Early stage gastric adenocarcinoma: clinical and molecular landscapes

Abstract

Gastric adenocarcinoma, even when diagnosed at an early (localized) disease stage, poses a major health-care burden with cure rates that remain unsatisfactorily low, particularly in Western countries. This lack of progress reflects, among other aspects, the impracticality of early diagnosis, considerable variations in therapeutic approaches that is partly based on regional preferences, and the ingrained heterogeneity of gastric adenocarcinoma cells and their associated tumour microenvironment (TME). Clinical trials have long applied empirical interventions with the assumption that all early stage gastric adenocarcinomas are alike. Despite certain successes, the shortcomings of these approaches can potentially be overcome by targeting the specific molecular subsets of gastric adenocarcinomas identified by genomic and/or multi-omics analyses, including microsatellite instability-high, Epstein-Barr virus-induced, DNA damage repair-deficient, HER2-positive and PD-L1-high subtypes. Future approaches, including the availability of sophisticated vaccines, novel antibody technologies, agents targeting TME components (including fibroblasts, macrophages, cytokines or chemokines, and T cells) and novel immune checkpoint inhibitors, supported by improved tissue-based and blood-based diagnostic assays, seem promising. In this Review, we highlight current knowledge of the molecular and cellular biology of gastric adenocarcinomas, summarize the current approaches to clinical management of the disease, and consider the role of novel management and/or treatment strategies.

Fig. 1:. Alterations and potential targets involving the RAS and/or PI3K–AKT–mTOR signalling pathways in localized gastric adenocarcinomas.

Percentage frequencies of the molecular alterations in genes encoding each receptor tyrosine kinase and the related downstream RAS–RAF and PI3K–AKT–mTOR signalling components. Targeted therapies that are currently either in preclinical or clinical development (light blue) or have already received FDA approval for use in patients with gastric adenocarcinoma (dark blue) are included.

Fig. 2:. Deregulated cancer stemness pathways and putative targeted therapy strategies in patients with localized gastric adenocarcinoma.

Alterations and putative targeted therapy strategies involve several different signalling pathways with important roles in subsets of gastric adenocarcinoma including Hippo–YAP1–TAZ (which regulates organ size, cellular proliferation and the acquisition of stem cell-like traits), Wnt signalling (which regulates epithelial homeostasis, proliferation and stemness), Notch signalling (which promotes gastric stem cell proliferation and determines the developmental fate of cancer cells and cancer stem cells in the stomach), and Hedgehog signalling (which has a crucial role in the development of the gastrointestinal tract and maintenance of the physiological function of the stomach), with aberrant activation of Hedgehog signalling implicated in carcinogenesis as well as the maintenance of cancer stem cells. Potential inhibitors targeting key proteins in each signalling pathway are indicated in blue boxes.

Fig. 3:. The interplay of tumour cells, cancer-associated fibroblasts and macrophages in the gastric adenocarcinoma TME.

The gastric adenocarcinoma tumour microenvironment (TME) is characterized by complex interactions between tumour cells, cancer-associated fibroblasts (CAFs), macrophages and T cells. For example, tumour cells with high levels of YAP1 and/or SOX9 produce immunosuppressive molecules such as Gal-9, DKK1, TGFβ and LIF, which promote M2 macrophage repolarization and impair both T cell activity and infiltration through receptor–ligand interactions. CAFs can also secrete tumour-promoting factors, such as SDC2 and/or periostin, which further promote tumour progression and metastatic dissemination. These factors can further suppress T cell function and promote M2 macrophage repolarization. Novel immune-related targets could be derived from these complex interactions, including agents targeting CD47–SIRPα, CD24–SIGLEC10, CCL2–IL10, TIM3–Gal-9, TIGIT–CD155–CD112, and CXCL12–CXCR4.

Fig. 4:. Western and Asian treatment algorithms.

a, Example Western treatment algorithm, in which preoperative and postoperative chemotherapy is the standard approach in patients with ≥cT2 advanced-stage gastric adenocarcinoma. b, Japanese treatment algorithm, in which preoperative chemotherapy is not the standard-of-care approach (except in patients with bulky N⁺ disease). The standard-of-care for ≥cT2 advanced-stage gastric adenocarcinoma is upfront D2 gastrectomy, potentially followed by adjuvant chemotherapy depending on tumour stage and grade. BSC, best supportive care; eCura, endoscopic curability score; ER, endoscopic resection; EUS, endoscopic ultrasonography; NAC, neoadjuvant chemotherapy; PAND, para-aortic lymph node dissection. Part a adapted with permission from ref., Elsevier. Part b reprinted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 5:. Surgical procedures for gastric cancer.

Distal gastrectomy (part a) and total gastrectomy with lymphadenectomy (part b). Lymph node territories for D1 (white) or D2 (yellow) lymphadenectomy are depicted. Both diagrams include the stomach, pancreas, duodenum and spleen. c, Endoscopic submucosal dissection of early stage gastric cancer located at the greater curvature of the middle gastric body (i, marking around the tumour; ii, incision of the tumour circumference; iii dissection of the submucosal layer; iv, post-resection observation).