HER2 loss in HER2‐positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research

Abstract

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.

Molecular classifications of gastric cancers: Novel insights and possible future applications

“…De Silva et al[34] confirmed in vitro that MET is likely to be a significant mechanism of lapatinib resistance in vivo . Finally, we recently showed that HER2 loss may be associated with acquired resistance to first-line trastuzumab-based treatment in patients with initially HER2-positive GC[35]. All these evidences enhance the complex cross-talk between HER2 and its downstream pathway and stress the importance of further elucidating the strategies to overcome resistance to HER2-targeted therapy.…”

Perspectives of HER2-targeting in gastric and esophageal cancer

“…This agent has had remarkable benefit in pretreated breast cancer patients, yet in the gastroesophageal cancer population, no demonstrable benefit was noted and the experimental arm was numerically slightly inferior. HER2 expression can change at the time of disease progression in approximately 1/3 of patients who have previously received trastuzumab-based therapy 84,85 . Similar results were seen in the second-line trial of MM-111 plus trastuzumab-based chemotherapy, where a lower rate of HER2 amplification was seen in pre-treatment biopsies than in archived tumor specimens 86 .…”

Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer

“…Second, IHC is semi-quantitative and notoriously subjective, while FISH is time-consuming and relatively expensive. Third, HER2 status might change during trastuzumab therapy[4], and neither IHC nor FISH are effective assays for reflecting the real-time scenario of HER2 status[5]. More convenient and reproducible detection methods are therefore needed to identify HER2-positive gastric cancer, thus facilitating the appropriate and effective use of HER2-targeted therapy[6].…”