TPS599 Background: Multi-parameter tumor gene expression assays (MPAs) are validated tools to assist adjuvant chemotherapy decisions for post-menopausal women with luminal-type node-negative breast cancer. Currently there is less certainty for women with 1-3 involved axillary lymph nodes and no information on MPA use for patients with higher level nodal involvement. Three RCTs with available data report chemotherapy benefit for premenopausal women; with limited use of ovarian function suppression (OFS) for non-chemotherapy treated participants, chemotherapy-induced menopause may explain these results. Methods: OPTIMA is an international academic, partially-blinded RCT of test-directed chemotherapy treatment with an adaptive design. Women and men aged 40 or older with resected luminal-type breast cancer may participate if they fulfil one of the following stage criteria: pN1-2; pN1mi with pT ≥20mm; pN0 with pT ≥30mm. Consenting patients are randomized between standard treatment with chemotherapy followed by endocrine therapy or to undergo Prosigna testing; those with high-Prosigna Score ( > 60) tumors receive standard treatment whilst those with low-score tumors are treated with endocrine therapy alone. Patients are informed only of their treatment; test details, and randomization for chemotherapy-treated patients are masked. Clinical choice of chemotherapy is declared at randomization from a menu of standard regimens. Endocrine therapy must be for at least 5 years. Women postmenopausal at trial entry should receive an AI; men, tamoxifen; and premenopausal women, either an AI or tamoxifen, and OFS for 3 or more years; OFS initiation may be deferred because of post-chemotherapy amenorrhea. OPTIMA aims to randomize 2250 patients in each arm to demonstrate non-inferiority of test directed treatment, defined as not more than 3% below the estimated 85% 5-year IDFS for the control arm with a one sided 5% significance level. Power is 81% assuming recruitment over 96-months from January 2017 and 12 months minimum follow-up. OPTIMA also has at least 80% power to demonstrate 3.5% non-inferiority of IDFS for patients with low Prosigna Score tumors (estimated 65% of participants). Cox proportional hazards models will be used to explore important prognostic factors including menopausal status. Additional secondary endpoints include DRFI. A cost-effectiveness analysis of protocol specified MPA driven treatment against standard clinical practice will be conducted. At 31/01/2021, 2004 patients had been randomized. The DMC reviewed the trial in December 2020 with knowledge of related trial results and suggested that the trial continues as planned. OPTIMA is registered as ISRCTN42400492 and funded by the UK NIHR Health Technology Assessment Programme, award number 10/34/501. Clinical trial information: ISRCTN42400492.

Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial collaboration between UK and NSABP investigators evaluating the biological and clinical effects of palbociclib with letrozole combination as neoadjuvant therapy. Methods: Postmenopausal women with ER+ primary breast cancer and tumors >2.0cm (ultrasound) were randomized to one of 4 treatment groups (3:2:2:2 ratio): Group A: letrozole (2.5mg/d) for 14 weeks; Group B: letrozole for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group C: palbociclib for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group D: letrozole + palbociclib for 14 weeks. Palbociclib was given 125mg/d PO on a 21 days on, 7 days off schedule. Post-14 week treatment was at the discretion of the treating clinician including letrozole until surgery. Core-cut biopsies were taken at baseline, 2 weeks and 14 weeks. Co-primary endpoints for letrozole alone vs palbociclib groups (Group A vs Groups B+C+D) were: (i) change in Ki67 (IHC) between baseline and 14 weeks (log-fold change, Mann-Whitney test); (ii) clinical response (ultrasound) after 14 weeks (4 group, ordinal, Mann-Whitney test). Complete cell-cycle arrest (CCCA) (Ki67≤2.7%) was analyzed using a logistic regression model adjusting for recruitment region. Pre-specified exploratory biomarkers included c-PARP (apoptosis). Results: 307 patients were recruited between 27 Feb 2015 and 08 Mar 2018; 103 were randomized to letrozole alone and 204 to letrozole + palbociclib. 279 (90.9%) patients were evaluable for 14 week clinical response. Clinical response was not significantly different between letrozole vs letrozole + palbociclib groups [(p=0.20; CR+PR 49.5% (46/93) vs 54.3% (101/186) and PD 5.4% (5/93) vs 3.2% (6/186)] nor was the small proportion of patients with pathological CR (1/87, 1.1% vs 6/180, 3.3%; p=0.43). 190 (61.9%) patients were evaluable for 14 week change in Ki67. The median log-fold change in Ki67 was greater with letrozole + palbociclib vs letrozole alone (-4.1 vs -2.2; p Conclusion: Adding palbociclib to letrozole markedly enhanced the suppression of malignant cell proliferation as assessed by Ki67 but did not substantially increase the clinical response of primary ER+ breast cancer over a 14-week period. Concurrent reductions in cell death may have reduced the speed of tumor shrinkage. Citation Format: Dowsett M, Jacobs S, Johnston S, Bliss J, Wheatley D, Holcombe C, Stein R, McIntosh S, Barry P, Dolling D, Snowdon C, Perry S, Batten L, Dodson A, Martins V, Modi A, Cornman C, Puhalla S, Wolmark N, Julian T, Pogue-Geile K, Robidoux A, Provencher L, Boileau JF, Shalaby I, Thirlwell M, Fisher K, Huang Bartlett C, Koehler M, Osborne K, Rimawi M. PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib [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 GS3-02.

