Abstract OT3-02-02: ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy
Authors: 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 
Published: May 2016

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&gt;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.