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Purpose Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. Materials and Methods In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted nextgeneration sequencing platform which included 106 genes. Results A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of -31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of = 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. Conclusion Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to evaluate treatment response to neoadjuvant chemoradiotherapy (CRT) with regard to mucin status in pathology and pretreatment magnetic resonance imaging (MRI) in locally advanced rectal cancer. Materials and Methods Between 2003 and 2011, 306 patients with locally advanced rectal cancer received neoadjuvant CRT followed by surgery, and mucinous adenocarcinoma (MAC) was found in 27 (8.8%). All MAC patients had MRI before and after CRT and mucin proportion at MRI was measured. Therapeutic response was assessed by pathology after total mesorectal excision. To determine the optimal cut-off for mucin proportion in predicting good CRT response (near total or total regression) and negative circumferential resection margin (CRM), the receiver operating characteristic analysis was performed. Results After neoadjuvant CRT, overall downstaging occurred in 44.4% of MAC and 72.4% of non-MAC (p=0.001), and positive CRM (≤ 1 mm) was observed more frequently in MAC (p < 0.001). The optimal threshold for treatment response was 30% for mucin proportion, and there are nine with low mucin proportion (< 30%) and 18 with high mucin proportion (≥ 30%) in pretreatment MRI. Negative CRM and tumor downstaging occurred more common in patients with mucin < 30%, although statistically insignificant (p=0.071 and p=0.072, respectively). Regarding oncologic outcomes, lower mucin proportion in pretreatment MRI was associated with better disease-free and overall survival in MAC group (p=0.092 and 0.056, respectively), but the difference did not reach statistical significance. Conclusion Poor treatment outcome with neoadjuvant CRT was observed in patients with MAC, especially those with high mucin proportion at pretreatment MRI. [ABSTRACT FROM AUTHOR]

Purpose This study was conducted to validate the prognostic influence of treatment response among patients with positive circumferential resection margin for locally advanced rectal cancer. Materials and Methods Clinical data of 197 patients with positive circumferential resection margin defined as P 2 mm after preoperative chemoradiotherapy followed by total mesorectal excision between 2004 and 2009 were collected for this multicenter validation study. All patients underwent median 50.4 Gy radiation with concurrent fluoropyrimidine based chemotherapy. Treatment response was dichotomized to good response, including treatment response of grade 2 or 3, and poor response, including grade 0 or 1. Results After 52 months median follow-up, 5-year overall survival (OS) for good responders and poor responders was 79.1% and 48.4%, respectively (p < 0.001). In multivariate analysis, circumferential resection margin involvement and treatment response were a prognosticator for OS and locoregional recurrence-free survival. In subgroup analysis, good responders with close margin showed significantly better survival outcomes for survival. Good responders with involved margin and poor responders with close margin shared similar results, whereas poor responders with involved margin had worst survival (5-year OS, 81.2%, 57.0%, 50.0%, and 32.4%, respectively; p < 0.001). Conclusion Among patients with positive circumferential resection margin after preoperative chemoradiotherapy, survival of the good responders was significantly better than poor responders. Subgroup analysis revealed that definition of positive circumferential resection margin may be individualized as involvement for good responders, whereas ≤2 mm for poor responders. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to colorectal cancer incidence in Korea.

Purpose Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. Materials and Methods We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. Results Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models. Conclusion In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations. [ABSTRACT FROM AUTHOR]

Purpose The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. Materials and Methods Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. Results The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-- period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). Conclusion Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea. [ABSTRACT FROM AUTHOR]