Abstract Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial collaboration between UK and NSABP investigators evaluating the biological and clinical effects of palbociclib with letrozole combination as neoadjuvant therapy. Methods: Postmenopausal women with ER+ primary breast cancer and tumors >2.0cm (ultrasound) were randomized to one of 4 treatment groups (3:2:2:2 ratio): Group A: letrozole (2.5mg/d) for 14 weeks; Group B: letrozole for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group C: palbociclib for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group D: letrozole + palbociclib for 14 weeks. Palbociclib was given 125mg/d PO on a 21 days on, 7 days off schedule. Post-14 week treatment was at the discretion of the treating clinician including letrozole until surgery. Core-cut biopsies were taken at baseline, 2 weeks and 14 weeks. Co-primary endpoints for letrozole alone vs palbociclib groups (Group A vs Groups B+C+D) were: (i) change in Ki67 (IHC) between baseline and 14 weeks (log-fold change, Mann-Whitney test); (ii) clinical response (ultrasound) after 14 weeks (4 group, ordinal, Mann-Whitney test). Complete cell-cycle arrest (CCCA) (Ki67≤2.7%) was analyzed using a logistic regression model adjusting for recruitment region. Pre-specified exploratory biomarkers included c-PARP (apoptosis). Results: 307 patients were recruited between 27 Feb 2015 and 08 Mar 2018; 103 were randomized to letrozole alone and 204 to letrozole + palbociclib. 279 (90.9%) patients were evaluable for 14 week clinical response. Clinical response was not significantly different between letrozole vs letrozole + palbociclib groups [(p=0.20; CR+PR 49.5% (46/93) vs 54.3% (101/186) and PD 5.4% (5/93) vs 3.2% (6/186)] nor was the small proportion of patients with pathological CR (1/87, 1.1% vs 6/180, 3.3%; p=0.43). 190 (61.9%) patients were evaluable for 14 week change in Ki67. The median log-fold change in Ki67 was greater with letrozole + palbociclib vs letrozole alone (-4.1 vs -2.2; p<0.001) corresponding to a geometric mean change of -97.4% vs -88.5%. Similarly, a greater proportion of patients who received letrozole + palbociclib achieved CCCA (90% vs 59%, p<0.001). 146 (47.6%) patients were evaluable for c-PARP and the log-fold change (suppression) was greater with letrozole + palbociclib vs letrozole alone (-0.80 vs -0.42; p=0.003) corresponding to a geometric mean change of -56.8% vs -31.4%. Other biomarkers of response / resistance are being evaluated. A higher proportion of patients had a grade ≥3 toxicity on letrozole + palbociclib than letrozole alone (49.8% vs 17.0%; p<0.001) mainly due to asymptomatic neutropenia. Conclusion: Adding palbociclib to letrozole markedly enhanced the suppression of malignant cell proliferation as assessed by Ki67 but did not substantially increase the clinical response of primary ER+ breast cancer over a 14-week period. Concurrent reductions in cell death may have reduced the speed of tumor shrinkage. Citation Format: Dowsett M, Jacobs S, Johnston S, Bliss J, Wheatley D, Holcombe C, Stein R, McIntosh S, Barry P, Dolling D, Snowdon C, Perry S, Batten L, Dodson A, Martins V, Modi A, Cornman C, Puhalla S, Wolmark N, Julian T, Pogue-Geile K, Robidoux A, Provencher L, Boileau JF, Shalaby I, Thirlwell M, Fisher K, Huang Bartlett C, Koehler M, Osborne K, Rimawi M. PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib [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 GS3-02.

Purpose: We share our experience at a London Cancer Centre of toxicities associated with trastuzumab emsantine (T-DM1) by reporting the common toxicities experienced by our patients. We also describe six cases of haemorrhagic or thrombocytopenic complications in greater detail, thereby contributing to the limited but expanding knowledge base regarding its toxicity profile.

In the original publication of the article, a part of acknowledgement section was missed out. The omitted acknowledgement is given below: 'The study was coordinated by the Imperial Clinical Trials Unit—Cancer, Imperial College London and Sponsored by Imperial College London. The Imperial Clinical Trials Unit receives funding from the National Institute for Health (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This study was supported by Imperial Experimental Cancer Medicine Centre and Cancer Research UK Imperial Centre'.

Background: Informed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding.Methods: Published guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above.Results: DevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained.Conclusions: The DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further.

Abstract Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay of treatment but benefits are frequently short-lived with rapid development of resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways in TNBC, making inhibition of AKT an attractive therapeutic target. Based on downstream pathway activation signatures, PI3K pathway activation appears higher in TNBC compared to other molecular subtypes, despite a relatively low percentage of activating PI3K mutations. Alternative means of activating the PI3K pathway have been identified in TNBC, including loss or mutation of PTEN (up to 35%) and INPP4B (up to 30%) and/or amplification of PIK3CA, AKT2 or AKT3, resulting in increased activation of AKT. Induction of AKT by chemotherapy can be an early compensatory mechanism that can be exploited therapeutically to increase the efficacy of chemotherapy. Preclinical TNBC models with activated AKT signalling have been shown to be highly sensitive to AKT inhibitors. AZD5363 is a potent pan-AKT inhibitor with good oral bioavailability. Multiple lines of investigation have demonstrated strong synergistic effects between AKT inhibition and taxane chemotherapy in models of TNBC both in vitro and in vivo, providing rationale for the combination of AZD5363 and paclitaxel in TNBC. PAKT is designed to test the hypothesis that inhibition of AKT will increase the anti-tumour activity of paclitaxel chemotherapy in TNBC. The study will try to characterize those patients who may benefit from this treatment to identify potential predictors of sensitivity. PAKT is an international investigator led and sponsored, double-blind, placebo controlled, randomised phase II trial. Patients are randomised 1:1 to receive paclitaxel weekly (90mg/m2) on days 1,8, and 15 plus AZD5363 (400mgBD) or placebo (400mgBD) on days 2-5, 9-12, 15-19 (28 day treatment cycles). Patients are stratified by the number of metastatic sites and the interval from the end of adjuvant chemotherapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Tumour assessments are carried out every 8 weeks. PAKT enrols patients with histologically documented locally advanced/metastatic TNBC (ER≤Allred2, PR≤Allred2, HER2=0,1+or2+), no prior systemic therapy for advanced TNBC, ECOG PS 0-2 and measurable disease per RECIST v1.1. Patients with brain metastases, significant cardiovascular disease, motor polyneuropathy are excluded. The primary endpoint is progression-free survival. Secondary endpoints are objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, and patient reported outcomes. Archival tumour tissue must be available to evaluate potential biomarkers associated with therapeutic response and resistance. PFS will be compared between treatment arms by the stratified log-rank test. HR for disease progression/death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each arm. Approximately 140 patients will be enrolled at ≈65 sites in the UK, France, Hungary, Romania, Georgia & South Korea. Citation Format: Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N. A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603). [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 OT1-03-13.

Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [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 OT3-02-02.

Abstract Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [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 OT3-02-02.

Introduction: TACT2, a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control (Poole NEJM 2006), tests two hypotheses in a 2×2 factorial design: A) accelerated epirubicin (aE) improves outcomes compared to standard epirubicin (E) (CALGB9741 Citron JCO 2003); and B) capecitabine (X) gives similar efficacy but preferential side-effect profile to CMF. Here we focus on the impact of accelerating epirubicin treatment on patient outcome. Tolerability and toxicity of this regimen have already been presented (Cameron 2010, SABCS); 33/4391 pts did not start chemotherapy. 4261 (97%) completed the initial 4 cycles (E 2143 (96%), aE 2118 (98%)) with RDI >85% for E 2061 (93%) and aE 1985 (91%). Serious CTCAE toxicity was less common with aE compared with E, however patients report poorer global QL, fatigue & role function which does not appear to be explained by impact on daily activities due to individual side-effects. Patients & Methods: Between December 2005 and December 2008, 4391 patients (4371 women, 20 men) were randomized to receive either E (100mg/m2 × 4) q3wk or aE (100mg/m2 × 4 plus pegfilgrastim, 6mg d2) q2wk followed by classical CMF q4wk × 4 or X (2500mg/m2/day × 14) q3wk × 4. Other adjuvant treatment was delivered according to local practice (HER2+ve – sequential trastuzumab for 1 year from June 2006; ER/PgR+ve - endocrine therapy for 5 years). Tumor blocks were collected prospectively to enable central biomarker testing. Median age of patients was 52 years (IQR 46–59). 53% patients had node +ve disease; 59% had tumors >2cm; 57% were grade 3. According to local assessment, of 4366 patients where both ER and HER2 status were known, 60% had ER+ve/HER2-ve tumors, 19% HER2+ve, 21% ER-ve/HER2-ve. Primary endpoint was time to recurrence (TTR), defined as time to loco-regional or distant relapse, or breast cancer-death. Secondary endpoints included disease-free survival (DFS), overall survival (OS), tolerability of regimens and quality of life. TACT2 has over 90% power to detect a clinically meaningful 4% difference in TTR between standard and accelerated epirubicin schedules (from 80% to 84% at 5 years). Survival estimates will be compared using stratified log-rank tests and Cox regression. Results: At 1st June 2012, median follow up was 49 months (interquartile range: 46–60) with 553 TTR events reported. The Independent Data Monitoring Committee consider these data sufficiently mature for presentation of analyses relating to the accelerated epirubicin hypothesis. A further data snapshot, after query resolution, for the main analysis will be taken in Q3 2012. Data to be presented, by treatment group, include TTR, DFS, OS, late toxicity and pre-planned subgroup analyses according to ER, PgR and HER2 status and Ki67 levels. Discussion: TACT2 will provide a definitive analysis to confirm or refute benefits previously reported for accelerating anthracycline chemotherapy in early breast cancer including, via pre-planned subgroup analyses, exploration of the potential benefits in phenotypic subtypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-3.

