Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials.

Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. IMPLICATIONS FOR PRACTICE: This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Comparing the clinical outcomes of young-onset and adult-onset ulcerative colitis: a multi-center Korean Association for the Study for Intestinal Diseases study.

BACKGROUND/AIMS: The aim of this study was to compare the clinical features and outcomes of ulcerative colitis (UC) according to the age of onset in Korea. METHODS: A total of 1,141 patients who were diagnosed with UC between July 1987 and November 2013 at 11 tertiary hospitals were enrolled. The baseline disease characteristic and disease state at onset, treatment during the disease course were retrospectively reviewed among patients with young-onset (YO, < 20 years) and adult-onset (AO, ≥ 20 years). Severe outcome was defined as use of intravenous (IV) steroids, infliximab, immunosuppressant, or UC-related operation. RESULTS: There were 55 YO patients (mean age, 17.8 ± 2.4) and 1,086 AO patients (mean age, 43.0 ± 13.6). High Mayo scores (7.7 ± 3.0 vs. 5.6 ± 2.7, p = 0.000), extensive UC (52.7% vs. 25.8%, p = 0.000) and IV steroid (41.8% vs. 18.0%, p = 0.000), immunosuppressant (47.3% vs. 26.9%, p = 0.002), and infliximab (20.0% vs. 7.2%, p = 0.001) use were more frequent in the YO than in the AO group. According to multivariate analysis, severe outcomes were related to YO disease (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.71), body mass index < 23 kg/m2 (HR, 1.46; 95% CI, 1.07 to 2.00), severe (HR, 2.29; 95% CI, 1.36 to 3.38), and moderate (HR, 2.48; 95% CI, 1.67 to 3.67) disease, extensive UC (HR, 2.90; 95% CI, 1.79 to 4.69), UC-related admission (HR, 63.89; 95% CI, 20.41 to 200.02), and oral steroid use (HR, 0.51; 95% CI, 0.39 to 0.67). CONCLUSIONS: UC with YO presented with more advanced clinical features at onset and more severe outcomes than the AO. YO cases require careful management and intense treatment strategies.

The Clinicopathologic Features and Treatment of 607 Hindgut Neuroendocrine Tumor (NET) Patients at a Single Institution.

The clinicopathologic features of hindgut neuroendocrine tumor (NET) as well as the treatment outcomes are not well known. There are currently no published data on treatment outcomes for patients with metastatic hindgut NET. The aim of this study was to conduct a comprehensive analysis of clinicopathologic features, treatments and survival in hindgut NET patients. Among patients who were pathologically diagnosed with hindgut NET at Samsung Medical Center between March 2001 and February 2015, 607 were analyzed in this study. Hindgut NETs were defined as NETs that originated from the transverse and distal colon, rectum, and anus. Primary sites included 81 colon (13.3%) and 526 rectum (86.7%). According to the WHO classification, 578 patients (95.2%) had grade 1 NETs, 17 (2.8%) grade 2 NETs, and 12 (2.0%) had neuroendocrine carcinoma (NEC). Forty-two patients (6.9%) had extensive disease, while the majority (93.1%, 565 patients) only exhibited localized disease. The 5- and 10-year survival rates of 565 localized NET patients were 98.1% and 95.3%, respectively. The median OS in 42 patients with extensive disease was 24.8 months (95% CI, 10.7-38.8). Among 565 patients with localized disease, the majority (484 patients, 85.7%) were treated with endoscopic procedure by gastroenterologists. For 42 patients with extensive disease, 17 patients were managed by supportive care, 3 by concurrent chemoradiotherapy (CCRT), and 22 by systemic therapy. Among these 22 patients, 12 patients received only first-line therapy, 8 had second-line, and only 2 patients had third-line therapy. As first-line chemotherapy, the most commonly used regimens were etoposide plus cisplatin (N = 7) and long acting octreotide (N = 7). During treatment courses, the most commonly used regimen was long-acting octreotide. The median OS in 22 metastatic NET patients receiving systemic therapy was 19.3 months (95% CI, 3.2-35.3). Multivariate analysis in all 607 hindgut NETs patients suggested that the extent and the primary site of disease were significant independent prognostic factors for long term survival. This analysis provides useful information about the clinicopathologic features, treatments and survival outcomes for hindgut NET patients.

Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study.

