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Background We investigated the association between body mass index (BMI) and breast cancer risk in women at increased risk of breast cancer receiving tamoxifen or anastrozole compared with placebo using data from the International Breast Cancer Intervention Studies [IBIS-I (tamoxifen) and IBIS-II (anastrozole)]. Methods Baseline BMI was calculated from nurse assessed height and weight measurements for premenopausal (n = 3138) and postmenopausal (n = 3731) women in IBIS-I and postmenopausal women in IBIS-II (n = 3787). The primary endpoint was any breast cancer event (invasive and ductal carcinoma in situ). We used Cox proportional hazards regression to calculate hazard ratios (HRs) for risk after adjustment for covariates. Results There were 582 (IBIS-I) and 248 (IBIS-II) breast cancer events [median follow-up = 16.2 years (IQR 14.4–17.7) and 10.9 years (IQR 8.8–13.0), respectively]. In adjusted analysis, women with a higher BMI had an increased breast cancer risk in both IBIS-I [HR = 1.06 per 5 kg/m2 (0.99–1.15), p = 0.114] and in IBIS-II [HR per 5 kg/m2 = 1.21 (1.09–1.35), p 2 = 1.14 (1.03–1.26), p = 0.01] but not premenopausal women [adjusted HR per 5 kg/m2 = 0.97 (0.86–1.09), p = 0.628]. There was no interaction between BMI and treatment group for breast cancer risk in either IBIS-I (p = 0.62) or IBIS-II (p = 0.55). Conclusions Higher BMI is associated with greater breast cancer risk in postmenopausal women at increased risk of the disease, but no effect was observed in premenopausal women. The lack of interaction between BMI and treatment group on breast cancer risk suggests women are likely to experience benefit from preventive therapy regardless of their BMI. Trial registration Both trials were registered [IBIS-I: ISRCTN91879928 on 24/02/2006, retrospectively registered (http://www.isrctn.com/ISRCTN91879928); IBIS-II: ISRCTN31488319 on 07/01/2005, retrospectively registered (http://www.isrctn.com/ISRCTN31488319)]

PURPOSE The Onco type DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences. PATIENTS AND METHODS Analyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)–negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied. RESULTS There were moderate to strong correlations among the four molecular scores (ρ = 0.63-0.74) except for RS versus ROR (ρ = 0.32) and RS versus BCI (ρ = 0.35). RS had strong negative correlation with its estrogen module (ρ = −0.79) and moderate positive correlation with its proliferation module (ρ = 0.36). RS’s proliferation module explained 72.5% of ROR’s variance, while the estrogen module explained only 0.6%. Most of EP’s and BCI’s variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively). CONCLUSION In contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests.

Background Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment. Methods One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate. Results Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (−0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (−1.35% (−1.70 to −0.98)). Conclusions These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.

Background Studies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)–I trial. Methods Women randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation. Results Women randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98–1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12–2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19–2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed. Conclusions Overall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.

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.

Background: During endocrine treatment of breast cancer, the occurrence of symptoms related to oestrogen depletion are important predictor of treatment efficacy. We have previously shown that appearance of vasomotor and joint related symptoms are a useful biomarker for a greater response to endocrine treatment (Cuzick et al., Lancet, 2008). Furthermore a prediction model including clinicopathological parameters (CTS5) has shown to be a good prognostic tool for the prediction of late distant recurrences (DR) (Dowsett et al., JCO, 2018). Here, we assessed whether the occurrence of endocrine related adverse events were predictive of late DR in the ATAC trial. Methods: The ATAC trial (N=4735) of postmenopausal women with estrogen receptor positive breast cancer treated with 5 years' tamoxifen or anastrozole was used for this analysis. Women who reported symptoms (hot flashes, joint symptoms, gynaecological symptoms) at any time during the trial were compared to those not reporting these symptoms for late DR. Time to late DR, defined beginning at 5 years after randomization, was the primary endpoint. Hazard ratios (HR) and corresponding 95% CIs were estimated by Cox proportional hazards regression models. Results: 2937 women (62%) who were recurrence free after 5 years, reported either hot flashes, joint symptoms, or gynaecological symptoms during the active treatment period. Women who reported joint symptoms (adjusted for CTS5: HR=0.74 (0.59-0.94)), or gynaecological symptoms (adjusted for CTS5: HR=0.68 (0.47-0.97)) had significantly fewer late DR compared to those not reporting these events during the active 5 years' treatment period. Those who reported any symptom during the treatment period had an overall 34% lower risk of a late DR (univariate: HR=0.66 (0.53-0.83), P Conclusions: This retrospective analysis of the ATAC trial showed that occurrences of endocrine related symptoms during the treatment period are associated with the risk of developing a late DR, irrespective of treatment allocation. Larger effects were found for joint or gynaecological symptoms and remained significant after adjustment for clinical parameters. These findings might help clinicians and patients in their decision making process about extended endocrine therapy. Citation Format: Sestak I, Dowsett M, Cuzick J. Importance of adverse events during endocrine treatment for the prediction of late distant recurrences [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 P4-08-02.

Background: EndoPredict (EPclin) is a validated prognostic test combining expression of 12 cancer-related genes for breast cancer patients with estrogen receptor (ER) positive, HER2-negative disease who received 5 years of endocrine therapy (Buus et al., 2017; Dubsky et al. 2012) and for women who received chemotherapy (Martin et al., 2014). Here, we determine the EPclin and 10-year distant recurrence free interval (DRFI) rates for patients who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) using data from five large clinical trials. Methods: A total of 3746 women with ER-positive, HER2-negative disease were included in this analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET+C (GEICAM 2003-02/9906). EPclin incorporates tumor size and nodal status and accounts for different EPClin scores between ET+C and ET alone cohorts. The primary objective was to evaluate the 10-year DRFI rates as a continuous function of EPclin separately for patients in ET+C and ET. Secondary objectives included assessing the difference in the prognostic ability of EPclin between ET+C and ET overall (years 0-10) and for specific follow-up periods (years 0-5 and years 5-10). The primary endpoint was DRFI and the secondary endpoint was breast cancer free interval (BCFI). Cox proportional hazard models were used to estimate 10-year DRFI rates and to assess the prognostic information provided by EPclin. Results: All of the women on ET alone and 49% of those on ET+C were postmenopausal. Women who received ET+C had more node positive disease, more poorly differentiated tumours, and higher EPclin scores than those who received ET alone. Women who received ET+C had significantly smaller increases in 10-year DRFI rates with increasing EPclin score than those receiving ET alone (Table). EPclin was highly prognostic for DRFI in all women who received ET alone (HR=2.79 (2.49-3.13), P Conclusion: In our results from a non-randomized analysis, we observed significantly smaller increases in 10-year DRFI rates with increasing EPclin scores for women who received ET+C compared to those who received ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease. 10-year DRFI risks (%) (95% CI) according to EPclin score for patients who received ET+C versus ET alone. ET+CETEPclin10-year DR risk (%)10-year DR risk (%)11.1% (0.5-1.7)1.0% (0.6-1.4)22.5% (1.5-3.5)2.8% (2.1-3.5)35.7% (4.1-7.2)7.6% (6.4-8.8)412.4% (10.1-14.6)19.8% (17.6-22.0)525.8% (22.0-29.5)46.1% (40.2-51.4) Citation Format: Sestak I, Martin M, Dubsky P, Rojo F, Cuzick J, Filipits M, Ruiz A, Buus R, Hlauschek D, Rodriguez-Lescure A, Dowsett M, Gnant M. Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) [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 P2-08-04.

AIM To determine whether a modified Clinical Treatment Score (CTS) based on continuous tumor size and 5 lymph node categories provided more prognostic information in an independent test set than the original CTS with and without the Immunohistochemical-4 (IHC4) algorithm for prediction of residual distant recurrence risk over 10-years. BACKGROUND Risk of recurrence information in patients with estrogen receptor-positive (ER+), early breast cancer informs decision-making on chemotherapy use. The CTS and IHC4 algorithms provide such information, particularly when used in combination (IHC4+C). Their derivation in the translational cohort of the Arimidex Tamoxifen Alone or in Combination trial (TransATAC) was described by Cuzick et al in 2011. In the original model tumor size and nodal status were each classified into three categories, causing prognostic information to be lost. METHODS We modeled a novel CTSn algorithm on outcome data from patients in the anastrozole and tamoxifen arms in ATAC incorporating tumor size as a continuous variable and sub-dividing nodal status into five categories. IHC4n was re-derived in the TransATAC cohort independent of CTSn. Patients were chemotherapy-naïve. We compared ability to predict risk of residual distant recurrence of the new IHC4n+Cn model with that of the original one when tested in a training cohort and in a validation set of chemotherapy-naïve patients from the Tamoxifen vs. Exemestane Adjuvant Multicentre (TEAM) trial using Cox regression models and the C-index. RESULTS The ATAC training set for CTSn comprised 4056 patients, the TransATAC training set for IHC4n comprised 1125 patients; 2591 patients were in the TEAM validation set. Patients in the TEAM set were older (median age in TransATAC: 63.5, TEAM: 68.3 years), had a higher nodal-burden (node-positive in TransATAC: 29.4%, TEAM: 51.8%) and had more Grade 3 tumors (TransATAC: 18.3%, TEAM: 32.2%). The new IHC4n+Cn was significantly prognostic, and non-significantly more prognostic than the original IHC4+C in both the training and validation cohorts. When assessed using the C-index statistic, IHC4n+Cn had a higher discriminatory ability than the original algorithm (Table 1). Table 1 TransATAC (N=1125)TEAM (N=2591) HR* (95% CI)C-indexHR* (95% CI)C-indexOld Models CTS2.26 (2.01-2.53)0.6811.88 (1.73-2.03)0.650IHC41.67 (1.46-1.91)0.6301.49 (1.35-1.63)0.604IHC4+C2.76 (2.40-3.18)0.7242.03 (1.87-2.21)0.671New Models CTSn2.64 (2.26-3.09)0.7212.16 (1.96-2.39)0.687IHC4n1.74 (1.52-2.01)0.6421.51 (1.36-1.68)0.603IHC4n+Cn2.91 (2.47-3.42)0.7382.28 (2.06-2.51)0.695(*Hazard Ratio for change in one Standard Deviation). CONCLUSION By separately remodellng the part of the IHC4+C score based on clinicopathological characteristics using the whole ATAC chemo-naïve cohort, and the part that uses IHC-derived information in chemo-naïve TransATAC patients, we increased the precision of the individual risk estimates produced by both CTSn and IHC4n compared to those given by the original algorithms. The new IHC4n+Cn shows a trend for improved prognostic ability compared to the original IHC4+C. Like its predecessor, it relies on information that is readily available to clinicians and integrates it in an evidence-based way to improve prognostication in ER+ early breast cancer. Citation Format: Dodson A, Sestak I, Bayani J, Dowsett M, Bartlett J, Cuzick J. A newly derived combined clinical treatment score and immunohistochemical-4 prognostic tool [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 P2-07-02.

