Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under
Qi Xu1,2, Xiaoqing Xu1,3, Haimeng Tang4
1Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China.
Abstract:
HER2-positive gastric cancer (GC) makes up 15-20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.
Insights
Understanding trastuzumab resistance in HER2-positive gastric cancer is key. This study identified genetic factors like chromosome instability and mutation burden, alongside tumor types, influencing treatment response and survival in advanced cases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- HER2-positive gastric cancer (GC) accounts for 15-20% of GC cases.
- Trastuzumab is the standard targeted therapy, but resistance mechanisms are poorly understood.
- Resistance to trastuzumab presents a significant clinical challenge.
Purpose of the Study:
- To identify clinicopathological and molecular features associated with trastuzumab resistance in HER2-positive GC.
- To investigate genetic alterations and tumor characteristics correlating with treatment response and survival.
- To gain insights into mechanisms of primary and acquired resistance to trastuzumab.
Main Methods:
- Whole exome sequencing (WES) of paired tumor tissues from 23 GC patients (baseline and progressive disease).
- Analysis of clinicopathological data, including Lauren classification.
- Assessment of tumor mutation burden (TMB), chromosome instability (CIN), and clonal branching patterns.
Main Results:
- Intestinal type GC showed longer progression-free survival (PFS) than diffuse type.
- Low TMB correlated with worse PFS; high CIN correlated with prolonged overall survival (OS).
- Responders had higher CIN, with a trend of increasing CIN correlating with improved response. Common acquired mutations included AURKA, MYC, STK11, and LRP6. Extensive clonal branching was linked to shorter PFS.
Conclusions:
- Clinicopathological factors like Lauren classification and molecular features such as TMB, CIN, and clonal architecture are associated with trastuzumab resistance in HER2-positive GC.
- High CIN may be a predictive marker for better survival and response to trastuzumab.
- Further research into these factors can guide personalized treatment strategies for advanced HER2-positive GC.
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