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Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

ABSTRACT: Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

SUBMITTER: M Naeini M

PROVIDER: S-EPMC10232490 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

M Naeini Marjan M Newell Felicity F Aoude Lauren G LG Bonazzi Vanessa F VF Patel Kalpana K Lampe Guy G Koufariotis Lambros T LT Lakis Vanessa V Addala Venkateswar V Kondrashova Olga O Johnston Rebecca L RL Sharma Sowmya S Brosda Sandra S Holmes Oliver O Leonard Conrad C Wood Scott S Xu Qinying Q Thomas Janine J Walpole Euan E Tao Mai G G Ackland Stephen P SP Martin Jarad J Burge Matthew M Finch Robert R Karapetis Christos S CS Shannon Jenny J Nott Louise L Bohmer Robert R Wilson Kate K Barnes Elizabeth E Zalcberg John R JR Mark Smithers B B Simes John J Price Timothy T Gebski Val V Nones Katia K Watson David I DI Pearson John V JV Barbour Andrew P AP Waddell Nicola N

Nature communications 20230531 1

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall surviv ...[more]

PMID: 37258531

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Project description:Background Less than 20 % of patients with resectable oesophageal adenocarcinoma obtain a pathological response following neoadjuvant chemotherapy. Studies using oesophageal cancer cell lines have shown that drug sensitive tumour cells undergo apoptosis in response to drug treatment, whereas resistant cells induce autophagy and can recover following withdrawal of drug. In this study, we evaluated markers of apoptosis (active/cleaved caspase-3) and autophagy (LC3B) to establish whether these markers are useful prognostic indicators following neoadjuvant therapy. Methods Oesophageal adenocarcinoma tumour tissue from the Northern Ireland Biobank at Queens University Belfast was examined retrospectively. Tumours from 144 patients treated with platinum-based neoadjuvant chemotherapy followed by surgical resection were assembled into tissue microarrays prior to immunohistochemical analysis. Kaplan-Meier survival curves and log-rank tests were used to assess the impact of cleaved caspase-3 and LC3B expression on survival. Cox regression was used to examine association with clinical risk factors. Results High levels of cleaved caspase-3 were found in 14.6 % of patients and this correlated with a significantly better overall survival (p = 0.03). 38.9 % of patients had high cytoplasmic LC3B expression, which correlated with poor overall survival (p = 0.041). In addition, a distinct globular pattern of LC3B expression was identified in 40.3 % of patients and was also predictive of overall survival (p < 0.001). LC3B globular structures are also associated with tumour recurrence (p = 0.014). When these markers were assessed in combination, it was found that patients who showed low/negative cleaved caspase-3 staining and high/positive staining for both patterns of LC3B had the worst overall survival (p < 0.001). Multi-variate analysis also indicated that this marker combination was an independent predictor of poor prognosis (p = 0.008; HR = 0.046, 95% CI = (0.005-0.443). Conclusions The expression of cleaved caspase-3 and specific LC3B staining patterns are associated with overall survival following neoadjuvant treatment. The combination of these markers is an independent indicator of outcome in neoadjuvant chemotherapy treated oesophageal adenocarcinoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09981-8.

Project description:BackgroundNeoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC.MethodsClinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided.ResultsTwo hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival.ConclusionsNeoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.

Project description:BackgroundThere are few data evaluating the extent of downstaging in patients with oesophageal adenocarcinoma and oesophageal squamous cell carcinoma and the difference in outcomes for a similar pathological stage in neoadjuvant-naive patients. The aim of this study was to characterize the prognostic value of downstaging extent in patients receiving neoadjuvant therapy for oesophageal cancer.MethodsOesophageal adenocarcinoma and oesophageal squamous cell carcinoma patients receiving either neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy between 2004 and 2017 were identified from the National Cancer Database. The extent of downstaging was defined as the extent of migration between groups (for example stage IVa to IIIb = one stage). Cox multivariable regression was used to produce adjusted models for downstaging extent.ResultsOf 13 594 patients, 11 355 with oesophageal adenocarcinoma and 2239 with oesophageal squamous cell carcinoma were included. In oesophageal adenocarcinoma, patients with downstaged disease by three or more stages (hazards ratio (HR) 0.40, 95 per cent c.i. 0.36 to 0.44, P < 0.001), two stages (HR 0.43, 95 per cent c.i. 0.39 to 0.48, P < 0.001), or one stage (HR 0.57, 95 per cent c.i. 0.52 to 0.62, P < 0.001) had significantly longer survival than those with upstaged disease in adjusted analyses. In oesophageal squamous cell carcinoma, patients with downstaged disease by three or more stages had significantly longer survival than those with less downstaged disease, no change, or upstaged disease. Patients with downstaged disease by three or more stages (HR 0.55, 95 per cent c.i. 0.43 to 0.71, P < 0.001), two stages (HR 0.58, 95 per cent c.i. 0.46 to 0.73, P < 0.001), or one stage (HR 0.69, 95 per cent c.i. 0.55 to 0.86, P = 0.001) had significantly longer survival than those with upstaged disease in adjusted analyses.ConclusionThe extent of downstaging is an important prognosticator, whereas the optimal neoadjuvant therapy remains controversial. Identifying biomarkers associated with response to neoadjuvant regimens may permit individualized treatment.

Dataset Information

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Publications

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

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