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

// Chan Kim 1, * , Choong-Kun Lee 2, * , Hong Jae Chon 1, * , Joo Hoon Kim 2 , Hyung Soon Park 2 , Su Jin Heo 2 , Hyun Jeong Kim 3 , Tae Soo Kim 3 , Woo Sun Kwon 3 , Hyun Cheol Chung 2, 3, 4 and Sun Young Rha 2, 3, 4 1 Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 2 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 3 Song Dang Institute for Cancer Research, Seoul, Korea 4 Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea * These authors contributed equally to this study Correspondence to: Sun Young Rha, email: rha7655@yuhs.ac Keywords: trastuzumab; resistance; gastric cancer; HER2; PTEN Received: August 08, 2017      Accepted: November 13, 2017      Published: December 09, 2017 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.