CHFR-Promoter-Methylation Status Is Predictive of Response to Irinotecan-based Systemic Chemotherapy in Advanced Colorectal Cancer

Abstract

Background/Aim: We investigated whether promoter methylation of the checkpoint-with-forkhead-andring-finger-domains (CHFR) gene is a predictor of the efficacy of irinotecan-based systemic chemotherapy for advanced colorectal cancer (CRC) patients. Materials and Methods: CHFR-promoter methylation was measured by quantitative methylation-specific PCR (qMSP). The histoculture drug response assay (HDRA) was used in vitro to analyze the correlation between CHFR-promoter methylation and the efficacy of the irinotecan-active-metabolite SN38 in colorectalcancer tissues from 44 CRC patients. CHFR promotermethylation was also analyzed for its correlation with clinical response to irinotecan-based systemic chemotherapy of 49 CRC patients. Results: CHFR-promoter methylation significantly-positively correlated with inhibition of colon cancer by SN38 in the HDRA (p=0.002). CHFR-promoter methylation also significantly-positively correlated with clinical response to irinotecan-based systemic chemotherapy (p=0.04 for disease control). CHFR-promoter methylation also significantly-positively correlated (p=0.01) with increased progression-free survival for patients treated with irinotecan-containing FLOFIRI in combination with bevacizumab, the most-frequent regimen in the cohort. Conclusion: Sensitivity of advanced CRC patients to irinotecan-based systemic chemotherapy can be predicted by the extent of CHFR-promoter methylation.Colorectal cancer (CRC) is the third most-common malignancy and the second-most-frequent cause of cancerrelated mortality worldwide (1). Recent advances in systemic chemotherapy have improved post-operative outcomes in advanced or metastatic CRC (2, 3). The current first-line therapies for unresectable CRC are oxaliplatinum-based and irinotecan-based regimens. The response rates (RR) are approximately 40-60% for these regimens (4, 5), with time to progression (TTP) of 7-8 months and median overall survival (OS) of 14-21 months (6). The two drugs are equivalent in efficacy in this clinical setting (7). Oxaliplatinum causes severe chronic neurotoxicity, which limits the duration of treatment (8). Therefore, irinotecanbased therapy is often preferred for advanced or metastatic CRC. However, there is currently no established biomarker that is predictive of the clinical benefit of irinotecan-based systemic chemotherapy (9).DNA methylation is altered in human cancer as originally discovered by Hoffman et al. (10). DNA methylation is involved in the development and progression of CRC (11,12). DNA methylation of tumor-suppressor genes is useful as a prognostic and susceptibility factor to anti-cancer drugs (13,14). Recently, checkpoint-with-fork-head-and-ringfinger-domains (CHFR)-promoter methylation has been suggested to be associated with favorable treatment 697 This article is freely accessible online.

Use of patient-derived explants as a preclinical model for precision medicine in colorectal cancer: A scoping review

“…Tumour tissue was either processed by mechanical fragmentation or slicing using an instrument such as vibratome or tissue chopper. Subsequently, the explants were maintained either as free-floating cultures or placed on scaffolds such as gelatin or collagen sponges [ 14 , 16 – 35 ], metal grids [ 36 – 43 ], or pore membranes [ 44 – 48 ], with or without agitation. Culture media formulations vary widely among studies but common base media include RPMI 1640 and Dulbecco's Modified Eagle Medium (DMEM), which are often supplemented with foetal bovine serum (FBS) and antibiotics.…”

“…Various immunohistochemical markers including p53 [ 19 ], p21 [ 19 ], and ATP binding cassette subfamily G member 2 (ABCG2) [ 65 ] have been correlated with response to various chemotherapeutic agents. Similarly, there were differential gene expressions of thymidylate synthase (TS) [ 22 , 30 ], DPD & OPRT [ 25 ], amphiregulin (AREG) & epiregulin (EREG) [ 64 ], microRNA 34a (miR-34a) [ 34 ], and checkpoint-with-forkhead-and-ring-finger-domains (CHFR) [ 35 ] between treatment responders and non-responders. Tumours with mismatch repair (MMR) defects were closely correlated with chemosensitivities to combined regimens of PDX101 with 5-FU + leucovorin + oxaliplatin (FLOX) and 5-FU + leucovorin + irinotecan (FLIRI) [ 27 ].…”