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

Ji Yeon Kim, Eunjin Lee, Kyunghee Park, Hae Hyun Jung, Woong Yang Park, Kyung-Hun Lee, Joohyuk Sohn, Keun Seok Lee, Kyung Hae Jung, Jee Hyun Kim, Ki Hyeong Lee, Seock-Ah Im, Yeon Hee Park

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1669-1678
Number of pages10
JournalInternational Journal of Cancer
Volume145
Issue number6
DOIs
StatePublished - 15 Sep 2019

Fingerprint

Phase II Clinical Trials
Biomarkers
Breast Neoplasms
Nucleotides
Disease-Free Survival
High-Throughput Nucleotide Sequencing
Survival
Neoplasm Genes
Survival Analysis
human ERBB2 protein
HM781-36B
RNA
Mutation

Keywords

  • HER2-positive
  • biomarker
  • metastatic breast cancer
  • poziotinib
  • targeted deep sequencing

Cite this

@article{b65765e64027412cb73953eb26fabf86,
title = "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",
abstract = "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.",
keywords = "HER2-positive, biomarker, metastatic breast cancer, poziotinib, targeted deep sequencing",
author = "Kim, {Ji Yeon} and Eunjin Lee and Kyunghee Park and Jung, {Hae Hyun} and Park, {Woong Yang} and Kyung-Hun Lee and Joohyuk Sohn and Lee, {Keun Seok} and Jung, {Kyung Hae} and Kim, {Jee Hyun} and Lee, {Ki Hyeong} and Seock-Ah Im and Park, {Yeon Hee}",
year = "2019",
month = "9",
day = "15",
doi = "10.1002/ijc.32188",
language = "English",
volume = "145",
pages = "1669--1678",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

}

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. / Kim, Ji Yeon; Lee, Eunjin; Park, Kyunghee; Jung, Hae Hyun; Park, Woong Yang; Lee, Kyung-Hun; Sohn, Joohyuk; Lee, Keun Seok; Jung, Kyung Hae; Kim, Jee Hyun; Lee, Ki Hyeong; Im, Seock-Ah; Park, Yeon Hee.

In: International Journal of Cancer, Vol. 145, No. 6, 15.09.2019, p. 1669-1678.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Molecular alterations and poziotinib efficacy, a pan-HER inhibitor, in human epidermal growth factor receptor 2 (HER2)-positive breast cancers

T2 - Combined exploratory biomarker analysis from a phase II clinical trial of poziotinib for refractory HER2-positive breast cancer patients

AU - Kim, Ji Yeon

AU - Lee, Eunjin

AU - Park, Kyunghee

AU - Jung, Hae Hyun

AU - Park, Woong Yang

AU - Lee, Kyung-Hun

AU - Sohn, Joohyuk

AU - Lee, Keun Seok

AU - Jung, Kyung Hae

AU - Kim, Jee Hyun

AU - Lee, Ki Hyeong

AU - Im, Seock-Ah

AU - Park, Yeon Hee

PY - 2019/9/15

Y1 - 2019/9/15

N2 - 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.

AB - 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.

KW - HER2-positive

KW - biomarker

KW - metastatic breast cancer

KW - poziotinib

KW - targeted deep sequencing

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EP - 1678

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

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ER -