Jun Ho Ji

Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer

The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5’ fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.

Metabolic response evaluated by 18F-FDG PET/CT as a potential screening tool in identifying a subgroup of patients with advanced non-small cell lung cancer for immediate maintenance therapy after first-line chemotherapy

PurposeAmong patients with advanced non-small cell lung cancer (NSCLC), identification of a subgroup of patients for immediate maintenance treatment after first-line chemotherapy has great importance in improving survival. The purpose of this study was to investigate whether the metabolic responses evaluated by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) may be a potential screening tool for identifying patients with early disease progression who may benefit from immediate maintenance treatment.MethodsA total of 52 patients with advanced NSCLC (36 men and 16 women, mean age 57.2u2009±u200910.6xa0years) who underwent baseline and follow-up 18F-FDG PET/CT after four cycles of first-line chemotherapy were enrolled. Maximum standardized uptake value (SUVmax), SUVpeak, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of the tumour lesions were measured and percentage decrease of the parameters was calculated. The prognostic significance of percentage decrease of these parameters and other clinical variables related to progression-free survival (PFS) and overall survival (OS) were assessed by Cox proportional hazards regression analysis. Receiver-operating characteristic (ROC) curve analysis was used to define the optimal cut-off value of percentage decrease of the parameters that could distinguish between early (PFSu2009<u20096xa0months) and late (PFSu2009≥u20096xa0months) disease progression groups.ResultsMultivariate analysis showed that percentage decrease of TLG [hazard ratio per 10xa0% decreaseu2009=u20091.030, 95xa0% confidence interval (CI)u2009=u20091.012–1.048, pu2009=u20090.001) was a significant predictor of PFS and OS. ROC curves identified a 50.0xa0% decrease in TLG as the optimal cut-off value to distinguish disease progression groups. Positive and negative predictive values of the optimal TLG value for selecting patients with late disease progression were 36.4 and 100.0xa0%, respectively.ConclusionThe percentage decrease in TLG of measurable tumour lesions may be a potential parameter to appropriately identify a subgroup of patients for immediate maintenance treatment after first-line chemotherapy in patients with advanced NSCLC.

The impact of baseline and interim PET/CT parameters on clinical outcome in patients with diffuse large B cell lymphoma.

Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification in patients with aggressive non-Hodgkins lymphoma (NHL). Here, we analyzed the predictive value of various PET/CT parameters in patients with DLBCL. Particularly, we were interested in patients with an IPI score of 1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb 2010, a total of 100 patients (including 57 patients with an IPI score of 1-3) who were treated with R-CHOP for DLBCL, and had assessable PET/CT parameters were analyzed in this study. Absolute value of SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta) from baseline and interim PET/CT, and ΔSUVsum, ΔSUVmax, and ΔTLGsum between baseline and interim PET/CT were selected as PET/CT parameters. The median number of R-CHOP cycles was 6, and interim PET/CT was performed after 2 or 3 cycles. None of the parameters which showed percentile change between initial and interim PET/CT were associated with prognosis. