Dataset Information

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study.

ABSTRACT:

Background

HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors.

Methods

84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2⁺n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2⁺n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value <0.05, adjusted for multiple testing correction.

Results

83 biopsies were eligible for analyses following quality control (TRAP cohort n = 40; control cohort n = 43); there were no significant differences in clinical characteristics between the TRAP vs. control the cohort or HER2 positive vs. HER2 negative biopsies. HER2 expression was found to associate with epithelial markers (EPCAM p < 0.001; E-cadherin p < 0.001). Moreover, HER2 expression was associated with a lower expression of immune cell infiltration, such as NK-cells (p < 0.001) and CD8 T-cells (p < 0.001), but also lower expression of immune exhaustion markers (PDCD1LG2, CTLA4; p < 0.001). In non-responders to anti-HER2 treatment, baseline biopsies showed increased expression of immune exhaustion markers, as well as hypoxia and VEGF signalling.

Discussion

HER2 expression was associated with epithelial tumor characteristics. The HER2 positive TIME showed reduced immune cell infiltration but also lower expression of inhibitory signals associated with immune exhaustion, questioning the mechanism behind potential clinical benefit of co-administration of anti-HER2 agents and checkpoint inhibitors. As limited response was associated with increased VEGF signalling, studies could investigate potential synergism of targeting VEGF and HER2.

SUBMITTER: Stroes CI

PROVIDER: S-EPMC11375138 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study.

Stroes Charlotte I CI Meijer Sybren L SL Creemers Geert-Jan GJ Hooijer Gerrit K J GKJ Mohammad Nadia Haj NH Los Maartje M Slingerland Marije M Hospers Geke A P GAP Cats Annemieke A Beerepoot Laurens V LV Bijlsma Maarten F MF van Laarhoven Hanneke W M HWM

Translational oncology 20240815

<h4>Background</h4>HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors.<h4>Methods</h4>84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2<sup>+</sup>n = 40) and a control cohort with ...[more]

PMID: 39151279

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Project description:Trastuzumab, a monoclonal antibody against HER2, has become standard of care for metastatic HER2-overexpressing esophagogastric adenocarcinoma and is currently investigated as (neo)adjuvant treatment option in HER2-positive esophagogastric adenocarcinoma. The HER2 status is commonly determined on archived material of the primary tumor. However, this status may change over the course of treatment or disease progression. The aim of this study was to assess the dynamics of HER2 status in esophageal adenocarcinoma (EAC) in patients with resectable and recurrent disease, and to determine the associations of these changes with clinical outcome. Discordance, defined as any change in HER2 status between matched biopsy and post-neoadjuvant chemoradiation therapy resection specimen (N = 170), or between matched resection specimen and recurrence of patients not eligible for curative treatment (N = 61), was determined using the standardized HER2 status scoring system. Clinically relevant positive discordance was defined as a change to HER2 positive status, as this would imply eligibility for HER2-targeted therapy. A difference in HER2 status between biopsy and resection specimen and resection specimen and metachronous recurrence was observed in 2.1% (n = 3) and 3.3% (n = 2) of the paired cases, respectively. Clinically relevant discordance was detected in 1.4% (n = 2) of the resectable patients and 1.6% (n = 1) of the patients with recurrent disease. Patients with HER2-positive status tumors before start of neoadjuvant treatment showed better overall survival, but not statistically significant. No association between HER2 status discordance and survival was found. Clinically relevant HER2 status discordance was observed and in order to prevent under-treatment of patients, the assessment of HER2 status in the metastatic setting should preferably be performed on the most recently developed lesions if the previous HER2 assessment on archival material of the primary tumor was negative.

Project description:PurposeApproximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC.Patients and methodsPatients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as ≥ 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score-matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses.ResultsOf the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score-matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on [18F]fluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor-bound protein 7 (Grb7) -positive tumors at baseline demonstrated significantly better survival (P = .007) or treatment response (P = .016), respectively.ConclusionAddition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively.

Project description:Pathological complete response (pCR) after neoadjuvant systemic treatment (NST) is an important prognostic factor in HER2-positive breast cancer. The majority of HER2-positive breast cancers are amplified at the HER2 gene locus, several genes are co-amplified with HER2, and a subset of them are co-expressed. The STARD3 gene belongs to the HER2 amplicon, and its role as a predictive marker was never addressed. The objective of this study was to investigate the predictive value of STARD3 protein expression on NST pathological response in HER2-positive breast cancer. In addition, we studied the prognostic value of this marker.MethodsWe conducted a retrospective study between 2007 and 2020 on 112 patients with non-metastatic HER2-positive breast cancer treated by NST and then by surgery. We developed an immunohistochemistry assay for STARD3 expression and subcellular localization and determined a score for STARD3-positivity. As STARD3 is an endosomal protein, its expression was considered positive if the intracellular signal pattern was granular.ResultsIn this series, pCR was achieved in half of the patients. STARD3 was positive in 86.6% of cases and was significantly associated with pCR in univariate analysis (p = 0.013) and after adjustment on other known pathological parameters (p = 0.044). Performances on pCR prediction showed high sensitivity (96%) and negative predictive value (87%), while specificity was 23% and positive predictive value was 56%. Overall, specific, relapse-free, and distant metastasis-free survivals were similar among STARD3 positive and negative groups, independently of other prognosis factors.ConclusionNST is an opportunity for HER2-positive cancers. In this series of over a hundred HER2-positive and non-metastatic patients, a STARD3-negative score was associated with the absence of pathological complete response. This study suggests that determining STARD3 overexpression status on initial biopsies of HER2-positive tumors is an added value for the management of a subset of patients with high probability of no pathological response.

Dataset Information

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study.

Background

Methods

Results

Discussion

Publications

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study.

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