Abstract LB-453: Phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC). A biomarker driven study using ultra deep genome sequencing technology
Authors: Swanton Charles , Sutherland Stephanie , Cromer Jamie , Kaci Mahmoud Ould 
Published: August 2012

Background:Personalized medicine in breast cancer (BC), by improving pt selection and predicting drug response, is challenging. Acquisition of tumor multidrug resistance is inevitable in advanced BC. Drug resistance is highly complex and single mechanisms fail to explain this phenomenon. Ultra-deep whole genome sequencing has shown unexpected and profound complexity and intra/inter-tumor heterogeneity. Strategies to identify biomarkers and drug resistance mechanisms will likely require in-depth analysis of pre/post-treatment resistant tumor biopsies to study dynamic changes in clonal tumor architecture during therapy. IBC is a rare, aggressive form of BC. It commonly lacks ER/PR, and more frequently harbors HER2 gene amplification and EGFR overexpression. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in trastuzumab (T)-resistant cell lines, HER2+ tumor xenografts and HER2- SUM 149 xenograft model, derived from an IBC cell line. Its clinical efficacy was shown in T-resistant, HER2+ metastatic BC. This biomarker-driven study in pts with T pretreated/naïve, HER2+ IBC, investigates efficacy/safety of afatinib with/without V, upon disease progression (PD) on afatinib monotherapy, and changes in clonal tumor architecture that occur through treatment.Methods: Pts with HER2+ IBC are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. All pts start afatinib monotherapy (40 mg/d oral; Part A). Upon PD, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week; Part B). Study endpoints:clinical benefit rate (CR, PR or SD) for ≥6 months, ORR, PFS, OS and safety. In Part A fresh tumor biopsies are taken pretreatment + upon PD and blood samples are taken pretreatment for ultra-deep whole genome sequencing (via DNA/RNA analysis) including gene expression, copy number and proteomic analysis to explore predictive markers of response/resistance to afatinib, and to describe IBC population which may benefit most. The use of pre/post-treatment ultra-deep whole genome sequencing aims to: identify bottlenecking resistance mechanisms to ErbB Family Blockers, identify pretreatment subclonal mutations that predict outcome to afatinib, establish trials network and tissue collection methodology, develop greater understanding of IBC biology and clarify the sensitivity of HER2+ IBC to HER2 inhibitors.Conclusions: Understanding subclonal architecture will be key in advancing our knowledge of resistance mechanisms. Evolutionary bottlenecking during drug resistance offers a tractable process to predict drug outcome and identify novel targets. This is the first prospective clinical trial to integrate whole genome sequencing into trial design to assess proof of principle of this personalized cancer medicine approach to improve pt stratification for therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-453. doi:1538-7445.AM2012-LB-453