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Molecular alterations and poziotinib efficacy, a pan‐HER inhibitor, in human epidermal growth factor receptor 2 (HER2)‐positive breast cancers: Combined exploratory biomarker analysis from a phase II clinical trial of poziotinib for refractory HER2‐positive breast cancer patients
Author(s) -
Kim JiYeon,
Lee Eunjin,
Park Kyunghee,
Jung Hae Hyun,
Park WoongYang,
Lee KyungHun,
Sohn Joohyuk,
Lee Keun Seok,
Jung Kyung Hae,
Kim Jee Hyun,
Lee Ki Hyeong,
Im SeockAh,
Park Yeon Hee
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32188
Subject(s) - hazard ratio , biomarker , medicine , breast cancer , erbb3 , metastatic breast cancer , trastuzumab , oncology , lapatinib , cancer , epidermal growth factor receptor , confidence interval , biology , genetics
We aimed to investigate the impact of genetic alterations on the efficacy of poziotinib in a phase II clinical trial of patients with heavily treated HER2‐positive metastatic breast cancer (BC). We performed targeted ultra‐deep sequencing with a customized cancer gene panel and RNA expression assay using BC specimens. Of 106 patients, biomarker data were available for 85. Copy number (CN) amplifications of HER2 were observed in 72 patients (85%), and CN >8 in 50 (59%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%). Genetic alterations of PIK3CA pathway were found in 40 patients (47%). Median progression free survival (PFS) of the biomarker analysis group was 3.61 months. In terms of PFS, HER2 with CN >8 prolonged (hazard ratio (HR) 0.61, 95% CI: 0.38, 0.97, p = 0.037) and alteration of PIK3CA pathway shortened the duration of survival (HR 2.25, 95% CI: 1.39, 3.63, p = 0.001). SNVs of HER2 increased survival duration, but the effect was not significant (HR: 0.58, 95% CI: 0.31, 1.08, p = 0.085). In addition, SNVs in the ERBB3 cytoplasmic domain decreased poziotinib response (HR: 4.58, 95% CI: 2.02, 10.37, p < 0.001). In multigene analysis, BC with HER2 CN >8 and intact PIK3CA pathway had significantly longer PFS compared to others (HR: 0.37, 95% CI: 0.21, 0.66, p = 0.001), while SNVs in the ERBB3 cytoplasmic domain predicted poor prognosis (HR: 4.28, 95% CI: 1.71, 10.71, p < 0.001). In conclusion, HER2 CN amplification, PIK3CA pathway alteration, and ERBB3 cytoplasmic mutation showed predictive roles on clinical outcomes of HER2‐positive MBC treated with poziotinib.