Abstract
Background
Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy
Methods and Findings
HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies.
Conclusions
Afatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease.
Citation: Goh G, Schmid R, Guiver K, Arpornwirat W, Chitapanarux I, Ganju V, et al. (2016) Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine. PLoS Med 13(12): e1002136. doi:10.1371/journal.pmed.1002136
Academic Editor: Andrew H. Beck, Harvard Medical School, UNITED STATES
Received: April 12, 2016; Accepted: August 22, 2016; Published: December 6, 2016
Copyright: © 2016 Goh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant clinical data and analyses are provided within the paper and its Supporting Information files: clinical data used for this study is provided in S5 Table; somatic mutation data are provided in S6 and S10 Tables; copy number profiles are provided in S8 and S11 Tables.
Funding: This study was funded by Boerhinger Ingelheim (https://www.boehringer-ingelheim.com/). CS is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169); by the UK Medical Research Council (grant reference MR/FC001169 /1); CS is funded by Cancer Research UK (TRACERx), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS) and support was provided to CS by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre. GG is supported by the Prostate Cancer Foundation and the Agency for Science, Technology and Research. Boehringer Ingelheim provided the study drug and designed the trial in collaboration with the investigators.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: CS declares advisory board or speaker fees on laboratory research over the last 3 years for Roche, Pfizer, Celgene, Boehringer Ingelheim, Novartis, Glaxo Smithkline and Eli Lilly. CS sits on the scientific advisory board and holds stock options for Epic Biosciences, APOGEN Biotech, Grail and is a founder of Achilles Therapeutics. RS KG NG and MUF are employees of Boehringer Ingelheim. SRJ has research funding from Pfizer and is on the advisory boards of Novartis, AstraZenaca and Genentech/Roche. All other authors have declared that no competing interests exist.
Abbreviations: AE, adverse event; CBR, clinical benefit rate; CCF, cancer cell fraction; CR, complete response; ECOG, Eastern Cooperative Oncology Group; ER, oestrogen; FISH, fluorescence in situ hybridization; IBC, inflammatory breast cancer; IHC, immunohistochemistry; OR, objective response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PgR, progesterone; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SCNA, somatic copy number alteration; SD, stable disease; SNV, single nucleotide variant; TCGA, The Cancer Genome Atlas; VAF, variant allele frequency; wGII, weighted Genomic Instability Index
