Canadian Consensus Recommendations for Predictive Biomarker Testing in Gastric and Gastroesophageal Junction Adenocarcinoma

Abstract

Gastric cancer is common globally and has a generally poor prognosis with a low 5-year survival rate. Targeted therapies and immunotherapies have improved the treatment landscape, providing more options for efficacious treatment. The use of these therapies requires predictive biomarker testing to identify patients who can benefit from their use. New therapies on the horizon, such as CLDN18.2 monoclonal antibody therapy, require laboratories to implement new biomarker tests. A multidisciplinary pan-Canadian expert working group was convened to develop guidance for pathologists and oncologists on the implementation of CLDN18.2 IHC testing for gastric and gastroesophageal junction (G/GEJ) adenocarcinoma in Canada, as well as general recommendations to optimize predictive biomarker testing in G/GEJ adenocarcinoma. The expert working group recommendations highlight the importance of reflex testing for HER2, MMR and/or MSI, CLDN18, and PD-L1 in all patients at first diagnosis of G/GEJ adenocarcinoma. Testing for NTRK fusions may also be included in reflex testing or requested by the treating clinician when third-line therapy is being considered. The expert working group also made recommendations for pre-analytic, analytic, and post-analytic considerations for predictive biomarker testing in G/GEJ adenocarcinoma. Implementation of these recommendations will provide medical oncologists with accurate, timely biomarker results to use for treatment decision-making.

Keywords: CLDN18; CLDN18.2; HER2; IHC; MMR; PD-L1; gastric cancer; immunohistochemistry; immunotherapy; targeted therapy.

Figure 1

Predictive biomarker testing for patients with gastric or gastroesophageal junction adenocarcinoma.

Figure 2

HER2 IHC (clone 4B5; performed with Ventana BenchMark Ultra according to the manufacturer’s protocol) showing scoring of representative gastric adenocarcinoma cases. (A) Positive 3+ staining demonstrating strong complete, basolateral, and lateral membranous reactivity in the tumour cells. (B) Positive 2+ staining demonstrating weak to moderate complete, basolateral, and lateral membranous reactivity in the tumour cells. (C) Negative 1+ staining demonstrating faint/barely perceptible membranous reactivity in the tumour cells. (D) Negative 0 staining demonstrating no reactivity or membranous reactivity in any tumour cell.

Figure 3

MMR IHC (performed with Ventana BenchMark Ultra according to the manufacturer’s protocol) with representative gastric adenocarcinoma cases showing the most common pattern of MMR deficiency. (A) MLH1(M1) showing loss of nuclear expression in the cancer cells but retention in surrounding inflammatory cells. (B) PMS2 (clone A16-4) showing loss of nuclear expression in the cancer cells but retention in surrounding inflammatory cells. (C) MSH2 (clone G219-1129) showing retained expression in the tumour cells. (D) MSH6(SP93) showing retained expression in the tumour cells.

Figure 4

CLDN18 IHC (clone 43-14A; performed with Ventana BenchMark Ultra according to the manufacturer’s protocol) showing scoring of representative gastric adenocarcinoma cases. (A) Positive 3+ staining demonstrating strong membranous reactivity. (B) Positive 2+ staining demonstrating moderate membranous reactivity. (C) Negative 1+ staining demonstrating weak membranous reactivity. (D) Negative 0 staining demonstrating no membranous reactivity.

Figure 5

PD-L1 IHC (PD-L1 IHC 28-8 pharmDx from Agilent; performed on the Autostainer Link 48 according to the manufacturer’s protocol) scoring of representative gastric adenocarcinoma cases. Scoring is performed using the combined positive score (CPS), a ratio of PD-L1-staining cells (tumour cells, lymphocytes, and macrophages) relative to viable tumour cells. (A) High CPS showing high tumour cell staining (CPS on the whole slide was 100). (B) Low CPS with focal tumour and lymphocyte and macrophage staining (CPS on the whole slide was 5). (C) Low CPS with lymphocyte and macrophage staining but without tumour cell staining (CPS on the whole slide was <1). The positive lymphocytes were very focal compared to the tumour. (D) CPS of 0.