In Swiss 3T3 fibroblasts, long-term stimulation with PDGF, but not insulin-like growth factor 1 (IGF-1) or EGF, results in the establishment of an elongated migratory phenotype, characterized by the formation of retractile dendritic protrusions and absence of actin stress fibers and focal adhesion complexes. To identify receptor tyrosine kinase-specific reorganization of the Swiss 3T3 proteome during phenotypic differentiation, we compared changes in the pattern of protein synthesis and phosphorylation during long-term exposure to PDGF, IGF-1, EGF, and their combinations using 2DE-based proteomics after S-35- and P-33-metabolic labeling. One hundred and five differentially regulated proteins were identified by mass spectrometry and some of these extensively validated. PDGF stimulation produced the highest overall rate of protein synthesis at any given time and induced the most sustained phospho-signaling. Simultaneous activation with two or three of the growth factors revealed both synergistic and antagonistic effects on protein synthesis and expression levels with PDGF showing dominance over both IGF-1 and EGF in generating distinct proteome compositions. Using signaling pathway inhibitors, PI3K was identified as an early site for signal diversification, with sustained activity of the PI3K/AKT pathway critical for regulating late protein synthesis and phosphorylation of target proteins and required for maintaining the PDGF-dependent motile phenotype. Several proteins were identified with novel PI3K/Akt-dependent synthesis and phosphorylations including eEF2, PRS7, RACK-1, acidic calponin, NAP1L1, Hsp73, and fascin. The data also reveal induction/suppression of key F-actin and actomyosin regulators and chaperonins that enable PDGFR to direct the assembly of a motile cytoskeleton, despite simultaneous antagonistic signaling activities. Together, the study demonstrates that longterm exposure to different growth factors results in receptor tyrosine kinase-specific regulation of relatively small subproteomes, and implies that the strength and longevity of receptor tyrosine kinase-specific signals are critical in defining the composition and functional activity of the resulting proteome. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.019778, 1690-1708, 2012.

1052 Background: Aromatase inhibitors (AI) block estrogen synthesis and are effective for the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women. Despite initial benefit, resistance to AIs and disease progression occur, at which point cytotoxic chemotherapy is often the remaining treatment option. Entinostat, an oral class 1 isoform-selective HDACi, has been shown in preclinical studies to restore sensitivity to acquired AI resistance. The goal of this study was to determine whether the addition of entinostat to AI therapy in patients currently progressing on AI therapy could restore AI sensitivity and prolong the clinical benefit. Methods: Postmenopausal women with ER+ breast cancer progressing on an AI after 3 months were enrolled. Additional entry criteria included measurable disease by RECIST and ≤1 chemotherapy for metastatic disease. Patients with rapidly-progressive breast cancer were excluded. Patients continued with the AI on which they progressed plus entinostat 5 mg wkly in 28-day cycles. Primary objective was CBR (CR, PR or SD >6 months) during the first 6 cycles; secondary objectives included ORR and PFS. Biomarkers and pharmacology were also measured. Results: Twenty-seven (27) patients were enrolled with median age of 69 years. Nineteen patients (70%) had visceral involvement; none had bone-only disease. Eighteen (67%) had adjuvant hormone therapy; 14 (52%) had adjuvant chemotherapy. Six (22%) had received chemotherapy in the metastatic setting. Eleven (41%) received study treatment >4 months, 3 (11%) >6 months. One had confirmed PR, and one patient had SD > 6 months. The most common toxicities were nausea, diarrhea, and fatigue, primarily low grade. Grade ≥3 toxicities were fatigue, dyspnea, diarrhea, and lethargy. Biomarker analysis revealed a trend of increased protein lysine acetylation in CD8, CD14, and CD19/20 cells; increased apoptosis in PMCs was also observed. Conclusions: Entinostat in combination with AIs in patients with progressive breast cancer demonstrated clinical benefit as evidenced by PR and SD > 6 months. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Syndax Syndax Syndax

6034 Background: CPOE systems have previously been reported to reduce prescription error. There are few studies of CPOE in oncology practice. We studied the effect of replacing manual prescribing (MP) by a specialized chemotherapy CPOE system, ChemoCare, on prescribing error in a hematology-oncology practice in a comprehensive cancer center. Methods: All errors made during a 12-week period prior to CPOE implementation detected at routine pre-treatment pharmacy checks were categorized according to error type, and were scored for severity using the U.K. National Patient Safety Agency risk matrix by a panel of 4 blinded adjudicators (2 pharmacists and 2 doctors) working independently of each other; conflicts were resolved by a fifth adjudicator. Errors involving chemotherapy and supportive care with the exception of anti-infectives were analyzed. An identical exercise was conducted 15 months later, 6 months following completion of CPOE implementation. Results: A total of 49 of 251 (19.5%) of MP prescriptions...