Anastrozole has been shown to prevent breast cancer in postmenopausal women at high risk of the disease, but has been associated with substantial accelerated loss of bone mineral density (BMD) and increased fractures. Here, we investigate the effect of risedronate on BMD after 5 years of follow-up in the IBIS-II prevention trial. 1410 women were enrolled in the bone sub-study and stratified into three strata according to the lowest baseline T-score at spine or femoral neck. The objective was to compare the effect of oral risedronate (35 mg weekly) versus placebo in osteopenic women in stratum II who were randomised to anastrozole in the main study. 258 osteopenic, postmenopausal women at high risk of developing breast cancer for whom baseline and follow-up bone mineral density measurements were available. 5-year mean BMD change at the lumbar spine for osteopenic women randomised to anastrozole and risedronate was −0.4% compared to −4.2% for those not on risedronate (P, Highlights • Results confirm anastrozole induced bone mineral density decrease in women at increased risk of developing breast cancer • Risedronate counterbalances the negative effect of anastrozole induced bone mineral density loss at the lumbar spine • Long-term intake of risedronate did not prevent bone loss at the total hip in osteopenic women • N-Terminal Propeptide of Type I Collagen (PINP) can predict bone mineral density changes

Multi-gene prognostic signatures including the Oncotype® DX Recurrence Score (RS), EndoPredict® (EP) and Prosigna® (Risk Of Recurrence, ROR) are widely used to predict the likelihood of distant recurrence in patients with oestrogen-receptor-positive (ER+), HER2-negative breast cancer. Here, we describe the development and validation of methods to recapitulate RS, EP and ROR scores from NanoString expression data. RNA was available from 107 tumours from postmenopausal women with early-stage, ER+, HER2− breast cancer from the translational Arimidex, Tamoxifen, Alone or in Combination study (TransATAC) where previously these signatures had been assessed with commercial methodology. Gene expression was measured using NanoString nCounter. For RS and EP, conversion factors to adjust for cross-platform variation were estimated using linear regression. For ROR, the steps to perform subgroup-specific normalisation of the gene expression data and calibration factors to calculate the 46-gene ROR score were assessed and verified. Training with bootstrapping (n = 59) was followed by validation (n = 48) using adjusted, research use only (RUO) NanoString-based algorithms. In the validation set, there was excellent concordance between the RUO scores and their commercial counterparts (rc(RS) = 0.96, 95% CI 0.93–0.97 with level of agreement (LoA) of −7.69 to 8.12; rc(EP) = 0.97, 95% CI 0.96–0.98 with LoA of −0.64 to 1.26 and rc(ROR) = 0.97 (95% CI 0.94–0.98) with LoA of −8.65 to 10.54). There was also a strong agreement in risk stratification: (RS: κ = 0.86, p κ = 0.87, p κ = 0.92, p

PurposeClinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer.MethodsThe validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5–10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan–Meier curves were used with associated 10-year DR risks (%).Results2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78–2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32–2.56)). The 10-year DR risks were 2.9% (1.9–4.5), 7.2% (5.3–9.9), and 12.9% (10.0–16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2–6.7), 6.9% (4.4–10.8), and 11.1% (7.4–16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded.ConclusionsThe CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.

Purpose: Invasive lobular carcinoma (ILC) accounts for approximately 5%–15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC). Experimental Design: The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0–10 in postmenopausal women with ILC. The primary outcome was DR. Results: 470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54–4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73–2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7–8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0–35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63–4.02)] and node-positive disease [HR = 3.70 (2.49–5.50)]. Conclusions: EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.

Background: Aromatase inhibitors (AIs) reduce the risk of breast cancer in women at increased risk and reduce recurrence in those with ductal carcinoma in situ (DCIS) (IBIS-2, MAP.3, NSABP B-33). The effectiveness of AIs depends on full adherence. We have previously reported adherence figures for the International Breast Cancer Intervention Studies 2 (IBIS-2) when 5 years of active treatment was not completed. Here, we assess reports of early symptoms on 5-year adherence with anastrozole in the prevention (versus placebo) and DCIS (versus tamoxifen) IBIS-2 after active treatment has been completed by all women. Methods: In IBIS-2, 3864 postmenopausal women in the prevention study were randomised to placebo vs. anastrozole (1mg/day) and 2980 postmenopausal women with DCIS were randomised to tamoxifen (20mg/day) vs. anastrozole (1mg/day). Women were excluded from the analyses (n=491 [262 prevention; 229 DCIS]) due to breast cancer, death, major adverse events, or failure to initiate preventive therapy. Adherence ( Results: In the IBIS-2 prevention study (N=3615), overall adherence to treatment was 67.7% and was statistically not significantly different between anastrozole (66.5%) and placebo (69.0%) (OR=0.89 (0.78-1.03), P=0.11). Adherence was significantly lower regardless of treatment allocation for those who developed arthralgia (68.3% vs. 72.8%, P=0.008) or gynaecological symptoms (vaginal changes, irregular bleeding) (65.1% vs. 72.2%, P=0.007), but not for those who reported hot flushes (71.1% vs. 71.8%, P=0.92), compared with those who did not report these symptoms at 6 months. In the IBIS-2 DCIS study (N=2759), adherence to treatment was 70.1% overall (anastrozole (70.2%) or tamoxifen (70.0%) (OR=1.01 (0.86-1.19), P=0.92)). Women treated with anastrozole reported significantly more arthralgia (30.6% vs. 20.5%, P Conclusions: In the IBIS-2 trials, we observed no significant differences in adherence between either anastrozole vs. placebo (prevention), or anastrozole vs. tamoxifen (DCIS). Significant associations between early symptoms and adherence were observed only in the prevention study, regardless of treatment allocation. Reporting symptoms in the first 6 months of preventive and adjuvant therapy is unlikely to explain non-adherence to medication. Further research is required to identify modifiable factors which may be altered by behavioural interventions to improve adherence. Citation Format: Sestak I, Smith S, Sleeth M, Howell A, Cuzick J. Participant-reported symptoms as predictors of long-term adherence of endocrine therapy in the International breast cancer intervention studies 2 (IBIS-2) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-15-01.

Background: Invasive lobular carcinomas (ILC) account for around 15% of all oestrogen receptor (ER) positive invasive breast cancers. The EndoPredict assay (EPclin) is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2-negative breast cancer patients treated with adjuvant endocrine therapy and has been validated in several retrospective translational studies. However, these validation studies did not include an analysis of the histological subtypes. Here, we investigate the role of EPclin for the prediction of distant recurrence in women with ILC and compare the prognostication to those with invasive ductal carcinoma (IDC) in TransATAC. Methods: Data on EPclin and histological type of tumour were available for 928 postmenopausal women with ER-positive, HER2-negative disease treated with 5 years of tamoxifen or anastrozole. The primary endpoint was distant recurrence and the primary objective was to assess the prognostic value of EPclin for the prediction of distant recurrence in women with invasive lobular carcinoma. Kaplan–Meier and Cox regression analyses were used to determine distant recurrence risk for 0-10 years of follow-up. Likelihood ratio tests were used to assess the prognostic information provided by EPclin. Hazard Ratios (HR) are for a change in 1 Standard Deviation. Results: 141 (15.2%) had ILC, 710 (76.5%) IDC, and the remaining 77 (8.3%) were of different histological type. EPclin provided highly significant prognostic value for distant recurrence in women with ILC (HR=3.33 (2.33-4.77), P Conclusions: This is the first analysis to focus on the role of EPclin for the prognostic assessment of women with ILC. Although numbers of women with ILC in TransATAC were small, EPclin provided highly significant prognostic information and risk stratification for this subgroup of women. 10-year distant recurrence risk in the EPclin low risk groups were similar between ILC and IDC, suggesting that chemotherapy is not indicated, irrespective of tumour type. Our results show that EPclin is informative in women with ILC. Citation Format: Sestak I, Kronenwett R, Denkert C, Cuzick J, Dowsett M. Prognostic performance of EndoPredict in invasive lobular carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-01.

