TFAP2E-DKK4 and chemoresistance in colorectal cancer.

BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy. METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation. RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism. CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).

The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway.

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/ß-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a ß-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of ß-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy.

Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan-Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.

FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109).

PURPOSE: This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, open-label, phase II trial in patients with untreated RAS wild-type (WT) metastatic colorectal cancer. PATIENTS AND METHODS: The primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI [mFOLFOXIRI] plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival. RESULTS: A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3% v 60.6%; odds ratio, 4.469; 95% CI, 1.61 to 12.38; P = .004). The secondary resection rate was improved with the addition of panitumumab (33.3% v 12.1%; P = .02). Progression-free survival was similar in the study arms, whereas overall survival showed a trend in favor of the panitumumab-containing arm (hazard ratio for death, 0.67; 95% CI, 0.41 to 1.11; P = .12). CONCLUSION: The addition of panitumumab to mFOLFOXIRI in patients with RAS WT metastatic colorectal cancer improved the ORR and rate of secondary resection of metastases and represents a treatment option in selected and fit patients in need of highly active first-line therapy. Future studies should determine whether the addition of panitumumab to mFOLFOXIRI prolongs survival.

[Colorectal liver metastases. Neoadjuvant chemotherapy: aspects of medical and surgical oncology]. / Kolorektale Leberfiliae. Neoadjuvante Chemotherapie aus internistischer und chirurgischer Sicht.

Colorectal liver metastases are detected in 15-20% of patients at the time of diagnosis of the primary tumor, they develop in an additional 20-30% of patients during further course of the disease. Radical resection enables 5-year survival rates of 30-50%. Resectability may be increased by surgical techniques including two-stage hepatectomy and portal vein embolization. Furthermore, modern chemotherapy including various combinations of oxaliplatin, irinotecan, bevacizumab, and cetuximab has led to secondary resectability correlating to response rates which may be up to 80%. Changes of hepatic histology such as sinusoidal obstruction (e.g. following oxaliplatin) or steatohepatitis (e.g. following irinotecan) have been described. Individually, this may increase the risk of subsequent liver resection. As of today the role of neoadjuvant chemotherapy for resectable lesions has not been definitively confirmed.