Abstract OT2-07-07: Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: The TRAIN-3 study
Authors: van der Voort A , Dezentjé VO , van der Steeg WA , Winter-Warnars GA , Schipper R-J , Scholten AN , Wesseling J , van Werkhoven ED , van Duijnhoven FH , Vrancken Peeters M-JT , Sonke GS 
Published: May 2019

Abstract
Background
The addition of pertuzumab to trastuzumab containing chemotherapy has boosted pathologic complete response (pCR) rates after neoadjuvant chemotherapy for HER2-positive breast cancer. PCR rates over 80% have been described and achieving a pCR is associated with a favorable long-term outcome. In addition, achieving a radiologic complete response (rCR) is predictive of the pathologic response in HER2-positive tumors. Therefore it is hypothesized that image-guided evaluation based on the early occurrence of rCR can be used to tailor the number of chemotherapy cycles.
Trial design
This is a single arm, multicenter study evaluating the efficacy of image-guided de-escalation of neoadjuvant treatment with paclitaxel, Herceptin®, carboplatin, and pertuzumab (PTC-ptz). Radiologic evaluation with contrast-enhanced breast MRI and ultrasound of the axilla (in cN+ patients) is performed at baseline and after 3, 6, and 9 cycles of treatment. In case of rCR of the breast (and axilla) after 3 or 6 cycles, early surgery will be performed. If residual tumor is present after 3 and 6 cycles, patients will continue the PTC-ptz regimen to complete a total of 9 cycles. All patients will receive adjuvant Herceptin® and pertuzumab to complete 1 year of anti-HER2 blockade and endocrine treatment according to local guidelines if HR-positive. The study will be performed in the Netherlands in approximately 35 centers.
Eligibility criteria
Eligible patients have histologically proven stage II/III HER2-positive primary breast cancer with known hormone-receptor status. Patients must have a measurable breast tumor on baseline MRI and can be either node negative or node positive.
Specific aims
The aim is to evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer on event-free survival (EFS) at 3 years as primary endpoint. Secondary endpoints are overall survival, rCR, concordance between rCR and pCR (ypT0/is, ypN0), differences in EFS and OS following pCR between patients who received 3, 6, or 9 cycles, and toxicity.
Statistical methods
This is a single-arm, two stage study with one interim-analysis and a final analysis. Statistics will be performed for each hormone receptor subgroup separately. Stopping rules are based on 3-year EFS-rates described in literature (88% for HR-negative tumors and 90% for HR-positive tumors) and calculated using the exact conditional Poisson distribution. The study is successful with ≤34 EFS-events in the HR-negative subgroup and ≤38 events in the HR-positive subgroup after 700 patient-years of follow-up. The three-year EFS-estimate will be calculated using Kaplan-Meier statistics.
Present accrual and target accrual
Target accrual is 231 patients for the HR-negative group and 231 patients for the HR-positive group. Present accrual will follow.
Funding
Investigator initiated trial sponsored by the Dutch Breast Cancer Research Group (BOOG), funded by Roche.
Contact information for people with a specific interest in the trial
Study coordinator: A van der Voort, MD
The Netherlands Cancer Institute
1006 BE Amsterdam
E: a.vd.voort@nki.nl, P:+31 20 512 2951
Citation Format: van der Voort A, Dezentjé VO, van der Steeg WA, Winter-Warnars GA, Schipper R-J, Scholten AN, Wesseling J, van Werkhoven ED, van Duijnhoven FH, Vrancken Peeters M-JT, Sonke GS. Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: The TRAIN-3 study [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 OT2-07-07.