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PLoS Med. 2016 Dec 6;13(12):e1002136. doi: 10.1371/journal.pmed.1002136. eCollection 2016 Dec.

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.

Author information

Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, United Kingdom.
Bill Lyons Informatics Centre, UCL Cancer Institute, London, United Kingdom.
Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany.
Boehringer Ingelheim Ltd, Bracknell, United Kingdom.
National Cancer Institute, Bangkok, Thailand.
Maharaj Nakhon Chiang Mai Hospital, Chiang Mai, Thailand.
Monash Medical Centre, Melbourne, Australia.
Seoul National University Hospital, Seoul, South Korea.
Asan Medical Center, University of Ulsan College of Medicine, Ulsan, South Korea.
Prince of Songkla University, Songkhla, Thailand.
Rajavithi Hospital, Bangkok, Thailand.
Duke University Medical Center, Durham, North Carolina, United States of America.
Queen Mary Hospital, Hong Kong.
Abderrahman Mami Hospital, Ariana, Tunisia.
Fahat Hached Hospital, Sousse, Tunisia.
Royal Marsden Hospital Breast Unit, London, United Kingdom.
The Francis Crick Institute, London, United Kingdom.



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 ( 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.


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.


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.


[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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.

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