PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer

Chan Kim, Choong Kun Lee, Hong Jae Chon, Joo Hoon Kim, Hyung Soon Park, Su Jin Heo, Hyun Jeong Kim, Tae Soo Kim, Woo Sun Kwon, Hyuncheol Chung, SunYoung Rha

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results: Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index ( < 5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

Original languageEnglish
Pages (from-to)113494-113501
Number of pages8
JournalOncotarget
Volume8
Issue number69
DOIs
Publication statusPublished - 2017 Jan 1

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Phosphoric Monoester Hydrolases
Stomach Neoplasms
R Factors
Class Ia Phosphatidylinositol 3-Kinase
Cisplatin
human ERBB2 protein
Tensins
Trastuzumab
Therapeutics
Fluorouracil
Disease-Free Survival
Disease Progression
Histology
Multivariate Analysis
Neoplasm Metastasis
Bone and Bones
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kim, Chan ; Lee, Choong Kun ; Chon, Hong Jae ; Kim, Joo Hoon ; Park, Hyung Soon ; Heo, Su Jin ; Kim, Hyun Jeong ; Kim, Tae Soo ; Kwon, Woo Sun ; Chung, Hyuncheol ; Rha, SunYoung. / PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer. In: Oncotarget. 2017 ; Vol. 8, No. 69. pp. 113494-113501.
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title = "PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer",
abstract = "Background: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results: Among 129 HER2+ GC patients, 25{\%} displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index ( < 5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.",
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PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer. / Kim, Chan; Lee, Choong Kun; Chon, Hong Jae; Kim, Joo Hoon; Park, Hyung Soon; Heo, Su Jin; Kim, Hyun Jeong; Kim, Tae Soo; Kwon, Woo Sun; Chung, Hyuncheol; Rha, SunYoung.

In: Oncotarget, Vol. 8, No. 69, 01.01.2017, p. 113494-113501.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer

AU - Kim, Chan

AU - Lee, Choong Kun

AU - Chon, Hong Jae

AU - Kim, Joo Hoon

AU - Park, Hyung Soon

AU - Heo, Su Jin

AU - Kim, Hyun Jeong

AU - Kim, Tae Soo

AU - Kwon, Woo Sun

AU - Chung, Hyuncheol

AU - Rha, SunYoung

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results: Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index ( < 5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

AB - Background: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results: Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index ( < 5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

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