 years of follow up in the TEAM trial. Results: Of 4595 eligible cases samples received, 16 were excluded, and 3993 had complete biomarker data for all markers for the final biomarker analysis. In univariate analysis nodal status, grade, size, age at diagnosis, HER1, HER2, PgR, ER and Ki67 were all prognostic. At 2.75 years nodal status, age, PgR histoscore, size, grade, HER2, ER histoscore and HER1 positivity were significant prognostic variables (ranked by WaldX2 statistic), Ki67 and HER3 were not included in this model. At 5 years median follow up; age, nodal status, size, PgR histoscore, grade, Ki67, HER2, and HER1 positivity were significant prognostic variables (ranked by WaldX2 statistic), ER and HER3 were not included in this model. Conclusion: Combined biological and pathological marker panels are of significant value in predicting early relapse in breast cancer patients treated with endocrine therapy, however duration of follow-up may impact on the inclusion of variables in the model. This provides significant information relevant to the choice of different adjuvant endocrine therapies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-04.

Recently, there is increased attention to neo-adjuvant endocrine therapy in breast cancer. Especially for selected tumour types and fragile elderly patients this might be a promising alternative to chemotherapy. Monitoring treatment effect during neo-adjuvant endocrine therapy is crucial to allow a timely switch to chemotherapy in case of a non-successful treatment. Most trials evaluating neo-adjuvant endocrine therapy use palpation as primary outcome and multiple radiological modalities as secondary outcomes. The aim of this study was to determine which evaluation corresponds best to pathological resection size after 6 months of neo-adjuvant endocrine therapy. This analysis was conducted in the TEAM-IIA trial in which 102 patients with early breast cancer (>2 cm and >50% ER expression) were treated with neo-adjuvant exemestane. In total, 83 patients were treated for 6 months and 19 for 3 months. Therapy response evaluation was performed using repeated palpation (mostly by the same clinician), mammography, ultrasound and MRI. Only measurements within 2 months before surgery were considered. After surgery, the size of the remaining tumour was reported and used as reference. In total, 93 resection size measurements were available. From the 93 patients for whom resection size was available, 69 patients were evaluated by palpation, 53 by ultrasound, 42 by mammography and 29 by MRI. Overall, palpation showed to be the most reliable predictor for resection size (correlation of 49%), followed by mammography (31%), ultrasound (14%) and MRI (1%). Mammography showed the smallest mean absolute error (MAE, 8.7 mm), followed by ultrasound (9.2 mm), palpation (11.4 mm) and MRI (12.3 mm). The low correlation of MRI with resection size was mostly due to a relative high number of radiological complete remissions (14%, n=4), of which only one was a true pathological complete response (pCR), while the other tumours were up to 80 mm at resection. Although of less influence on the correlation to resection size, false complete remissions were observed in all other modalities. Time to surgery was an important factor for all modalities. After correcting for non-predictive radiological complete responses and limiting the measurements to one month before surgery, all correlations increased significantly (mammography=72%, palpation=70%, ultrasound=58%, MRI=50%) with a concomitant decrease in mean absolute error. The low correlation of MRI with resection size was mostly due to non-visible measurements, interpreted as radiological complete remissions of which only one in four was a true pathological complete response (pCR) while the other tumours were 25, 65, and 80 mm at resection. This is the first study to report on the reliability of radiological evaluation during neo-adjuvant endocrine therapy. In this study, mammography was the most reliable radiological method, with stronger correlation and small mean absolute error. Non- visible observations in neo-adjuvant endocrine therapy did not always reflect pCR. Hence, in the neo-adjuvant endocrine therapy setting, radiological complete responses should be interpreted carefully, especially in MRI, and use of other modalities or improved image processing methods may be considered. Citation Format: Blok EJ, Charehbili A, Kroep JR, Seynaeve CM, van de Velde CJH, Kuppen PJK. Radiological evaluation of neo-adjuvant endocrine therapy in hormone-receptor positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-01-05.