The goal of this study is to shed more light on the influence of fertilisation on radionuclide transfer from soil to crops, which is a significant ecological issue in present-day agriculture due to the intensive use of soil amendments. Research on this subject has not been extensive, hence there are still numerous open questions that require an interdisciplinary approach involving agroecology and radioecology. Maize was chosen for our investigation because it has been used, in considerable quantities and worldwide, as both food and feed, which makes it part of numerous food chains with humans as final consumers. The agricultural part of the experiment was carried out on an acidic soil in northwestern Croatia, and it was based on seven treatments with different levels of NPK fertilisation. Radionuclide activity concentrations in sampled soil, stem, and grain were measured by means of high-resolution γ-ray spectrometry. We found that the radiological properties of the soil were not affected by the addition of the fertiliser. Soil-to-stem uptake for radionuclides of the whole 232Th decay chain was first suppressed by mild fertilisation, and then, at higher fertiliser concentrations, it stayed low and became independent of fertilisation level. The same effect was observed for the 238U decay chain before gaseous 222Rn. We present arguments in favour of the cause of the observed suppression being radionuclide complexation with constituents of the fertiliser. However, the concentration of 210Pb in stem did not depend on fertilisation, which was most probably a consequence of the decay of airborne 222Rn and the deposition of its progenies onto stem. Radionuclide translocation from stem to grain did not depend on fertilisation either, and it was appreciable only for 40K and 137Cs. In grain, radionuclide concentrations were lower than in stem. Overall, in our case, fertilisation had positive effects, reducing the presence of radionuclides in the maize while having no detectable impact on the radiological properties of the soil. This finding may have implications for future work, especially regarding concerns about the impact of soil amendments on food production.

Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor-negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined.Quantitative immune scores of cell abundance and spatial heterogeneity were computed using a fully automated hematoxylin and eosin-stained image analysis algorithm and spatial statistics for 1178 postmenopausal patients with ER+ breast cancer treated with five years' tamoxifen or anastrozole. The prognostic significance of immune scores was compared with Oncotype DX 21-gene recurrence score (RS), PAM50 risk of recurrence (ROR) score, IHC4, and clinical treatment score, available for 963 patients. Statistical tests were two-sided.Scores of immune cell abundance were not associated with recurrence-free survival. In contrast, high immune spatial scores indicating increased cell spatial clustering were associated with poor 10-year, early (0-5 years), and late (5-10 years) recurrence-free survival (Immune Hotspot: LR-χ2 = 14.06, P.001, for 0-10 years; LR-χ2 = 6.24, P = .01, for 0-5 years; LR-χ2 = 7.89, P = .005, for 5-10 years). The prognostic value of spatial scores for late recurrence was similar to that of IHC4 and RS in both populations, but was not as strong as other tests in comparison for recurrence across 10 years.These results provide a missing link between tumor immunity and disease outcome in ER+ disease by examining tumor spatial architecture. The association between spatial scores and late recurrence suggests a lasting memory of protumor immunity that may impact disease progression and evolution of endocrine treatment resistance, which may be exploited for therapeutic advances.

Background: Previous reports from the Anastrozole Tamoxifen Alone or in Combination (ATAC) trial have shown significantly prolonged disease-free survival, lower rates of recurrence and distant recurrence, and reduced contralateral breast cancer in patients treated with anastrozole compared to tamoxifen (Cuzick et al., Lancet, 2010). Here, we compare the long-term effects of anastrozole versus tamoxifen in patients randomised to either monotherapy arm in the ATAC trial. Methods: Postmenopausal women with hormone receptor positive breast cancer randomised to anastrozole or tamoxifen in the main ATAC trial were eligible for the LATTE observational study. The primary objective was to compare the long-term effects of tamoxifen and anastrozole on time to recurrence and death beyond 10 years after randomisation. Secondary objectives included time to distant recurrence, cancer-specific survival, new breast primaries, other cancers, fractures, and cardiac/cerebrovascular events. Cox proportional hazard methods were used to compute hazard ratios (95% CI) for recurrence from the time of last publication (10 years median follow-up). Results: 2452 women from 11 countries were entered into the LATTE study. 40 women withdrew consent and 759 women died or had a recurrence within 10 years, which left 1653 women for analysis (838 anastrozole vs. 815 tamoxifen). A total of 118 breast events (69 anastrozole (8.2%) vs. 49 tamoxifen (6.0%)) were reported. No significant difference between the two treatment arms were observed (HR=1.36 (0.94-1.97), P=0.098). 57 women had a distant recurrence (33 (3.9%) vs. 24 (2.9%)), 41 reported a loco-regional recurrence (23 (2.7%) vs. 18 (2.2%)), and 26 contra-lateral breast cancer were recorded (17 (2.0%) vs. 9 (1.1%)). None of the treatment comparisons were statistically significant. 305 deaths were recorded (147 (17.5%) vs. 158 (19.4%)), of which 31 were due to breast cancer. Significantly fewer gynaecological cancers were recorded with anastrozole (7 vs. 16; OR=0.42 (0.15-1.09), P=0.05), but overall the effect on other cancers was not significant (54 (6.4%) vs. 64 (7.9%). Fractures, cardiovascular, and cerebrovascular events were evenly distributed between the treatment arms. Conclusions: Although anastrozole was associated with significant fewer recurrences compared to tamoxifen in the first 10 years of follow-up, in this analysis, with limited number of patients, we could not find a significant difference between the two treatment arms. Citation Format: Cuzick J, Sestak I, Bianco A, Strobbe L, Bergh J, Hanusch C, Neven P, Dowsett M, Forbes JF, Buzdar A, Smith R, Howell A. Long-term comparison of anastrozole versus tamoxifen: Results from LATTE/ATAC [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 P2-09-03.

Background: EndoPredict (EPclin) and Oncotype Recurrence Score (RS) have both shown their prognostic ability for women with estrogen receptor positive (ER), HER2-negative breast cancer, with EPclin outperforming RS specifically in node-positive population and for the prediction of late distant recurrence (DR). Age is an important risk factor for breast cancer but no data is available on the performance of genomic assays according to patient’s age. Here, we investigate whether EPclin and RS provide differential prognostic value in different age groups. Methods: 928 postmenopausal women with ER-positive, HER2-negative breast cancer were included in this analysis for whom information on EPclin and RS were available. None of the patients included in this analysis received chemotherapy. Age at diagnosis was treated as a categorical variable (≤60 years, 60-70 years, >70 years). Primary endpoint was DR and we used Cox regression models to assess the prediction of DR by EPclin and RS according to age. Results: 300 (32.3%) women were aged 60 years or younger, 377 (40.6%) between 60 and 70 years, and 251 (27.1%) were older than 70 years. Women aged 60 years or older had significantly more node-positive disease, higher grade tumors, and more DR than those aged 60 or younger. RS scores were similar between age groups whereas EPclin scores were significantly higher in older women compared to younger women, reflecting the combined molecular plus clinical nature of the EPclin. Overall, both RS and EPclin were prognostic but with decreasing prognostic value with increasing age (Table). We observed a significant interaction between continuous age and both tests (RS: P=0.004; EPclin: P=0.026). In women aged 70 years and older, RS did not provide any prognostic information (HR=1.22 (0.96-1.55); LR-χ2=2.5) whereas EPclin showed significant prognostic ability in this age group (HR=2.02 (1.59-2.57); LR-χ2=30.4) (Table). Kaplan-Meier estimates were significantly different between low and high risk groups for both tests in women aged less than 70 years. No significant risk stratification was achieved by RS in women aged 70 years or older whereas EPclin distinctively stratified older patients into low and high risk groups with significant different 10-year DR risks. Conclusion: Genomic assays are increasingly used in the clinic to determine prognosis for women with ER-positive, HER2-negative breast cancer. Here, we show that the effect sizes and prognostic value of EPclin and RS are different across age groups, and only the EPclin was prognostic in elderly patients. Our results indicate that tests that incorporate clinical parameters in their score are likely to be more prognostic in elderly patients and should be used in the decision-making process when using genomic assays. Hazard Ratios (HRs (95% CI)) for continuous EPclin/RS scores and risk groups according to age groups≤60 years60-70 years>70 years(N=300)(N=377)(N=251)RS2.23 (1.57-3.15)1.59 (1.32-1.91)1.22 (0.96-1.55)LowReferenceReferenceReferenceIntermediate3.79 (1.40-10.24)2.74 (1.44-5.23)1.75 (0.97-3.15)High8.86 (3.07-25.57)6.55 (3.25-13.19)1.63 (0.67-3.96)EPclin3.47 (2.28-5.27)2.74 (2.17-3.45)2.02 (1.59-2.57)LowReferenceReferenceReferenceHigh9.60 (3.60-25.57)5.55 (2.91-10.61)3.68 (1.89-7.17) Citation Format: Ivana Sestak, Ralf Kronenwett, Richard Buus, Jack Cuzick, Mitchell Dowsett. Prognostic value of EndoPredict and Oncotype Recurrence Score according to patient's age [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 P5-06-04.

