Dataset Information

Rad51 expression is a useful predictive factor for the efficacy of neoadjuvant chemoradiotherapy in squamous cell carcinoma of the esophagus.

ABSTRACT:

Background

Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear.

Methods

Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT.

Results

Lymph node metastasis was more frequently observed in Rad51-positive cases than negative cases (58.5 vs. 30.6%, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51-positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3%, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5%, P = 0.0171).

Conclusions

Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT.

SUBMITTER: Nakanoko T

PROVIDER: S-EPMC3929771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long-term survival in oesophageal squamous cell carcinoma (ESCC) is related with pathological response after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. However, effective biomarkers to predict the pathologic response are still lacking. Therefore, a systematic analysis focusing on genes associated with the efficacy of chemoradiotherapy in ESCC will provide valuable insights into the regulation of molecular processes. By screening publications deposited in PubMed, we collected genes associated with the efficacy of chemoradiotherapy. A specific subnetwork was constructed using the Steiner minimum tree algorithm. Survival analysis in Kaplan-Meier Plotter online resources was performed to explore the relationship between gene mRNA expression and the prognosis of patients with ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical staining (IHC) were used to evaluate the expression of key genes in cell lines and human samples. The areas under the receiver operating characteristic (ROC) curves (AUCs) were used to describe performance and accuracy. Transwell assays assessed cell migration, and cell viability was detected using the Cytotoxicity Assay. Finally, we identified 101 genes associated with efficacy of chemoradiotherapy. Additionally, specific molecular networks included some potential related genes, such as CUL3, MUC13, MMS22L, MME, UBC, VAPA, CYP1B1, and UGDH. The MMS22L mRNA expression level showed the most significant association with the ESCC patient outcome (p < 0.01). Furthermore, MMS22L was downregulated at both the mRNA (p < 0.001) and protein levels in tumour tissues compared with that in normal tissues. Lymph node metastasis was significantly associated with low MMS22L expression (p < 0.01). MMS22L levels were inversely correlated with the NCRT response in ESCC (p < 0.01). The resulting area under the ROC curve was 0.847 (95% CI: 0.7232 to 0.9703; p < 0.01). In conclusion, low expression of MMS22L is associated with poor response to NCRT, worse survival, lymph node metastasis, and enhanced migration of tumour cells in ESCC.

Project description:BACKGROUND:Neoadjuvant chemoradiotherapy (CTRT) can effectively downstage esophageal squamous cell carcinoma (SCC) in patients with locally advanced disease and prolonged survival have been observed in patients with a pathological complete response (ypCR). AIMS AND METHODS:This exploratory study aimed to identify immunological predictors of pCR after neoadjuvant CTRT within SCC microenvironment. The tumor regression after neoadjuvant therapy was measured according to the Mandard score system. Eighty-eight consecutive patients with SCC of the thoracic esophagus who received neoadjuvant CTRT were included in this retrospective study. Inclusion criteria were neoadjuvant CTRT and the availability of representative histological samples taken at diagnosis. We investigated immunohistochemical expression of CD4, Tbet, FoxP3, CD8, CD80, PD-L1, and PD-1, in the pretreatment biopsies and correlated the immunohistochemical profiles to patients' outcomes. RESULTS:After neoadjuvant CTRT, 23 patients had pCR, while 65 ones had partial response, stable disease or progression. PD-L1 expression and CD8+ and CD4+ lymphocyte rate were significantly higher in patients who had ypCR compared to those who had not (10 (0-55) vs 0 (0-0), P = 0.004, 73 (36-147) vs 21 (7-47), P = 0.0006 and 39 (23-74) vs 5 (0-13), P < 0.0001 respectively). The accuracy of expression of PD-L1+, CD8+, and CD4+ lymphocyte rate in identifying responders was AUC = 0.76 (P = 0.001), AUC = 0.81 (P = 0.0001) and AUC = 0.75 (P = 0.0001), respectively. Within the ypCR group, all patients with high infiltration of CD4+ T cell recurred/relapsed while only the 38.9% of those with low CD4+ T cell infiltration did the same (P = 0.058). CONCLUSIONS:PD-L1 expression and CD8+ and CD4+ lymphocyte rate were predictive of ypCR after neoadjuvant CTRT for SCC of the thoracic esophagus with adequate accuracy. Furthermore, recurrence/relapse was associated with high level of CD4+ T cell infiltration. However, the small sample size prevented to draw definitive conclusions; further studies are necessary to evaluate the prognostic role of these markers.

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