Background: Obesity is associated with an increased risk of breast cancer (BC) recurrence and decreased survival, also in case of adjuvant endocrine therapy. It is still not clear whether the activity of aromatase inhibitors and tamoxifen (T) given as adjuvant therapy is affected by body mass index (BMI), although both drugs are widely prescribed. In this analysis, we explored the outcome of TEAM patients (pts) treated with exemestane (E) versus T (2.75 yrs), and with E versus T followed by E (T/E) (5 yrs) in relation to BMI. Patients and Methods: The TEAM trial is a randomized, international phase III study in postmenopausal hormone sensitive early BC pts comparing the activity and safety of adjuvant E (25 mg daily) or the sequence of T (20 mg daily) followed by E (T/E), both regimens given for five years. WHO BMI definitions were used: normal 18.5-24.9 kg/m2, overweight 25-30 kg/m2, obese >30 kg/m2. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method; results were compared by using the log-rank test and Cox proportional hazard modelling adjusted for country. Results: Weight and height was known in 4741 pts. Mean BMI was 26.9 kg/m2 (SD 4.9); 39% had a normal BMI, 36.9% overweight, and 23.3% of pts was obese. Underweight pts (n=41, 0.9%) were excluded from further analysis. At 2.75 yrs (E vs T) disease relapse in normal weight, overweight and obese pts using E was observed in 8.1%, 6.8% and 7.5% respectively (p=0.57), and in 9.1%, 8.8%, and 12.5%, respectively (p=0.06) of pts using T. The hazard ratio (HR for risk of relapse on E vs T) in the three subgroups was 0.91 (95%CI 0.66-1.24), 0.78 (95%CI 0.55-1.089), and 0.57 (95%CI 0.39-0.84, p=0.004), respectively. At a median follow-up of 5.1 years, disease relapse in normal weight, overweight and obese pts using E occurred in 14.8%, 15.1% and 15.1%, respectively; and in pts using T in 17.0%, 16.9%, and 18.3%, respectively. Regarding DFS, the HR in normal weight, overweight, and obese pts was 0.87 (95%CI 0.69-1.10), 0.88 (95%CI 0.70-1.11), and 0.75 (95%CI 0.56-1.01, p=0.058), respectively, and with respect to OS 0.87 (95%CI 0.65-1.15, p= 0.32), 0.89 (95%CI 0.67-1.18, p= 0.43), and 0.71 (95% CI 0.51-1.01, p= 0.053), respectively. Conclusions: After 2.75 years more disease events were observed in obese women using tamoxifen, which was not seen in obese exemestane users, whereas at 5 years these differences in disease recurrences disappeared in this group. In contrast to recent reports, there seems to be a difference regarding the influence of a high BMI on recurrence rate between tamoxifen and the aromatase inhibitor exemestane. Further research on this topic is warranted. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-3.

A. Valachis, A. Nearchou, N.P. Polyzos, D. Mauri, P.A. Lind. General Hospital of Eskilstuna, Department of Oncology, Eskilstuna, Sweden; Panhellenic Association for Continual Medical Research (PACMeR), Section of Obstetrics & Gynecology, Athens, Greece; Panhellenic Association for Continual Medical Research (PACMeR), Section of Oncology, Lamia, Greece; Karolinska Institute, Oncology, Stockholm, Sweden