Purpose: Extended adjuvant hormone therapy improves estrogen receptor (ER)-positive breast cancer outcome. The total duration of endocrine therapy is still a subject for debate. The CTS5 score, developed by Dowsett et al1., predicts late distant recurrence (LDR) between years 5 and 10 after diagnosis in ER-positive invasive breast cancers in postmenopausal women. This LDR risk might be used to select patients for extended endocrine therapy. The CTS5 score is calculated using age at the start of endocrine therapy, tumor size, grade, and lymph node status. The aim of this study is the validation of this tool in a series of women from the UZ Leuven. Methods: This retrospective cohort study included 1125 postmenopausal women consecutively diagnosed with invasive estrogen receptor (ER) positive breast cancer who stopped endocrine therapy after 4.5 to 5.5 years. Tissue was tested for ER positivity and considered positive if >1% of tumor nuclei were stained. HER2 status was defined according to ASCO guidelines. Statistical analysis was performed by Cox proportional hazards models which determined the prognostic performance of the CTS5 score for LDR. Results: A total of 1125 patients were included in this analysis, of which 1097 had a known HER2 status and 1023 were negative. 62 of 1125 (5.5%) developed an LDR between years 5 and 10. The continuous CTS5 was a significant predictor for LDR (HR =2.69 (1.99-3.60), p Conclusion: In our series of postmenopausal women, CTS5 accurately predicts late distant recurrence in ER-positive, HER2-negative early invasive breast cancers. The CTS5-score, identifying a patient group with LDR risk of ≥5%, might be used to discuss the benefits of extended endocrine therapy for individual patients. However, the exact predictive value for the benefit of prolonged therapy can only be based on a randomized controlled trial (RCT) using the LDR risk as a stratification factor. It would be of great value to expand the study population, especially HER2-positive tumors, and define the prognostic performance of the CTS5 score in premenopausal women. Further research is needed. 1. Dowsett, M. et al. Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5. J. Clin. Oncol. 36, 1941-1948 (2018). Citation Format: Josephine Van Cauwenberge, Ivana Sestak, Kevin Punie, Hans Wildiers, Giuseppe Floris, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Caroline Weltens, Hilde Janssen, Patrick Neven. Predicting distant recurrence of ER+ HER2- breast cancer after 5 years of endocrine therapy: The CTS5-tool validation in real life [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 P5-06-08.

Background: Several multigene assays are available for managing ER-positive, HER2-negative early stage breast cancer but with little direct comparative information within this patient population. Existing evidence suggests that current multigene assays provide broadly equivalent risk information for the population of women with ER-positive, HER2-negative breast cancers. However, for the individual patient tests may provide differing risk categorization (Bartlett et al, JNCI 2016). We have previously demonstrated the prognostic value of different commercially available tests including Prosigna (ROR) and Oncotype Dx (RS) (Dowsett et al, JCO 2013; Sestak et al, JAMA Onc 2018). Here, we investigate risk classification and 10-year DR rates in patients that had discordant risk categorization between ROR and RS. Methods: A total of 663 postmenopausal women with ER-positive, HER2-negative, node-negative early stage breast cancer from the TransATAC study for whom both signatures were available were included in this analysis. The primary endpoint was distant recurrence (DR). Predefined ROR cut-off points for low/intermediate and intermediate/high of 40/60 were used. Comparisons were made using two sets of RS cut-off points 1) TailoRX cut-off points of 10/25 and 2) original cut-off points of 18/31. Kaplan-Meier curves were used to estimate the mean risk of DR after 10 years of follow-up in predefined risk groups. Results: Using original RS cut-off points, 25 patients (3.8%) had a high-low discordance compared to ROR, with a total of 295 (44.5%) discordant cases. Using the TailoRx cut-off points, 40 patients (6.0%) had a high-low discordance compared to ROR, with a total of 396 (59.7%) discordant cases. Applying original RS cut-off points, patients categorized into ROR low but into intermediate or high by RS (86/365 (23.6%)) had a 10-year DR rate of only 6.3% (2.7-14.6) (Table). In contrast, patients categorized into RS low but into intermediate or high by ROR (144/423 (48.6%)) had a 10-year DR rate of 13.4% (8.3-21.2). Using the TailoRx cut-off points, patients categorized into ROR low but into intermediate or high by RS (261/365 (71.5%)) had a 10-year DR rate of 2.9% (1.4-5.9), while patients with an RS low but intermediate or high by ROR (62/166 (37.3%)) had a 10-year DR rate of 18.2% (10.2-31.2) (Table). Conclusion: Discordance in risk categorization at the individual patient-level between commercially available multigene assays for early stage breast cancer is not uncommon. Our results show that node-negative patients that were classified by ROR as low risk, regardless of RS risk stratification, had an excellent 10-year DR risk with endocrine therapy alone. In contrast, patients that were classified as RS low risk by either cut-off points but were classified as intermediate or high risk by ROR had a significantly worse 10-year outcome. Our results indicate that ROR better categorized women with node negative disease into respective risk groups. Risk stratification and 10-year DR risk (%) according to ROR and RS cut-off points.ROR cut-offsLow (N=365)Intermediate/High(N=298)Original RS cut-offsNumber10-year risk (%)Number10-year risk (%)Low (N=423)2791.5%14413.4%Intermediate/High (N=240)866.3%15424.8%TailoRx cut-offsLow (N=166)1042.1%6218.2%Intermediate/High (N=497)2612.9%23619.5% Citation Format: Ivana Sestak, Sean Ferree, Itay Shemesh, Wesley Buckingham, Jack Cuzick, Mitchell Dowsett. Discordant classification and outcomes between Prosigna and Oncotype Dx Recurrence Score for ER-positive, HER2-negative, node-negative breast cancer [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 P5-06-05.

Background: Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period. Methods: IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer. Findings: 3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105–156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39–0·66, p

Purpose: To test the validity of OncoMasTR Molecular Score (OMm), OMclin1, and OncoMasTR Risk Score (OMclin2) prognostic scores for prediction of distant recurrence (DR) in estrogen receptor (ER)-positive/HER2-negative breast cancer treated with 5 years' endocrine therapy only and compare their performance with the Oncotype DX Recurrence Score (RS). Experimental Design: OMm incorporates three master transcription regulator genes. OMclin1 combines OMm, tumor size, grade, and nodal status; OMclin2 incorporates OMm, tumor size, and nodal status. OMclin1 and OMclin2 were evaluated for 646 postmenopausal patients with ER-positive/HER2-negative primary breast cancer with 0–3 involved lymph nodes in TransATAC. Patients were randomized to 5 years' anastrozole or tamoxifen without chemotherapy. RS was available in all cases. We used likelihood ratio-χ2, C-index, and Kaplan–Meier analyses to assess prognostic information. Results: OMm, OMclin1, and OMclin2 were highly prognostic for prediction of DR in years 0–10 among all patients [likelihood ratio (LR)-χ2 = 25.4, 48.7, and 45.0, respectively, all P < 0.001; C-index = 0.67, 0.71, and 0.71, respectively], compared with RS (LR-χ2 = 18.8; P < 0.001; C-index = 0.63). All three scores provided significant additional prognostic value beyond clinical treatment score, Nottingham Prognostic Index, and Ki67. OMclin1 and OMclin2 categorized 190 and 267 node-negative patients as low risk (DR rates: 2.9% and 4.9%, respectively). In comparison, RS categorized 296 node-negative patients as low-risk and 128 patients as intermediate-risk (DR rate: 6.6% and 17.3%, respectively). Conclusions: OMm, OMclin1, and OMclin2 were highly prognostic for early and late DR in women with early-stage ER-positive breast cancer receiving 5 years' endocrine therapy. In TransATAC, OMclin1 and the OncoMasTR Risk Score (OMclin2) were superior to RS in identifying patients at increased risk of DR.

Purpose EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C). Methods A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses. Results EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49–3.13), P

Background: Two large clinical trials have reported divergent results in their initial analysis of the benefit of aromatase inhibitors compared to tamoxifen in women with ductal carcinoma in situ (DCIS) (IBIS-II and NSABP B-35). Here, we report blinded 12-year median follow-up efficacy and adverse event data for the IBIS-II trial, which compared anastrozole to tamoxifen in women with hormone receptor positive DCIS and focus on the post-treatment follow-up period.Methods: A multi-centre randomised trial of 1mg/day anastrozole (N=1471) vs. 20mg/day tamoxifen (N=1509) for five years was conducted in postmenopausal women with locally excised DCIS diagnosed between 2003 and 2009. The primary objective of this analysis was to determine the efficacy of anastrozole compared to tamoxifen in preventing recurrences overall, and in particular in the post 5-year treatment period. Secondary endpoints included type of recurrence, breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths.Results: After a median follow-up of 11.6 years (IQR 9.9 to 13.4), a total of 221 breast cancer recurrences (7.4%) have been recorded. No difference in overall recurrence was observed (102 (6.9%) anastrozole vs. 119 (7.9%) tamoxifen; HR=0.87 (0.67-1.14), P=0.32) overall (Table), in the 5-year treatment period (HR=0.82 (0.53-1.27), P=0.37), or the post treatment follow-up period (HR=0.91 (0.65-1.27), P=0.57). Oestrogen receptor (ER) positive breast cancers were reduced by 28% with anastrozole when compared to tamoxifen (58 vs. 82; HR=0.72 (0.52-1.01), P=0.056) but this did not reach significance. In contrast, no effect was observed for ER-negative breast cancer with anastrozole (Table). No significant difference for the reduction in invasive breast cancer recurrence was observed with anastrozole when compared to tamoxifen (Table). Invasive ER-positive breast cancer was non-significantly reduced by 24% with anastrozole when compared to tamoxifen (44 vs. 59; HR=0.76 (0.51-1.12), P=0.17). A total of 127 deaths have been reported, with no significant difference in all-cause mortality between the two treatment arms (61 vs. 66; HR=0.94 (0.67-1.33), P=0.74). Only 7 deaths from breast cancer (3 vs. 4) were reported, with so few deaths from breast cancer at 12 years, any impact on survival is unlikely to emerge with longer follow-up. 214 cancers other than breast were reported, with a non-significant decrease observed with anastrozole (97 vs. 117, OR=0.84 (0.63-1.12), P=0.22). Endometrial (2 vs. 13, OR=0.16 (0.02-0.0.69)), ovarian cancer (1 vs. 9, OR=0.11 (0.003-0.82)), and non-melanoma skin cancer (11 vs. 21) were less common with anastrozole. Significantly higher rates of fractures (181 vs. 145, OR=1.32 (1.04-1.68)) and transient ischaemic attacks (15 vs. 5, OR=3.10 (1.07-10.92)) were observed with anastrozole compared to tamoxifen. A comprehensive adverse event profile will be reported. Conclusions: No clear efficacy differences were seen between the two treatments, although the data suggests possible greater efficacy for anastrozole over tamoxifen for prevention of ER-positive breast cancers. There were some clear differences in adverse events and anastrozole may be more appropriate for some women with contraindications for tamoxifen. Table: Number of events and Hazard Ratios (95% CI) according to treatment allocation.Anastrozole(N=1471)Tamoxifen(N=1509)HR (95% CI)Any recurrence1021190.87 (0.67-1.14)ER-positive58820.72 (0.52-1.01)ER-negative24151.63 (0.86-3.11)Invasive66760.89 (0.64-1.23)ER-positive44590.76 (0.51-1.12)ER-negative17121.44 (0.69-3.02)DCIS35420.85 (0.54-1.33)ER-positive14230.62 (0.32-1.21)ER-negative732.38 (0.61-9.20)Numbers do not add up due to missing information Citation Format: Ivana Sestak, Jack Cuzick, Bernardo Bonanni, Nigel Bundred, Christelle Levy, Sibylle Loib, Patrick Neven, Michael Stierer, Chris Holcombe, Robert Coleman, John Forbes, Anthony Howell. 12 year results of anastrozole versus tamoxifen for the prevention of breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-02.

