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Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype.

ABSTRACT: Immune checkpoint inhibition is effective in a subset of patients with advanced gastric cancer. Genomic profiling has revealed the heterogeneity of gastric adenocarcinomas, but the immune microenvironment and predictors of immunotherapy response remain poorly understood. We aimed to better characterize the underlying immune response to gastric cancer. Retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent curative intent resection of gastric adenocarcinoma from 2006 to 2016. Tumors were classified according to modified TCGA subtype: Epstein-Barr virus (EBV)-associated, microsatellite instability (MSI)-high, intestinal as a surrogate for chromosomal instability, diffuse as a surrogate for genomically stable. Tumor-infiltrating leukocytes were measured using immunohistochemistry. Forty-three patients were identified: 6 EBV, 11 MSI, 14 intestinal, 12 diffuse. The most prevalent tumor-infiltrating leukocytes were CD8 T lymphocytes and CD68 macrophages, comprising 15% and 13% of all tumor cells. EBV and MSI tumors were the most infiltrated, harboring 30% to 50% T cells and 20% macrophages. Intestinal tumors contained fewer T cells but disproportionately more macrophages. Diffuse tumors were the least infiltrated. Programmed cell death protein 1 was most frequently expressed in intestinal tumors, whereas 70% of EBV and MSI tumors expressed programmed death-ligand 1. We herein demonstrate a heterogenous immune response to gastric cancer, which varies by tumor subtype and has implications for future immunotherapy trials. Checkpoint inhibition is unlikely to be effective as single-agent therapy against intestinal and diffuse tumors lacking prominent T-cell infiltration or substantial programmed death-ligand 1 expression.

SUBMITTER: Kim TS

PROVIDER: S-EPMC6867704 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype.

Kim Teresa S TS da Silva Edaise E Coit Daniel G DG Tang Laura H LH

The American journal of surgical pathology 20190601 6

Immune checkpoint inhibition is effective in a subset of patients with advanced gastric cancer. Genomic profiling has revealed the heterogeneity of gastric adenocarcinomas, but the immune microenvironment and predictors of immunotherapy response remain poorly understood. We aimed to better characterize the underlying immune response to gastric cancer. Retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent curative intent resecti ...[more]

PMID: 30969179

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Project description:BackgroundTwo primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting.MethodsWe examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided.ResultsNM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated.ConclusionsOur data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.

Project description:BackgroundTo investigate whether intratumoral and peritumoral radiomics may predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer.MethodsClinical, pathological, and CT data from 231 patients with advanced gastric cancer who underwent neoadjuvant chemotherapy at our hospital between July 2014 and February 2022 were retrospectively collected. Patients were randomly divided into a training group (n = 161) and a validation group (n = 70). The support vector machine classifier was used to establish radiomics models. A clinical model was established based on the selected clinical indicators. Finally, the radiomics and clinical models were combined to generate a radiomics-clinical model. ROC analyses were used to evaluate the prediction efficiency for each model. Calibration curves and decision curves were used to evaluate the optimal model.ResultsA total of 91 cases were recorded with good response and 140 with poor response. The radiomics model demonstrated that the AUC was higher in the combined model than in the intratumoral and peritumoral models (training group: 0.949, 0.943, and 0.846, respectively; validation group: 0.815, 0.778, and 0.701, respectively). Age, Borrmann classification, and Lauren classification were used to construct the clinical model. Among the radiomics-clinical models, the combined-clinical model showed the highest AUC (training group: 0.960; validation group: 0.843), which significantly improved prediction efficiency.ConclusionThe peritumoral model provided additional value in the evaluation of pathological response after neoadjuvant chemotherapy against advanced gastric cancer, and the combined-clinical model showed the highest predictive efficiency.Critical relevance statementIntratumoral and peritumoral radiomics can noninvasively predict the pathological response against advanced gastric cancer after neoadjuvant chemotherapy to guide early treatment decision and provide individual treatment for patients.Key points1. Radiomics can predict pathological responses after neoadjuvant chemotherapy against advanced gastric cancer. 2. Peritumoral radiomics has additional predictive value. 3. Radiomics-clinical models can guide early treatment decisions and improve patient prognosis.

Dataset Information

Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype.

Publications

Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype.

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