The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P=0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P=0.0061) and p53-phospho (P=0.0064). Expression of p53 correlated with expression of p53-phospho (P<0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma

The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy±surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC