Goh, Gerald; Schmid, Ramona; Guiver, Kelly; Arpornwirat, Wichit; Chitapanarux, Imjai; Ganju, Vinod; Im, Seock-Ah; Kim, Sung-Bae; Dechaphunkul, Arunee; Maneechavakajorn, Jedzada; Spector, Neil; Yau, Thomas; Afrit, Mehdi; Ahmed, Slim Ben; Johnston, Stephen R; Gibson, Neil; Uttenreuther-Fischer, Martina; Herrero, Javier; Swanton, Charles
PLoS medicine
2016Dec ; 13 ( 12 ) :e1002136.
PMID : 27923043
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Goh, Gerald -
Schmid, Ramona -
Guiver, Kelly -
Arpornwirat, Wichit -
Chitapanarux, Imjai -
Ganju, Vinod -
Im, Seock-Ah -
Kim, Sung-Bae -
Dechaphunkul, Arunee -
Maneechavakajorn, Jedzada -
Spector, Neil -
Yau, Thomas -
Afrit, Mehdi -
Ahmed, Slim Ben -
Johnston, Stephen R -
Gibson, Neil -
Uttenreuther-Fischer, Martina -
Herrero, Javier -
Swanton, Charles -
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-naive 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-naive 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-naive 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-naive 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325428.
Adolescent; Adult; Aged; Antineoplastic Agents/adverse effects/*therapeutic use; Antineoplastic Agents, Phytogenic/adverse effects/therapeutic use; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use; Cohort Studies; Female; Humans; Inflammatory Breast Neoplasms; Middle Aged; Quinazolines/adverse effects/*therapeutic use; Receptor, ErbB-2/*antagonists & inhibitors; Vinblastine/adverse effects/*analogs & derivatives/therapeutic use; Young Adult
MESH
Adolescent, Adult, Aged, Antineoplastic Agents/adverse effects/*therapeutic use, Antineoplastic Agents, Phytogenic/adverse effects/therapeutic use, Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use, Cohort Studies, Female, Humans, Inflammatory Breast Neoplasms, Middle Aged, Quinazolines/adverse effects/*therapeutic use, Receptor, ErbB-2/*antagonists & inhibitors, Vinblastine/adverse effects/*analogs & derivatives/therapeutic use, Young Adult
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