Background: PgR is only expressed significantly in ER+ breast cancers and is generally considered a classical estrogen-sensitive protein, however, while ER+ cells are almost always expressed in a non-clustered pattern across the tumour bed, PgR+ cells form clusters or clumps with surrounding areas of PgR- cells when assessed by IHC in about 20-25% of PgR+ tumours. This is an ill-described and unexplained feature of intratumoural heterogeneity of a widely measured biomarker. The prognostic significance of the PgR clumpiness is also unknown. Aims: to determine the (i) biologic and (ii) prognostic significance of PgR clumpiness in ER+ primary breast cancer. Methods: (i) Biologic study: 40 primary ER+PgR+ tumours were identified with distinct PgR clumpiness by IHC. Areas of PgR+ and PgR- cells (PgR-rich and PgR-poor areas, respectively) were needle microdissected from unstained sections by juxtaposing them with PgR-stained sections from the same tumour. Areas were also dissected from 8 homogeneous PgR+ and 8 PgR- tumours for reference. NanoString gene expression analysis using a 50-gene code set (45 oestrogen-responsive or proliferation genes + 5 housekeeping genes) was performed on RNA extracts from the samples. (ii) Prognostic study: we developed a PgR heterogeneity score (PgR Het-score, range 0-18) as the product of (A) the number of PgR+ clumps/cm2 of tumour area (range 0 to 6) and (B) the level of overall PgR-positivity (0-4% or 96-100%, score 0; 5-19% or 80-95%, score 1; 20-39 or 60-79%, score 2; 40-59%, score 3). PgR Het-scores were derived from images (Hamamatsu NanoZoomer-XR) of PgR-stained sections from two sets of tumour biopsies taken at diagnosis after which all patients received adjuvant endocrine therapy: 322 tumours from the Royal Marsden and from Southern Sweden collected for a case:control study of risk of recurrence (recurrence:no recurrence, 1:1) and 591 patients from the TransATAC cohort study with time to recurrence as the end-point. Results: (i) Biologic study: In unsupervised hierarchical clustering of RNA expression from all samples, 33/40 pairs of PgR-rich and PgR-poor areas from a single tumour paired together and all 8 positive and negative control samples were grouped separately. Eight genes were differentially expressed between the PgR-rich and -poor areas (FDR Conclusion: Major, functionally significant differences in PgR expression occur within some ER+ tumours that are not explained by differences in ER expression and are not associated with differences in expression of most other estrogen-dependent genes. Further work is on-going to provide a mechanistic explanation for the PgR heterogeneity. Given the discordance in results from the two clinical studies its prognostic significance is uncertain. This work was funded by BCRF. Citation Format: Lila Zabaglo, Richard Buus, Eugene Schuster, Belinda Yeo, Marie Klintman, Ivana Sestak, Jack Cuzick, Ian Smith, Mitch Dowsett. Intratumoural heterogeneity in PgR expression: Molecular and prognostic significance [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-10.

Purpose: Previous results from the TransATAC study demonstrated that both the Breast Cancer Index (BCI) and the OncotypeDX Recurrence Score (RS) added significant prognostic information to clinicopathologic factors over a 10-year period. Here, we examined cross-stratification between BCI and RS to directly compare their prognostic accuracy at the individual patient level. Experimental Design: A total of 665 patients with hormone receptor–positive (HR+) and lymph node–negative disease were included in this retrospective analysis. BCI and RS risk groups were determined using predefined clinical cut-off points. Kaplan–Meier estimates of 10-year risk of distant recurrence (DR) and log-rank tests were used to examine cross-stratification between BCI and RS. Results: As previously reported, both RS and BCI were significantly prognostic in years 0 to 10. BCI provided significant additional prognostic information to the Clinical Treatment Score (CTS) plus RS (ΔLR-χ2 = 11.09; P < 0.001), whereas no additional prognostic information was provided by RS to CTS plus BCI (ΔLR-χ2 = 2.22; P = 0.1). Restratification by BCI of the low and intermediate RS risk groups led to subgroups with significantly different DR rates (P < 0.001 and P = 0.003, respectively). In contrast, restratified subgroups created by RS of BCI risk groups did not differ significantly. Conclusions: In this retrospective analysis, BCI demonstrated increased prognostic accuracy versus RS. Notably, BCI identified subsets of RS low and RS intermediate risk patients with significant and clinically relevant rates of DR. These results indicate that additional subsets of women with HR+, lymph node–negative breast cancer identified by BCI may be suitable candidates for adjuvant chemotherapy or extended endocrine therapy. Clin Cancer Res; 22(20); 5043–8. ©2016 AACR. See related commentary by Brufsky and Davidson, p. 4963

Purpose Immunohistochemical 4 (IHC4) score plus Clinical Treatment Score (CTS) is an inexpensive tool predicting risk of distant recurrence in women with early breast cancer (EBC). IHC4 score is based on ER, PR, HER2 and Ki67 index. This study explores the role of the combined score (IHC4 + CTS) in predicting risk of locoregional recurrence (LRR) in women with EBC who had breast conservation surgery (BCS) without adjuvant radiotherapy (study group). The secondary objective was to evaluate the clinicopathological differences between our study group and women who had adjuvant radiation following BCS (control group). Methods and materials Patients were selected from the local database over a 13-year period. IHC testing was done where results were missing. Combined scores were calculated using the appropriate formulae. Results Patients in the study group (81 patients) had favorable clinicopathological features compared to the control group (1406 patients). The Cox regression indicated a statistically significant association between the combined score and the risk of LRR ( p = 0.03). The incidence of LRR was zero, 20% and 33.3% in the low, intermediate and high risk groups respectively ( p = 0.007). Margin status was the only variable not included in the combined score. The Cox regression analysis demonstrated that the combined score ( p = 0.02) and the ordinal measure of margins ( p = 0.03) were significant independent predictors of LRR. Conclusion This is the first study of its kind. The IHC4 score + CTS can be used to identify low risk women who can potentially avoid adjuvant radiotherapy.

The gynaecological toxicity profile of tamoxifen presents a significant burden to the patients and oncologist as tamoxifen-related side effects result in additional investigations, procedures and referrals. Aromatase inhibitor have been shown to result in significant reduction in gynaecological problems, possibly including endometrial cancer. Areas covered: We reviewed the main breast cancer trials, observation or cohort studies investigating tamoxifen or an aromatase inhibitor to report on endometrial adverse events and cancer. Expert commentary: Evidence for an increase in endometrial cancers with tamoxifen in breast cancer treated patients is now very clear. Aromatase inhibitors have shown to have a beneficial effect on the endometrium. There is an important need for further studies to clearly determine the influence of aromatase inhibitors on the endometrial in tamoxifen-naïve women. The effect of aromatase inhibitors on gynaecological problems may have potentially a very important impact in clinical practice.

Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings.

Clinical variables and several gene signature profiles have been investigated for the prediction of (distant) recurrence in several trials. These molecular markers are significantly correlated with overall and late distant recurrences. Here, we retrospectively explore whether age and body mass index (BMI) affect the prediction of these molecular scores for distant recurrence in postmenopausal women with hormone receptor-positive breast cancer in the transATAC trial. 940 postmenopausal women for whom the Clinical Treatment Score (CTS), immunohistochemical markers (IHC4), Oncotype Recurrence Score (RS), and the Prosigna Risk of Recurrence Score (ROR) were available were included in this retrospective analysis. Conventional BMI groups were used (N = 865), and age was split into equal tertiles (N = 940). Cox proportional hazard models were used to determine the effect of a molecular score for the prediction of distant recurrence according to BMI and age groups. In both the univariate and bivariate analyses, the effect size of the IHC4 and RS was strongest in women aged 59.8 years or younger. Trends tests for age were significant for the IHC4 and RS, but not for the CTS and ROR, for which most prognostic information was added in women aged 60 years or older. The CTS and ROR scores added significant prognostic information in all three BMI groups. In both the univariate and bivariate analyses, the IHC4 provided the most prognostic information in women with a BMI lower than 25 kg/m(2), whereas the RS did not add prognostic information for distant recurrence in women with a BMI of 30 kg/m(2) or above. Molecular scores are increasingly used in women with breast cancer to assess recurrence risk. We have shown that the effect size of the molecular scores is significantly different across age groups, but not across BMI groups. The results from this retrospective analysis may be incorporated in the identification of women who may benefit most from the use of these molecular scores, but our findings need further evaluation before these scores can be used in clinical decision making.

