Abstract OT2-04-03: An intrinsic subtype-based platform of translational randomized phase II trials of response-guided neoadjuvant therapy in breast cancer (PREDIX)
Authors: Foukakis T , Hellström M , Johansson H , Bergh J , Hatschek T 
Published: May 2016

Abstract
Background: Pathologic complete response (pCR) after neoadjuvant therapy of breast cancer is associated with a better prognosis. The impact of pCR on outcome differs between intrinsic subtypes.
Trial design: With the aim to improve treatment on an individual level, the PREDIX platform is designed as a compilation of randomized phase II studies based on functional "intrinsic subgroups" with the intention to direct treatment in relation to response. Four trials will be pursued:
1.Luminal A,N- (ER+ and/or PR+ without node metastases and age &gt;40);
2.Luminal A,N+ (ER+ and/or PR+ with node metastases or age ≤40)/Luminal B (ER+ and high proliferation);
3.HER2 amplified (including HER2 positive luminal B tumors);
4.Triple-negative (this trial is currently in planning phase)
The clinical management is accompanied by repeated core biopsies and blood sampling. Besides mammography and ultrasound, functional imaging with PET-CT, confined to the breast and regional lymph nodes is applied.
Treatment plan:
Trial 1. Eligible patients are treated with endocrine therapy (ET) for 4 weeks. A biopsy for Ki67 is obtained before start and after 2 weeks. If no decrease of Ki67 is observed, or no objective response (OR) is seen after 4 weeks of treatment, palbociclib is added to ET. Patients with decrease of Ki67/OR are randomized to continuous therapy with or without the addition of palbociclib for 12 weeks, followed by surgery.
Trial 2. Patients are randomized to 12 weeks of palbociclib + ET or weekly paclitaxel, followed by switch to the other arm for additional 12 weeks before surgery.
Trial 3. Patients are randomized to the combination of pertuzumab + trastuzumab + docetaxel or trastuzumab emtasine for 2 three-weekly cycles. If OR is documented, 4 additional cycles will be administered followed by surgery. Non-responding patients will switch to the opposite arm.
In trials 2 and 3, additional anthracycline-based chemotherapy will be administered postoperatively. Adjuvant ET and radiotherapy will be used according to standard practice.
Eligibility criteria: Patients &gt;18y with primary breast cancer &gt;2 cm or node metastases, with adequate performance status and organ function are eligible. Intrinsic subtype defined by immunohistochemistry or, preferably, by genomic profiling using RNA Seq.
Specific aims: To evaluate the impact of response-guided treatment on objective response and long-term outcome and to identify tumor characteristics and treatment-related changes of tumor biology predictive of long-term prognosis.
Statistical methods: The PREDIX trials are based on current knowledge of molecular characteristics of breast cancer and designed to find the distribution of objective response to primary medical treatment (primary endpoint) and to find predictors of response, disease-free and overall survival, and to evaluate toxicity and quality of life in the two treatment groups (secondary endpoints).
Present accrual and target accrual: Present accrual (May 2015) in the HER2 positive trial is 14 patients. Trials 1 and 2 will open in July and September 2015. Target accrual is based on an explorative design and is between 180 to 200 patients in each trial.
Citation Format: Foukakis T, Hellström M, Johansson H, Bergh J, Hatschek T. An intrinsic subtype-based platform of translational randomized phase II trials of response-guided neoadjuvant therapy in breast cancer (PREDIX). [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 OT2-04-03.