Background: Aromatase inhibitors (AI), reduce peripheral conversion of androgen to estrogen, and are standard treatment for ER+ breast cancer (BCA); however, despite initial benefit, the disease eventually progresses. Once patients become resistant to AI, cytotoxic chemotherapy is often used for palliation. Histone deacetylase inhibitors (HDACi) have been shown preclinically to reverse AI resistance and sensitize tumor to AI. Entinostat, an oral selective HDACi, reverses both de novo and acquired hormone resistance in BCA in cell lines and xenograph models and has been well-tolerated, in humans, as a single agent and in combination with other agents tested to date.Methods: Postmenopausal women with ER+ BCA progressing while receiving AI for > 3 months were enrolled. Eligibility criteria included: measurable disease by RECIST criteria, PS 0 or 1, and ≤ 1 chemotherapy for metastatic disease. Exclusion criteria included: rapidly-progressing BCA, life-threatening metastases, chemotherapy within 3 months, and previous exposure to epigenetic modulating agents. Patients continued the AI therapy on which the cancer was progressing, with the addition of entinostat 5 mg weekly in 28-day cycles. Primary objective was to determine clinical benefit rate during the first 6 cycles, defined as the proportion of patients achieving CR, PR or SD lasting > 6 months. Secondary objectives included ORR and PFS. Exploratory biomarkers for anti-tumor activities and entinostat pharmacology were also measured.Results: To date, 24 patients have been enrolled from October 2008 – May 2009. Interim results from 20 patients are described here. The median age is 69 yrs. Eight (40%) and 12 (60%) patients had ECOG scores of 0 and 1, respectively. Fifteen patients (80%) had received tamoxifen; 12 (60%) had prior chemotherapy or immunotherapy. Nine patients (45%) had visceral involvement (lung, pleura, and liver), and 10 had metastases to bone, 3 to breast, and 1 to skin. Among the 10 patients who have completed ≥ 2 cycles, preliminary analysis indicates that the longest durations of SD thus far are > 6 months in 1 and > 5 months in 2 patients. Preliminary analysis of biomarkers in paired samples from 6 patients indicates that HDAC inhibition correlates with changes in cellular molecular targets. Entinostat has been well-tolerated. The majority of AEs were mild to moderate in severity, and the character of AEs was generally consistent with that seen with AI therapy.Conclusion: Entinostat in combination with AI was well-tolerated in patients with progressive BCA. Disease stabilization in several patients was observed. At dose administered, expected pharmacological effects were achieved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6111.

Ovarian reserve can be diminished following treatment for breast cancer. This study evaluated biochemical and biophysical parameters of ovarian reserve in these patients. Biochemical and biophysical tests of ovarian reserve were performed simultaneously in young (age 22–42 years), regularly menstruating women with breast cancer ( n =22) and age-matched controls ( n =24). All tests were performed before (baseline) and after transient ovarian stimulation in the early follicular phase. Patients were recruited both before and after completion of chemotherapy, with some patients being followed up prospectively. Serum samples were analysed for follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol (E 2 ), inhibins A and B, and antimullerian hormone (AMH). Biophysical (ultrasound) tests included ovarian volume, antral follicle count (AFC), ovarian stromal blood flow and uterine dimensions. Significant differences were revealed (when compared with the controls) for basal FSH (11.32±1.48 vs 6.62±0.42 mIU ml −1 , P <0.001), basal AMH (0.95±0.34 vs 7.89±1.62 ng ml −1 , P <0.001) and basal inhibin B (19.24±4.56 vs 83.61±13.45 pg ml −1 , P <0.001). Following transient ovarian stimulation, there were significant differences in the increment change (Δ) for inhibin B (3.02±2.3 vs 96.82±16.38 pg ml −1 , P <0.001) and E 2 (107.8±23.95 vs 283.2±40.34 pg ml −1 , P <0.01). AFC was the only biophysical parameter that was significantly different between patients and the controls (7.80±0.85 vs 16.77±1.11, P <0.001). Basal and stimulated biochemical (serum AMH, FSH, inhibin B and E 2 ) and biophysical (AFC) tests may be potential markers of ovarian reserve in young women with breast cancer.