BACKGROUND: Although a rising trend in the incidence of inflammatory bowel disease (IBD) in Asia has been recognized, national-level, population-based studies are lacking. In this study, we investigate the epidemiological features and natural course of IBD in Korea, including incidence, bowel resection rates, survival, and cause of death. METHODS: We analyzed the Rare Intractable Disease registration and Health Insurance Review and Assessment Services claims database, which include information on every patients with IBD diagnosed through uniform criteria from 2006 to 2012. Twenty-seven thousand four hundred nineteen patients with IBD newly diagnosed from 2006 to 2012 were traced to bowel resection, survival, and cause of death. RESULTS: During study period, mean annual incidence for ulcerative colitis was 4.6 per 10 and for Crohn's disease (CD) was 3.2 per 10. Bowel resection rates at 1 and 5 years for patients with ulcerative colitis were 0.8% and 2.1%, respectively, and for patients with CD were 5.0% and 9.1%, respectively. Survival of patients with CD was lower than that of the general population, whereas patients with ulcerative colitis had similar survival. In patients with CD, mortality for colon cancer, lung cancer, and gastrointestinal disease was significantly increased compared with general population. CONCLUSIONS: Incidence of IBD found in our study is the highest in East Asia. Lower bowel resection rates and higher survival compared to those of Western nations suggest that the natural course of IBD may be different between East Asia and the West.

NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line.

BACKGROUND: We have investigated the incidence of NTRK1 rearrangements in metastatic gastrointestinal cancer patients and demonstrated the potential for clinical response of these patients to targeted therapy. METHODS: We prospectively collected tumor tissue specimens for one year and simultaneously generated patient-derived tumor cells (PDCs). Specimens were initially screened for TrkA protein expression using TrkA immunohistochemistry (IHC). In the case of TrkA IHC positive results, samples were further examined by fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) to confirm the presence of NTRK1 rearrangements. RESULTS: From January 2014 to December 2014, a total of 74 metastatic colorectal cancer (CRC) patients and 66 gastric cancer (GC) patients were initially screened by TrkA IHC. Two of the 74 CRC patients (2.7%) and one of the 66 GC patients (1.5%) were positive for TrkA expression by IHC. All three IHC positive cases had evidence of NTRK1 rearrangements by FISH. NGS was performed on the 3 IHC positive cases and confirmed TPM3-NTRK1 rearrangements in the two CRC cases. One GC patient with TrkA expression by IHC did not harbor an NTRK1 rearrangement. PDCs established from the NTRK1 positive CRC patients were positive for the NTRK1 rearrangement. Entrectinib, a pan-TRK inhibitor, profoundly inhibited cell proliferation of NTRK1-rearranged PDCs with such inhibition associated with inactivation of TrkA, and down-regulation of downstream signaling pathways. CONCLUSIONS: TrkA IHC is an effective, initial screening method for NTRK1 rearrangement detection in the clinic. Inhibition of the TrkA kinase is a promising targeted therapy for cancer patients whose tumors harbor a NTRK1 rearrangement.

The NEXT-1 (Next generation pErsonalized tX with mulTi-omics and preclinical model) trial: prospective molecular screening trial of metastatic solid cancer patients, a feasibility analysis.

We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.

Predictive factors of complementary and alternative medicine use for patients with inflammatory bowel disease in Korea.

OBJECTIVES: The aim of this study was to assess characteristics and predictive factors of complementary and alternative medicine (CAM) use for patients with inflammatory bowel disease (IBD) in Korea. DESIGN: Prospective, questionnaire based study for patients with IBD in Korea. SETTING: Six university hospitals and one primary IBD clinic. MAIN OUTCOME MEASURE: Overall characteristics and predictors of CAM use were compared between CAM users and non-users. RESULTS: During the study period, 366 patients with IBD (ulcerative colitis=228, Crohn's disease=138) completed the full questionnaire; 29.5% (n=108) reported CAM use and 70.5% (n=258) reported no CAM use after diagnosis of IBD. In total, 64.0% were male, the mean patient age was 42.3±15.5 years, and the mean duration of IBD was 5.5±5.8 years. Using logistic regression analysis, university education (p=0.040), higher income levels (p=0.009), and longer duration of IBD (p=0.003) were found to be independent predictors of CAM use. Among CAM users, 65% of CAM was attained within 2 years of IBD diagnosis and only 28.7% discussed CAM use with their physician. Furthermore, 13.9% of CAM users discontinued conventional IBD therapy while using CAM. CONCLUSIONS: The overall use of CAM in Korea was comparable with those in the West. Physicians should be aware of the high prevalence of CAM use by patients with IBD, especially among those with higher education levels, higher income levels, and longer IBD duration. Furthermore, physicians should ask about CAM use, and help their IBD patients make a more informed choice about CAM use.