Background: Breast Cancer Index (BCI) is a gene expression-based assay that reports two distinct results: 1) BCI predictive based on HoxB13/IL17BR ratio (H/I), and 2) BCI prognostic based on an algorithm incorporating H/I with the Molecular Grade index (MGI). Both biomarkers have been validated independently in randomized trial cohorts. However, integrated results to better correlate recurrence risk with endocrine response have not been evaluated. The aim of this post-hoc analysis was to examine patient outcomes within BCI prognostic and predictive groups using the translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC). Methods: Primary tumor samples (N=742) from hormonal receptor-positive, N0 breast cancer patients treated with 5 years of tamoxifen (TAM) or anastrozole (ANA) in the ATAC trial were examined. Kaplan-Meier analysis was used to examine the risk of distant recurrence (DR) in patient subgroups derived from BCI and H/I results. A separate series of clinical cases submitted for BCI testing (N=853) were analyzed to determine distribution of the combined BCI and H/I groups in clinical practice. Results: Summary of patient distribution across the 6 BCI clinical subgroups showed that a large number of patients (331/742, 45%) were BCI low risk with low likelihood of benefit, whereas 108/742 (15%) of patients with endocrine responsive disease (High H/I) were classified as BCI low risk (Table 1). Kaplan-Meier analysis demonstrated that patients classified as BCI low risk had a very similar 10-year risk of DR irrespective of H/I status (H/I low: 5.5% vs. H/I high: 4.0%), indicating that prognosis was largely determined by BCI vs H/I. Table 1: Distribution of BCI and H/I risk groups in TransATAC BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood3318717435 (59%)High Likelihood10895104307 (41%)Total439 (59%)182 (25%)121 (16%)742 In 853 node negative cases submitted for BCI clinical testing, the distribution of BCI and H/I risk groups were similar to that from the TransATAC cohort (Table 2). Table 2: Distribution of BCI and H/I risk groups in clinical cases submitted for BCI testing BCI: PrognosticH/I: PredictiveLow RiskIntermediate RiskHigh RiskTotalLow Likelihood36410523492 (58%)High Likelihood96107158361 (42%)Total460 (54%)212 (25%)181 (21%)853 Discussion: Both prognostic and predictive components reported from the BCI assay may be used to stratify patients into 6 clinical subgroups based on prognostic risk of distant recurrence and endocrine responsiveness. Findings from this analysis indicate that patients classified as BCI low risk, regardless of H/I status, had sufficiently low DR rates and identifies patients that may be adequately treated with 5 years of endocrine therapy. Citation Format: Zhang Y, Sestak I, Schroeder BE, Dowsett M, Cuzick J, Schnabel CA, Sgroi DC. Prognostic impact of the combined risk groups by breast cancer index and HOXB13/IL17BR ratio in hormonal receptor positive, node negative breast cancer: A TransATAC study. [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 P5-08-03.

Background: BCI is a genomic signature (Molecular Grade Index (MGI) and HOXB13/IL17BR (H/I)) that significantly predicts risk of distant recurrence (DR) in hormonal receptor-positive, lymph node negative (LN-) breast cancer. As previously shown in the TransATAC and MA.14 studies, BCI was also prognostic for DR in lymph node-positive (LN+) patients. Here, a distinct BCI model that integrates tumor size and grade was evaluated for prediction of DR in women with 1-3 lymph node positive disease. Methods: 219 primary tumor samples from hormonal receptor-positive patients with 1-3 positive lymph nodes treated with 5 years of tamoxifen or anastrozole were examined. Women with four or more positive lymph nodes were excluded. BCI was combined with tumour size and grade into a comprehensive risk score, BCIN+. Kaplan-Meier (KM) estimates of 10 year DR and hazard ratios (HR) and 95% confidence intervals (CI) were estimated. Change in likelihood ratio 2 (LR-2) values were used to measure prognostic information of each variable alone or combined in new score. New cutpoints for low versus high risk groups for the new model were determined to ensure the low risk patients had minimal 10-year residual disease. Results: In 219 LN+ patients, BCI alone provided substantial additional prognostic information to tumor size (LR-2=11.83, P=0.0006) and grade (LR-2=8.33, P=0.004). Both clinical variables provided additional significant prognostic information to BCI alone (BCI alone: LR-2=9.59, P=0.0004; T: LR-2=7.09, P=0.008; G: LR-2=27.59, P Discussion: Integration of tumor size and grade significantly enhanced the prognostic ability of BCI to predict 10 year DR risk in hormonal receptor-positive patients with 1-3 positive nodes. A significant number of patients have been identified to have a very low 10-year risk for DR, who may choose to safely forego unnecessary adjuvant chemotherapy or extended adjuvant endocrine therapy. Validation of BCIN+ in other datasets is ongoing. Citation Format: Sestak I, Zhang Y, Schroeder B, Dowsett M, Sgroi D, Cuzick J, Schnabel CA. Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes. [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 P2-08-12.

Chemoprevention is a risk reduction option for women who have increased risk of breast cancer. Selective Estrogen Receptor Modulators (SERMs) have been extensively tested, and alternative agents are being evaluated. Long-term adherence to chemoprevention is critical to obtaining the drug's full benefit. We systematically reviewed articles reporting uptake rates and adherence among healthy adult women, who were prescribed medication to prevent primary breast cancer. We also extracted data on the clinical, socio-demographic and psychological predictors of uptake and adherence. Searches were performed in PubMed, CINAHL, EMBASE, and PsychInfo, yielding 3851 unique articles. Title, abstract and full text screening left 53 articles that met inclusion criteria, and a further 4 studies were identified from reference lists, giving a total of 57. The mean quality score using the Mixed Methods Appraisal Tool was 3 out of 4. Thirty-one articles reported uptake, of which 14 tested predictors, and 23 reported adherence of which 11 tested predictors. Seven studies reported qualitative data. Most studies (50) involved SERMs, but 5 tested Aromatase Inhibitors, 1 tested Aspirin, 1 tested a statin. Twenty studies included data from a clinical setting, 35 reported trial data, and 2 reported both. Twenty-four studies reporting 26 instances of uptake in 21,423 women were included in a meta-analysis. The pooled uptake estimate was 16.3% (95% CI, 13.6-19.0), with high heterogeneity (I^2=98.9%, p Chemoprevention uptake for the prevention of breast cancer is low, and long-term adherence is often insufficient for the full preventive effect. Uptake rates were higher in trials than in clinical settings, suggesting further work should focus on implementing chemoprevention within routine patient care. Further research is warranted to identify factors amenable to modification and to improve informed decision-making surrounding chemoprevention. Citation Format: Smith SG, Sestak I, Forster A, Partridge A, Side L, Horne R, Wardle J, Cuzick J. Factors affecting uptake and adherence to breast cancer chemoprevention: A systematic review and meta-analysis. [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 PD1-08.

1020 Background: Accurate prediction of distant metastasis (DM) in early stage ER+/HER2- breast cancer (BC) patients is vital to avoid over/under-treatment with adjuvant chemotherapy (CT). The OncotypeDX Recurrence Score (RS) is a widely used tool to assist clinical decision-making for CT. The StemPrintER Risk Score (SPRS) is an alternative genomic predictor based on the biology of cancer stem cells that predicts recurrence risk in ER+/HER2- BCs (Pece S. et al., EBioMedicine 2019). Here, we analyze the prognostic value of SPRS in the TransATAC cohort of post-menopausal ER+/HER2- BC patients, and compare the prognostic information provided by SPRS and RS for 10-year risk of DM. Methods: The likelihood χ2 (LRχ2) and Kaplan-Meier survival analyses were used to assess prognostic information provided by SPRS, RS and the clinical treatment score (CTS) in 818 TransATAC patients treated with anastrozole or tamoxifen for 5 years. Comparative analyses were made for DM risk over the 10-year follow-up, as well as in the early (0-5 years) or late (5-10 years) interval, according to nodal status. Results: Used as a continuous variable, SPRS was an independent predictor of DM in years 0-10 among all patients when adjusted for clinical parameters as expressed by the CTS [HR=1.43 (1.18-1.73), PHIGH vs. LOW=2.96 (1.85-4.73); P2=33.4; RS: HR=1.52, P2=22.1), with even greater differences in late DM prediction in N0 patients. SPRS also provided more prognostic information than RS to CTS (ΔLRχ2: SPRS+CTS vs. CTS= 14.9; RS+CTS vs. CTS= 9.7). Conclusions: In ER+/HER2- TransATAC BC patients, SPRS was highly prognostic for DM and was superior to RS in providing additional prognostic information to conventional clinicopathological parameters.

