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Exploratory biomarker analyses of the phase 3 CheckMate 649 trial show that in patients with advanced gastroesophageal cancer, KRAS alterations were associated with greater overall survival (OS) benefit when treated with nivolumab plus chemotherapy vs chemotherapy alone, whereas high regulatory T-cell signatures were associated with greater OS benefit when treated with nivolumab plus ipilimumab.

Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.

The characterization of gastroesophageal cancer into subtypes on the basis of diverse genotypes has evolved; however, patients require new treatment options, particularly when standard therapies are exhausted. Improved molecular classification of gastroesophageal cancer subtypes enhances patient selection for biological therapy. The authors of this Review summarize the current awareness of the unique biology of gastroesophageal cancer and discuss the clinically applicability of these findings.

In a retrospective analysis of patients with Lynch syndrome and primary cancers treated with immune checkpoint inhibitors, 12% developed subsequent malignancies, suggesting that this treatment may not eliminate risk in individuals predisposed to mismatch repair-deficient cancers, and ongoing surveillance is warranted.

Interim analysis of a phase III clinical trial of HER2-positive gastric adenocarinoma shows pembrolizumab plus trastuzumab and chemotherapy improves response rates compared with trastuzumab and chemotherapy alone.

Mutations in BRCA1/2 are associated with a homologous recombination deficiency phenotype in BRCA-associated cancers. Reversion mutations can restore BRCA1/2 function and result in treatment resistance in these cancer-types. Here, the authors show that, in select cases, reversion mutations in BRCA1/2 can indicate prior BRCA-mediated tumorigenesis in non-canonical histologies.

Results in the CheckMate 649 phase 3 trial for first-line combined nivolumab and chemotherapy treatment continue to show clinically meaningful efficacy in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma after 24 months, with no new safety signals.

Clinical evidences have demonstrated limited efficacy of HER2-targeted therapies in patients with gastric cancer (GC). Here the authors show that survival benefit to anti-HER2 antibody Trastuzumab is reduced in GC patients with high levels of the caveolin-1 and that, in preclinical cancer models, antibody drug efficacy can be improved by modulating caveolin-1 levels with cholesterol-depleting drugs, statins.

Trastuzumab binding to tumor cells depends on the availability of HER2 at the cell membrane. Here the authors show that caveolin-1 (CAV1) regulates HER2 density at the cell membranes and that CAV1 gene knockdown or protein depletion via the cholesterol modulator lovastatin, increases trastuzumab binding and anti-tumor activity.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.

In recent years, the molecular characterization of gastric adenocarcinoma — the most common stomach cancer — has identified numerous targets for potential exploitation into therapy. However, advances are still lagging compared with other cancers of similar incidence. In this Primer, Ajani et al. describe these advances and the work still needed to be done.