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

Abstract

BackgroundTrastuzumab 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.ResultsAmong 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).ConclusionIn 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.MethodsHER2+ 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.

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

“…Indeed, in a small case series, a patient with a co-amplification of HER2 and MET was treated with a combination of trastuzumab, crizotinib, and paclitaxel and experienced near-complete disease response [ 99 ], and combined targeted blockade warrants further investigations. Additionally, loss of PTEN expression and low HER2 amplification index have been correlated with primary resistance to first-line trastuzumab-based therapy and poor prognosis in a study involving 129 HER2 positive GC [ 100 ].…”

Durable Clinical Response to Pyrotinib After Resistance to Prior Anti-HER2 Therapy for HER2-Positive Advanced Gastric Cancer: A Case Report

“…Constitutively activated Akt via PTEN deletion leads to trastuzumab resistance (12)(13)(14). A retrospective study that included 129 patients with HER2-positive gastric cancer treated with first-line trastuzumab-based regimens, indicates that patients with loss of PTEN expression have a significantly shortened median PFS (4.5 vs. 12.4 months) and OS (12.3 vs. 28.9 months) compared with those with intact PTEN expression (15). In our case, pyrotinib has been effective, although the patient demonstrated PTEN deletion and resistance to trastuzumab and lapatinib.…”

Hsa_circ_0033155: A potential novel biomarker for non‑small cell lung cancer

“…These results indicated that hsa_circ_0033155 may serve a cancer-suppressive role in NSCLC progression. PTEN, a modulator of cell survival and cell cycle progression, has been identified as a tumor suppressor that is downregulated and mutated in various cancers, including hepatocarcinoma, glioblastoma, ovarian and prostate cancer (13,24,25). Therefore, aberrant hsa_circ_0033155 may be associated with the regulation of PTEN, thus regulating cell biological functions.…”