Background: Two large clinical trials have shown the benefit of aromatase inhibitors in healthy women to reduce the risk of developing breast cancer (MAP.3 and IBIS-II). Here, we report blinded 10-year median follow-up efficacy data for the IBIS-II trial, which compared anastrozole to placebo in women at increased risk of developing breast cancer. Material and Methods: 3864 postmenopausal women at increased risk of developing breast cancer were recruited into a double-blind trial of anastrozole (N=1920) versus matching placebo (N=1944) for 5 years. The primary objective of this study was to determine the efficacy of anastrozole in preventing breast cancer (both invasive and ductal carcinoma in situ (DCIS)), overall and particularly for the post 5-year time period. Secondary endpoints included prevention of oestrogen receptor positive breast cancer, breast cancer mortality, non-breast cancer deaths, other cancers, cardiovascular disease, fractures, and musculoskeletal events. Results: After a median follow-up of 10.9 years (IQR 8.8-13.0), a total of 241 breast cancers have been reported (HR=0.50 (0.38-0.65), P Conclusion: This updated analysis of the IBIS-II trial confirms the significant reduction in breast cancer occurrence with anastrozole in the post-treatment follow-up period. These results indicate a long-term preventive benefit with anastrozole for ER-positive breast cancer in postmenopausal women. Table: Number of events and Hazard Ratios (95% CI) according to follow-up period.Number of eventsHR (95% CI)P-valueOverall241 (81 vs. 160)0.50 (0.38-0.65) Citation Format: Jack Cuzick, Ivana Sestak, John Forbes, Mitchell Dowsett, Simon Cawthorn, Robert Mansell, Sibylle Loibl, Bernardo Bonanni, Anthony Howell, IBIS-II investigators. Ten year results of the international breast cancer intervention study II [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 GS4-04.

Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological parameters (nodal status, tumor size, grade, and age) to estimate distant recurrence (DR) risk after 5 years of endocrine treatment for postmenopausal women with estrogen receptor (ER) positive breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Here, we evaluate whether the CTS5 is prognostic in women who were distant recurrence (DR) free 5 years after adjuvant treatment who participated in the TAILORx study. Methods: 10273 women with ER-positive, HER2-negative, and node-negative disease were entered into the TAILORx study and assigned or randomized to four treatment arms according to their Oncotype Recurrence Score (RS) (endocrine therapy alone (ET) or chemo-endocrine therapy (CET)). Primary endpoint of this analysis was DR and the primary objective of this analysis was to evaluate the CTS5 in the TAILORx study, stratified by chemotherapy use. Secondary objectives included validation of the CTS5 in two specific age groups (age≤50 years vs. age>50 years) and in the four separate treatment arms. Cox regression models were used to determine the prognostic value of CTS5. Kaplan-Meier curves were used to estimate conditional 9-year DR risks (%). Hazard ratios are reported for an increase of 1-standard deviation of CTS5 in the overall analysis population. Results: 7353 (71.6%) women were DR free 5 years after diagnosis with follow-up beyond 5 years, had information for all clinical parameters, and were included in this analysis. Median follow-up after 5 years was 2.9 years (1.8-3.9). Overall, mean age was 55.7 years (SD 9.0), mean tumor size 17.1mm (SD 7.8), and the vast majority had low or moderately differentiated disease (84.7%). CTS5 was significantly higher for women in arm D (RS 26-100, CET) compared to the other three arms (mean CTS5 3.09 vs. 2.82, P Conclusions: Low risks of late DR of 3.1% (2.4-4.0) for RS scores 0-25 (ET) and 3.8% (2.9-4.8) for RS scores 11-100 (CET) were observed in this ER-positive, HER2-negative and node negative TAILORx cohort. We confirm the prognostic ability of the CTS5 for late DR in the TAILORx cohort, specifically for patients older than 50 years and/or those who were deemed intermediate or high risk by Oncotype Dx RS (11-100). Our results show that the CTS5 is less prognostic for late DR in women aged 50 years or younger who received 5 years of endocrine therapy only. Further evaluation of the CTS5 in premenopausal cohorts is needed before it can be applied to younger patients. Table: Hazard Ratios (95% CI) for prognostic value of CTS5 overall and according to sub-groups.HR (95% CI )P-valueAll (N=7353)1.57 (1.36-1.82) 50 years (N=5094)1.78 (1.48-2.14) Citation Format: Ivana Sestak, Michael Crager, Jack Cuzick, Mitchell Dowsett, Steven Shak, Gong Tang, Robert Gray, Joseph Sparano. Validation of the clinical treatment score post 5 years (CTS5) in women with hormone receptor positive, HER2-negative, node-negative disease from the TAILORx 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 GS4-03.

Purpose of review There is growing consensus that genomic assays provide useful complementary information to clinicopathological features in oestrogen receptor-positive breast cancers. Here, ongoing research with multigene tests used for postmenopausal breast cancer and new emerging prognostic and predictive markers for pre and postmenopausal women are summarised. Recent findings Results of the TAILORx trial have shown that women with an intermediate risk score do not benefit from adjuvant chemotherapy. Prosgina has been further investigated in a contemporary patient population in postmenopausal women and its use has been extended for premenopausal women. The EndoPredict was extensively used in decision-impact studies showing that its use can potentially reduce the need for adjuvant chemotherapy. Several new genomic assays have been developed, with some of them showing promising use for women with early oestrogen receptor-positive breast cancer. Summary New areas of research for prediction of recurrence and risk stratification involve the development of immune gene signatures that carry modest but significant prognostic value. The recent expansion of high-throughput technology platforms including circulating tumour DNA/RNA and microRNA offer new opportunities to improve prediction models, particularly in women with oestrogen receptor-negative disease and premenopausal women. Genomic assays have clearly improved prognostication of early oestrogen receptor-positive breast cancer but it is clear that standard clinicopathological parameters are still very important when identifying patient for adjuvant chemotherapy.

Background Several prognostic signatures for early oestrogen receptor-positive (ER+) breast cancer have been established with a 10-year follow-up. We tested the hypothesis that signatures optimised for 0–5-year and 5–10-year follow-up separately are more prognostic than a single signature optimised for 10 years. Methods Genes previously identified as prognostic or associated with endocrine resistance were tested in publicly available microarray data set using Cox regression of 747 ER+/HER2− samples from post-menopausal patients treated with 5 years of endocrine therapy. RNA expression of the selected genes was assayed in primary ER+/HER2− tumours from 948 post-menopausal patients treated with 5 years of anastrozole or tamoxifen in the TransATAC cohort. Prognostic signatures for 0–10, 0–5 and 5–10 years were derived using a penalised Cox regression (elastic net). Signature comparison was performed with likelihood ratio statistics. Validation was done by a case-control (POLAR) study in 422 samples derived from a cohort of 1449. Results Ninety-three genes were selected by the modelling of microarray data; 63 of these were significantly prognostic in TransATAC, most similarly across each time period. Contrary to our hypothesis, the derived early and late signatures were not significantly more prognostic than the 18-gene 10-year signature. The 18-gene 10-year signature was internally validated in the TransATAC validation set, showing prognostic information similar to that of Oncotype DX Recurrence Score, PAM50 risk of recurrence score, Breast Cancer Index and IHC4 (score based on four IHC markers), as well as in the external POLAR case-control set. Conclusions The derived 10-year signature predicts risk of metastasis in patients with ER+/HER2− breast cancer similar to commercial signatures. The hypothesis that early and late prognostic signatures are significantly more informative than a single signature was rejected. Electronic supplementary material The online version of this article (10.1186/s13058-018-1040-9) contains supplementary material, which is available to authorized users.

There are three main ways in which women can be identified as being at high risk of breast cancer i) family history of breast and/or ovarian cancer, which includes genetic factors ii) mammographically identified high breast density, and iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. The highest risk is seen in women with lobular carcinoma in situ (LCIS), but this is very rare. More common is atypical hyperplasia (AH), which carries a 4–5-fold risk of breast cancer as compared to general population. Even more common is hyperplasia of the usual type and carries a roughly two-fold increased risk. Women with aspirated cysts are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with AH, with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS-I. The aromatase inhibitors (AIs) also are highly effective for AH and LCIS. There are no published data on the effectiveness of tamoxifen or the AIs for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. Improving diagnostic consistency, breast cancer risk prediction and education of physicians and patients regarding therapeutic prevention in women with benign breast disease may strengthen breast cancer prevention efforts.

Background: In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals' metastasis risk are needed to reduce overtreatment. Patients and methods: Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2-3N+), using log-likelihood ratio tests. Results: At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2-3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1% versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2-3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2-3N+ patients. Conclusion: PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients.

Purpose: To identify the individual genes or gene modules that lead to the OncoptypeDx 21-gene recurrence score's reduced performance after 5 years and thereby identify indices of residual risk that may guide selection of patients for extended adjuvant therapy. Experimental Design: We conducted a retrospective assessment of the relationship between (i) the individual genes and gene modules of the Recurrence Score and (ii) early (0–5 years) and late (5–10 years) recurrence rates in 1,125 postmenopausal patients with primary estrogen receptor–positive breast cancer treated with anastrozole or tamoxifen in the Arimidex, Tamoxifen, Alone or Combined (ATAC) randomized clinical trial. Results: In the HER2-negative population (n = 1,009), estimates of recurrence risk were similar between years 0–5 and 5–10 for proliferation and invasion modules but markedly different for the estrogen module and genes within it (all split at the median): for low estrogen module, annual recurrence rates were similar across the two time windows (2.06% vs. 2.46%, respectively); for high estrogen module, annual rates were 1.14% versus 2.72%, respectively (Pinteraction = 0.004). Estrogen receptor transcript levels showed inverse prediction across the time windows: HR, 0.88 (0.73–1.07) and 1.19 (0.99–1.43), respectively (Pinteraction = 0.03). Similar time-, module-, and estrogen-dependent relationships were seen for distant recurrence. Conclusions: Patients with tumors with high estrogen receptor transcript levels benefit most from 5 years' endocrine therapy but show increased recurrence rates after 5 years and may benefit from extended therapy. Improved prognostic profiles may be created by considering period of treatment and follow-up time. Clin Cancer Res; 21(12); 2763–70. ©2015 AACR.

