Clinical impact of tumour biology in the management of gastroesophageal cancer

Abstract

The characterization of oesophageal and gastric cancer into subtypes based on genotype has evolved in the past decade. Insights into the molecular landscapes of gastroesophageal cancer provide a roadmap to assist the development of new drugs and their use in combinations, for patient stratification, and for trials of targeted therapies. Trastuzumab is the only approved treatment for gastroesophageal cancers that overexpress HER2. Acquired resistance usually limits the duration of response to this treatment, although a number of new agents directed against HER2 have the potential to overcome or prolong the time until resistance occurs. Beyond that, anti-VEGFR2 therapy with ramucirumab was the first biological treatment strategy to produce a survival benefit in an unselected population of patients with chemotherapy-refractory gastroesophageal cancer. Large initiatives are starting to address the role of biomarker-driven targeted therapy in the metastatic and in the perioperative setting for patients with this disease. Immunotherapy also holds promise, and our understanding of subsets of gastroesophageal cancer based on patterns of immune response continues to evolve. Efforts are underway to identify more relevant genomic subsets through genomic screening, functional studies, and molecular characterization. Herein, we provide an overview of the key developments in the treatment of gastroesophageal cancer, and discuss potential strategies to further optimize therapy by targeting disease subtypes.

Figure 1. Proposed treatment algorithm for advanced gastroesophageal cancer based on publish recommendations^,

ECOG, Eastern Cooperative Oncology Group; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization. Adapted with permission © Lordick, F. Nat. Rev. Clin. Oncol. 12, 7–8 (2015).

Figure 2. Key features of gastric cancer subtypes according to The Cancer Genome Atlas (TCGA)

This schematic lists some of the salient features associated with each of the four molecular subtypes of gastric cancer identified by the TCGA. Distribution of molecular subtypes in tumours obtained from distinct regions of the stomach is represented in inset charts. CIMP, CpG island methylator phenotype; CIN, chromosomal instability; GE, gastroesophageal; GS, genomically stable; MSI, microsatellite instability. Reproduced with permission © Bass, A. J. et al. Nature 513, 202–209 (2014).

Figure 3. Biopsy of a gastric cancer

Gastric cancer biopsy with a mixed histological type showing intestinal areas with strong HER2 immunoreactivity adjacent to diffuse areas with weak staining for HER2.

Figure 4. Angiogenic signalling network and inhibition by antiangiogenic drugs

Binding of VEGFR2 results in intracellular phosphorylation and activation of multiple downstream pathways, including PLCγ, MAPK, PI3K, AKT, and SRC. Proangiogenic signals and VEGFR activity are modulated by several receptors, including integrins, FGFR, PDGFR, Notch, and TIE2. Activation of VEGFR1 leads to downstream effects on haematopoietic stem cells (HSCs), dendritic cell (DC) maturation, and chemotaxis, whereas VEGFR3 signalling promotes lymphangiogenesis. General drug targets are illustrated for aflibercept, bevacizumab, ramucirumab, and multiple receptor tyrosine kinase inhibitors. Adapted with permission © Clarke, J. M. & Hurwitz, H. I. Expert Opin. Biol. Ther. 13, 1187–1196 (2013).

Figure 5. Mutational heterogeneity in oesophageal and gastric cancer

Mutation frequencies observed in exomes from 3,083 tumour–normal pairs are shown [L153]. Each dot corresponds to a tumour–normal pair, with vertical position indicating the total frequency of somatic mutations in the exome. Tumour types are ordered by their median somatic mutation frequency, with the lowest frequencies (left) found in haematological and paediatric tumours, and the highest frequencies (right). The lowest and highest mutation frequencies vary more than 1,000–fold across different cancers and also within several tumour types. The bottom panel shows the relative proportions of the six different possible base-pair substitutions, as indicated in the legend on the left. Reproduced with permission © Lawrence, M. S. et al. Nature 499, 214–218 (2013).