Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma.

The overall prognosis for operable gastro-oesophageal adenocarcinoma remains poor and therefore neoadjuvant chemotherapy has become the standard of care, in addition to radical surgery. Certain anticancer agents (e.g. anthracyclines and cisplatin) generate damaging reactive oxygen species as by-products of their mechanism of action. Drug effectiveness can therefore depend upon the presence of cellular redox buffering systems that are often deregulated in cancer. The expression of the redox protein, thioredoxin interacting protein, was assessed in gastro-oesophageal adenocarcinomas. Thioredoxin interacting protein expression was assessed using conventional immunohistochemistry on a tissue microarray of 140 adenocarcinoma patients treated by primary surgery alone and 88 operable cases treated with neoadjuvant chemotherapy. In the primary surgery cases, high thioredoxin interacting protein expression associated with a lack of lymph node involvement (p=0.005), no perineural invasion (p=0.030) and well/moderate tumour differentiation (p=0.033). In the neoadjuvant tumours, high thioredoxin interacting protein expression was an independent marker for improved disease specific survival (p=0.002) especially in cases with anthracycline-based regimes (p=0.008). This study highlights the potential of thioredoxin interacting protein as a biomarker for response in neoadjuvant treated gastro-oesophageal adenocarcinoma and may represent a useful therapeutic target due to its association with tumour progression.

Caspase-cleaved cytokeratin-18 and tumour regression in gastro-oesophageal adenocarcinomas treated with neoadjuvant chemotherapy.

AIM: To examine cytokeratin-18 (CK-18) and caspase-cleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade (TRG) response. METHODS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays. The first set consisted of 122 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 97 gastric/gastro-oesophageal cancer cases exposed to pre-operative platinum-based chemotherapy. Expression of CK-18 and caspase-cleaved CK-18 was investigated using immunohistochemistry. RESULTS: CK18 was commonly expressed in gastro-oesophageal tumours (92.6%). Fifty-six point seven percent of tumours previously exposed to neoadjuvant chemotherapy were positive for caspase-cleaved CK-18 expression compared to only 24.6% of tumours not previously exposed to neoadjuvant chemotherapy (P = 0.009). In patients who received neoadjuvant chemotherapy, caspase-cleaved cytokeratin-18 expression correlated with favourable TRG response (TRG 1, 2 or 3, P = 0.043). CONCLUSION: This is the largest study to date of CK-18 and caspase-cleaved CK-18 expression in gastro-oesophageal tumours. We provide the first evidence that caspase-cleaved CK-18 predicts tumour regression with neoadjuvant chemotherapy.

Tumour regression grade (TRG) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. The aims were to validate the utility of the tumour regression grade (TRG) in patients who have received chemotherapy and to investigate if (i) TRG correlates with tumour downstaging and (ii) TRG could provide a comparative platform for future predictive biomarker investigations. METHODS AND RESULTS: Three pathologists were blinded to the treatment approaches. Review included diagnosis, tumour grade, TNM staging, vascular invasion, perineural invasion, resection margin involvement and histopathological response to chemotherapy, as measured by TRG. In the neoadjuvant chemotherapy (CS) group (n = 84), 46.7% of gastric/gastro-oesophageal junction adenocarcinomas, and 45.5% of lower third oesophageal adenocarcinomas had TRG 1, 2 or 3 compared with 13.7% in the primary surgery group (n = 124) (P < 0.001 and P = 0.006, respectively). In the CS group, responders (TRG 1, 2 or 3) showed significant tumour downstaging [early ypT-stage disease (P = 0.002)]. In gastric cancers specifically, additional associations were seen with negative nodal disease (P = 0.044) and absence of vascular invasion (P = 0.027). CONCLUSIONS: TRG may reflect response to chemotherapy. In addition, positive correlations between TRG and ypTNM staging were demonstrated that would suggest tumour downstaging.