Background: Several randomised clinical trials have shown the benefit of tamoxifen in healthy women to reduce their risk of breast cancer. Here, we report the blinded median 16 year follow-up of the IBIS-I trial to update the long-term prevention of breast cancer with tamoxifen treatment. Methods: 7154 pre- and postmenopausal women were randomised to receive daily 20mg tamoxifen (N=3579) or matching placebo (N=3575) for 5 years. The primary endpoint of this analysis was the occurrence of breast cancer (invasive and ductal carcinoma in situ (DCIS)). Secondary endpoints included overall mortality, other cancers, and breast cancer specific mortality. Cox proportional hazard models were used to assess occurrence of breast cancer and survival. All statistical tests were two-sided. Results: After a median of 16.2 years (IQR 14.4 to 17.7) of follow-up, a total of 589 breast cancers have been reported (tamoxifen: 246 (6.9%) vs. placebo: 343 (9.6%)). Tamoxifen reduced the incidence of all breast cancer overall by 29% (HR=0.71 (0.60-0.83), P Conclusion: This updated analysis of the IBIS-I trial confirms the significant reduction in breast cancer occurrence with tamoxifen in the post-treatment follow-up period. These results indicate tamoxifen has a long-term preventive effect on invasive ER+ breast cancer in both pre- and postmenopausal women. Citation Format: Jack Cuzick, Ivana Sestak, Simon Cawthorn, Hisham Hamed, Kaija Holli, Anthony Howell, John F Forbes. 16 year long-term follow-up of the IBIS-I breast cancer prevention trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-07.

Background: BCI is a genomic signature that significantly predicts risk of both early (0-5 years) and late (5-10 years) distant recurrence (DR) in hormonal receptor-positive, lymph node negative (LN-) breast cancer. In LN- disease, tumor size (TS) and grade (TG) are important independent prognostic factors of breast cancer recurrence. In this analysis, the effect of integrating these traditional clinicopathological factors on the ability of BCI to predict distant recurrence was evaluated in the translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC). Methods: 709 primary tumor samples from hormonal receptor-positive, LN- patients treated with 5 years of tamoxifen or anastrozole were examined. Multivariate Cox proportional hazards regression was used to fit 2 models: 1) BCI+TS; 2) BCI+TS+TG. To facilitate comparison across models, cut points were chosen based on the pre-specified 10 year DR rates of 20% (high). Kaplan-Meier (KM) estimates of 10 year DR and hazard ratios (HR) were examined. Change in likelihood ratio χ2 (LR-χ2) values were used to quantitate relative prognostic information beyond standard clinicopathological variables (CTS, Clinical Treatment Score). Results: In the univariate analysis, all models were significantly prognostic for 10 year DR risk; BCI was somewhat less predictive vs BCI+TS, whereas TG did not provide significant additional value beyond BCI+TS [HR (95% CI): 3.26 (2.29-4.63), 2.72 (2.11-3.50), 2.72 (2.11-3.50); LR-χ2 (p value): 45.54 (p Comparison of Risk Categorization and 10 year DRBCIBCI+TS% Patients10 year DR% Patients10 year DRLow Risk53.7%5.3%54.7%5.2%Intermediate Risk29.3%15.5%29.2%16.5%High Risk17.0%28.0%16.2%27.3% In cross stratification analysis between BCI and BCI+TS, no significant re-classification was observed (Table 2), however 14.5% of BCI and 9.7% of BCI+TS intermediate risk patients were re-stratified as low risk. Re-classification of BCI and BCI+TS for all patientsBCIBCI+TSLowIntermediateHighTotalLow358300388 (54.7%)Intermediate2016323206 (29.1%)High31498115 (16.2%)Total381 (53.7%)207 (29.2%)121 (17.1%)709 Discussion: Integration of tumor size, but not grade, statistically enhanced the prognostic ability of BCI to predict 10 year DR risk in patients with ER+, LN- early stage breast cancer. However, there was limited clinical impact on risk stratification, indicating that the prognostic information provided by these clinicopathological factors is effectively captured by BCI alone. Citation Format: Ivana Sestak, Yi Zhang, Brock E Schroeder, Paul E Goss, Mitch Dowsett, Dennis C Sgroi, Catherine A Schnabel, Jack Cuzick. Integration of breast cancer index (BCI) with clinicopathological factors for prediction of distant recurrence in ER+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-19.

Background: The annual recurrence rates of post-menopausal ER-positive breast cancers persist beyond the first 5 years of diagnosis and treatment and the mortality rates in this period are higher versus ER-negative cancers. Extended endocrine therapy past 5 years has been shown to be of benefit but is associated with increased toxicity and cost thus the ability to predict patients who are at highest risk of late relapse would be of significant benefit in clinical decision making in this context. β-catenin is an intracellular protein that undergoes Wnt-mediated nuclear translocation where it transactivates genes implicated in tumour development and progression. We have also previously reported that β-catenin can play a role in aggressive resistance that accompanies prolonged endocrine treatment in vitro. In this study, we thus investigated whether β-catenin expression in ER+ breast cancer was predictive of recurrence beyond 5 years in an analysis of three separate endocrine-treated cohorts. Methods: Associations between β-catenin gene expression and relapse free survival (RFS) were performed using the online KMplotter tool. Immunostaining for total β-catenin was performed on tissue samples from 3 ER+ primary breast cancer series with long-term follow-up data: Nottingham 2000 (n=384, tamoxifen-only); ABC (n=570; tamoxifen only); transATAC (n=743; tamoxifen or ansatrozole). The association between subcellular (nuclear or cytoplasmic) β-catenin expression and RFS was determined in (i) the entire cohort, (ii) the first 5 years of tamoxifen treatment versus post-5 years. Results: KMplotter analysis of β-catenin in ER+, tamoxifen-treated patient samples (n=665) revealed a significant relationship with improved RFS in the post-five year cohort [HR: 0.48 (0.34-0.68); p=0.000019) versus the first 5 years [HR: 0.91 (0.61-1.36; p=0.64)]. No significant association was observed in untreated ER+ patients. In the Nottingham series, nuclear β-catenin positivity was significantly associated with improved survival in the 20-year follow-up for tamoxifen-treated patients (p=0.047) but not in the first five years (p=0.239). Cytoplasmic β-catenin did not associate with survival. Further analysis in the ABC series revealed an association between nuclear β-catenin positivity and improved survival for tamoxifen-treated patients in the entire cohort (HR: 0.52 (0.18, 0.55); p=0.00005). However, nuclear β-catenin was more strongly associated with improved outcome in the post 5-year treatment group (HR: 0.30 (0.14, 0.66); p=0.01) versus the first five years of treatment (HR: 0.33 (0.15,0.73); p=0.06). No significant associations were seen with cytoplasmic β-catenin. The transATAC trial material again revealed an association between presence of nuclear β-catenin and reduced distant recurrence in the post 5-years endocrine-treated cohort (HR: 0.54 (0.33, 0.91): x2=5.52, p=0.018) versus years 1-5 (HR: 1.16 (0.67, 2.01); x2=0.29, p=0.59). Conclusions: This is the first study to demonstrate that nuclear β-catenin may represent a predictive biomarker for late relapse following tamoxifen treatment in ER+ breast cancer where, contrary to traditional hypotheses and pre-clinical data, its nuclear expression is strongly associated with good outcome post-five years of treatment. Citation Format: Stephen Hiscox, Chris Smith, Robert I Nicholson, Julia Gee, Adrian Harris, Judith Bliss, Eleftheria Kalaizak, Ivana Sestak, Mitch Dowsett, Jack Cuzick, Ian Ellis, Peter Barrett-Lee. Nuclear β-catenin negativity predicts for late relapse in ER+, tamoxifen-treated breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-01.

Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20–4.99); p value 0.02; anastrozole 0.80 (0.36–1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment.

Purpose We have previously shown that the PAM50-based risk of recurrence (ROR) score is significantly correlated with distant recurrence in both the translational research cohort within the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (TransATAC) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) randomized trials. Here, we focus on the ROR score for predicting distant recurrence after 5 years of follow-up in a combined analysis of these two randomized trials. Methods Long-term follow-up data and tissue samples were obtained from 2,137 postmenopausal women with hormone receptor–positive early-stage breast cancer from the ABCSG 8 and TransATAC trials. We used Cox proportional hazard regression models to determine the prognostic value of ROR for distant recurrence beyond 5 years in the combined data set. Results A total of 2,137 women who did not have a recurrence 5 years after diagnosis were included in the combined analyses. The Clinical Treatment Score (CTS) was the strongest prognostic factor 5 years after diagnosis (univariable: likelihood ratio [LR] χ2 = 94.12, bivariable: LR χ2 = 61.43). The ROR score was significantly prognostic by itself in years 5 to 10. In the node-negative/human epidermal growth factor receptor 2–negative subgroup, more prognostic value for late distant recurrence was added by the ROR score compared with the CTS. Conclusion The ROR score added clinically meaningful prognostic information to the CTS in all patients and all subgroups in the late follow-up period. These results suggest that the ROR score may be helpful for separating patients into risk groups who could be spared or potentially benefit from extended hormonal therapy beyond 5 years of treatment.

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.