Poor efficacy response to trastuzumab therapy in advanced gastric cancer with homogeneous HER2 positive and non-intestinal type

Abstract

IntroductionFactors affecting trastuzumab efficacy in advanced gastric cancer (GC) are largely unknown. Heterogeneity is a notable feature of HER2 in GC. Whether the heterogeneity influences trastuzumab efficacy is still unknown.ResultsThe HER2homogeneous group and HER2heterogeneous group showed no statistical difference in RR (46.4% vs 55.0%, P = 0.558), PFS (5.80 vs 6.30 months, P = 0.804) and OS (16.00 vs 16.00 months, P = 0.787). The Laurenintestinal group and Laurennon-intestinal group demonstrated no discrepancy in PFS (6.00 vs 6.00 months, P = 0.912) and OS (16.50 vs 14.00 months, P = 0.227). However, by combining HER2 heterogeneity and Lauren classification, PFS and OS of HER2homogeneous/Laurennon-intestinal subgroup was the shortest among the 4 subgroups (P = 0.012 and P = 0.037), which was much shorter than the other patients (PFS:3.00 vs 6.30 months, P = 0.003; OS: 4.50 vs 16.50 months, P = 0.004). Univariate and multivariate analysis showed that HER2 heterogeneity combined with Lauren classification was an independent prognostic factor in both PFS (P = 0.031 and P = 0.002) and OS (P = 0.039 and P = 0.013).Materials and Methods48 patients with HER2 positive advanced GCs accepting trastuzumab treatment were retrospectively analyzed. Based on HER2 heterogeneity, the patients were divided into a HER2homogeneous group and a HER2heterogeneous group. Response rate (RR), progression free survival (PFS), and overall survival (OS) were compared. Main clinicopathological factors including Lauren classification were subjected to subgroup analysis.ConclusionsHER2 heterogeneity alone may not correlate with trastuzumab efficacy in HER2 positive advanced GCs. HER2 heterogeneity combined with Lauren classification may help to identify a subgroup with poor response to trastuzumab which is homogeneous HER2 positive and non-intestinal type.

Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer

“…Clinical significance of intratumoral HER2 heterogeneity as a predictive factor for trastuzumab was reported in breast cancer; namely, homogeneously HER2 overexpressed breast cancer showed more benefit from trastuzumab-based treatment compared with heterogeneously HER2 overexpressed breast cancer [ 23 ]. However, its clinical significance in gastric cancer is still unclear [ 24 ].…”

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer

“…Targeting at HER2, the monoclonal humanized antibody trastuzumab inhibits the signal pathway modulated by HER2 and triggers cytotoxicity . In terms of HER2‐positive advanced GC patients, the safety and efficacy of cotreatment of chemotherapy and trastuzumab are remarkably higher than those of chemotherapy treatment alone . Thus, more effective predictors of trastuzumab response in HER2‐positive cancer are required for personalized clinical treatment.…”

External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry

“…This is also in line with various studies that report that trastuzumab is less effective on tumors with heterogenous HER2 expression, diffuse histopathology, or other molecular alterations that provide resistance. [35][36][37] These considerations may be relevant when choosing treatment schemes in future trials with immunotherapy, since, although the evidence is still limited, preliminary data indicate that oxaliplatin would also be more immunogenic than other platins, given its greater capacity to induce immunogenic cell death. 38 Finally, CarFU-T combinations were the least active, even after controlling for confounding factors.…”