Expressions of 10 genes as candidate predictors of recurrence in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Approximately 30% patients with stage III colon cancer (CC) develop local recurrence and/or distant metastasis, even if postoperative adjuvant chemotherapy with oxaliplatin plus 5-fluorouracil and leucovorin (5-FU/LV) has been completed. In the present study, molecular analysis was performed to identify molecular markers of tumor recurrence in patients with stage III CC receiving oxaliplatin-based adjuvant chemotherapy. The FACOS study was conducted as a phase II study to evaluate the safety and efficacy of oxaliplatin-based treatment for stage III CC patients. Of the 132 CC patients enrolled in the present study, gene expression analysis using a microarray was conducted in 51 patients. Of these 51 patients, 6 developed recurrence within 5 years. The topmost 5% genes that showed differential expressions between cases that developed/did not develop recurrence were selected, and a set of predictive molecular markers for recurrence was identified. Of the 34,694 genes in the microarray, 1,734 genes were extracted as topmost 5% genes showing differential expressions between cases with and without recurrence. Among these, 10 genes, includingADH1A, ADH1C, CA12, CHP2, HMGCS2, SNAR-A1, TPI1, MS4A12, PLA2G10 and PTPRO, were identified as markers that could clearly divide patients with and without recurrence. Although several prediction models of tumor recurrence have been reported for CC, the set of 10 genes that the present study identified may be useful to predict the risk of recurrence in stage III CC patients receiving oxaliplatin-based adjuvant chemotherapy. Based on these results, high-risk patients with CC should be carefully observed to detect tumor recurrence during the follow-up period.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

Involvement of ABC transporters in chemosensitivity of human renal cell carcinoma, and regulation of MRP2 expression by conjugated bilirubin.

In this study, the involvement of ATP-binding cassette (ABC) transporters in in vitro chemosensitivity of surgically removed human renal cell carcinomas was investigated. The relative expression levels of transporter mRNAs in the renal tumors from 13 patients were similar to those in the surrounding normal kidney tissues. Five renal cell carcinomas cultured successfully in vitro for 14 days showed significantly decreased expression of multi-drug resistance-associated proteins 2 and 6 (MRP2 and MRP6) mRNAs. In vitro chemosensitivity testing of the same specimens using the collagen-gel matrix assay indicated that some anticancer drugs were effective, especially cisplatin, which is an MRP2 substrate. MRP2 mRNA expression in renal carcinoma was significantly increased when cells were cultured in the presence of conjugated bilirubin. In an established renal proximal tubule epithelial cell line (RPTEC), conjugated bilirubin increased MRP2 expression at the mRNA and protein levels, and decreased the cisplatin sensitivity of the cells. These results indicate that MRP2 expression in renal cell carcinoma may be regulated by conjugated bilirubin in the body and decreased during in vitro culture. Thus, the effectiveness of anticancer drugs selected on the basis of in vitro chemosensitivity testing of clinical cancers may be overestimated.