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HER2-low in gastro-oesophageal adenocarcinoma: a real-world pathological perspective
Valentina Angerilli1, Paola Parente2, Michela Campora3
1Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padova, Italy.
Aims:
In the DESTINY-Gastric01 trial, a novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan proved to be effective in HER2-low gastro-oesophageal adenocarcinomas. The aim of our study is to investigate the clinicopathological and molecular features of HER2-low gastric/gastro-oesophageal junction cancers in the real-world setting of a large multi-Institutional series.
Methods:
We retrospectively evaluated 1210 formalin-fixed paraffin-embedded samples of gastro-oesophageal adenocarcinomas which were analysed by immunohistochemistry for HER2 protein expression in 8 Italian surgical pathology units from January 2018 to June 2022. We assessed the prevalence of HER2-low (ie, HER2 1+ and HER2 2+ without amplification) and its correlation with clinical and histopathological features, other biomarkers' status, including mismatch repair/microsatellite instability status, Epstein-Barr encoding region (EBER) and PD-L1 Combined Positive Score.
Results:
HER2 status could be assessed in 1189/1210 cases, including 710 HER2 0 cases, 217 HER2 1+, 120 not amplified HER2 2+, 41 amplified HER2 2+ and 101 HER2 3+. The estimated prevalence of HER2-low was 28.3% (95% CI 25.8% to 31.0%) overall, and was higher in biopsy specimens (34.9%, 95% CI 31.2% to 38.8%) compared with surgical resection specimens (21.0%, 95% CI 17.7% to 24.6%) (p<0.0001). Moreover, HER2-low prevalence ranged from 19.1% to 40.6% among centres (p=0.0005).
Conclusions:
This work shows how the expansion of the HER2 spectrum might raise problems in reproducibility, especially in biopsy specimens, decreasing interlaboratory and interobserver concordance. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastro-oesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued.
Insights
The prevalence of HER2-low gastro-oesophageal cancer is 28.3%, but its detection can be challenging in biopsy specimens. This highlights potential issues with HER2 testing reproducibility for future targeted therapies.
Area of Science:
- Oncology
- Gastroenterology
- Pathology
Background:
- The DESTINY-Gastric01 trial demonstrated trastuzumab deruxtecan's efficacy in HER2-low gastro-oesophageal adenocarcinomas.
- HER2-low expression represents a significant subset of these cancers, necessitating further investigation.
Purpose of the Study:
- To investigate the clinicopathological and molecular features of HER2-low gastric and gastro-oesophageal junction cancers.
- To assess the real-world prevalence of HER2-low status in a large, multi-institutional series.
Main Methods:
- Retrospective analysis of 1210 gastro-oesophageal adenocarcinoma samples from 8 Italian pathology units (Jan 2018-June 2022).
- Immunohistochemistry was used to assess HER2 protein expression, defining HER2-low as HER2 1+ and non-amplified HER2 2+.
- Correlation with clinical, histopathological, and other biomarker statuses (MSI, EBER, PD-L1) was evaluated.
Main Results:
- HER2 status was assessed in 1189 cases; HER2-low prevalence was 28.3% (95% CI 25.8%-31.0%).
- HER2-low prevalence was significantly higher in biopsy specimens (34.9%) versus surgical resections (21.0%) (p<0.0001).
- Prevalence varied notably among participating centers (19.1%-40.6%, p=0.0005).
Conclusions:
- The study identified significant variability in HER2-low prevalence, particularly impacting biopsy specimens.
- Expansion of the HER2 spectrum may introduce reproducibility challenges, affecting interlaboratory and interobserver concordance.
- A potential shift in HER2 status interpretation may be required if future trials confirm anti-HER2 agent activity in HER2-low cancers.
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