Background: The TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial is a contemporary multinational study of the effects of 5 years of adjuvant hormonal therapy, either exemestane (E) or tamoxifen switching to E (TàE). Five-year results were presented at SABCS 2009 showing no difference in outcome between E vs TàE (Rea D, SABCS Abstract 11), thus giving us the opportunity to analyze the causes of mortality in the entire population of 9766 women. Methods: Postmenopausal women with hormone receptor positive (HR+) early breast cancer (BC) were randomized to E or TàE for 5 years after completion of surgery, adjuvant chemotherapy (when indicated), and radiation therapy based on local guidelines. All data were collected and analyzed at the Central Data Center in Leiden. The primary outcome of DFS as well as safety and other secondary outcomes were analyzed in 2009 after 1285 events had occurred to trigger the analysis. Results: Between 2001 and January 2006, 9766 women were randomized; 100% were HR+, 50% had node negative disease, 68% received adjuvant radiotherapy, and 36% received adjuvant chemotherapy. The median follow-up was 5.1 years with over 60% of women having been followed for 5 or more years. Among 961 deaths, 568 (59%) were caused by BC and 393 (41%) by causes other than BC. The cumulative incidence of death from BC vs. other causes at 5-years for all women and by nodal status is as follows (see table): There was a general relationship with non-breast cancer deaths and increasing age at diagnosis (≥70 years), as expected. Non-breast cancer causes of mortality included second malignancy (105); cardiac (71), cerebral (33), or pulmonary (28) events; miscellaneous other causes (105); and unknown (51). Conclusions: Among 9766 postmenopausal women with HR+ BC treated with contemporary hormonal strategies following standard primary treatment, the probability of death from causes other than BC was nearly as high as the probability of dying from BC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-03.

Abstract #15 Background: Exemestane (E) is a steroidal aromatase inactivator, which has been demonstrated to be more effective than tamoxifen (T) in metastatic breast cancer (BC). The role of E in adjuvant therapy has been established after 2 to 3 years of T compared to 5 years of T in the Intergroup Exemestane Study (Lancet 2007; 369: 599-70). One objective of the TEAM study was to evaluate E compared to T as initial adjuvant endocrine therapy. Methods: Using common criteria, eligible postmenopausal patients in 9 countries with invasive ER+ and/or PR+ early BC, were prospectively randomized to either open-label E 25 mg/day or T 20 mg/day. All patients had completed primary therapy of surgery and chemotherapy if indicated. All data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with a primary endpoint of DFS between T and E. In 2004, based on results of the IES, TEAM was modified such that all patients on T were switched to E at 2.5-3 years. The modified design includes 2 primary endpoints: DFS of T versus E followed up to 2.75 years, and DFS of E for 5 years versus T switched to E treated for a total of 5 years. The present analysis focuses on the first primary endpoint: DFS for T compared to E at 2.75 years with censoring of events after 2.75 years. Log rank test with a 2-sided significance level of 2.98% stratified by country and factors nested in protocols will be utilized. Results: Between January 2001 and January 2006, 9775 women were randomized to T or E of which 9300 will be followed for 2.75 years by October 2008: 99% were ER and/or /PgR+, 50% were node negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% chemotherapy. There have been 693 DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) by April 2008 within 2.75 years of randomization. In accordance with the statistical analysis plan, the first planned analysis will be based on 723 events or 9300 patients with at least 2.75 years follow-up. We will present a detailed analysis of the first primary endpoint of DFS between T and E at 2.75 years at the 2008 SABCS. The TEAM study represents the largest of the 3 major trials to compare efficacy of an aromatase inhibitor/inactivator versus tamoxifen as initial endocrine therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 15.

Abstract #81 Background: The multinational TEAM trial evaluated the steroidal aromatase inactivator Exemestane (E) compared to Tamoxifen (T) as initial adjuvant endocrine therapy. The trial was initiated in 2001 with a primary endpoint of DFS between T and E. In 2004, based on results of the Intergroup Exemestane Study (IES) TEAM was modified so all patients on T were switched to E after 2.5-3 years. The modified design includes 2 co-primary endpoints: DFS of T vs E at 2.75 years, and DFS of E vs T followed by E at 5 years. A prospective pathology study was initiated in 2001 involving patients from 5/9 countries participating in the main trial. Methods: Pathology blocks were collected and centralized in the Edinburgh laboratory. The prospective hypotheses defined in 2001 were 1) PgR poor and 2) HER1-3+ve tumors derive additional benefit from EvsT. Sample size was increased to 5000 cases in 2004. TMAs were constructed in sextuplet. Results: 4805 tumor samples collected centrally and TMAs constructed from 4556 cases (UK/Ireland, Netherlands/Belgium, Germany and Greece contributed tumour samples). Quantititive ER & PgR data for 4300 cases were included in this analysis of ER/PgR status and treatment benefit, for ER 106 cases were excluded ( Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 81.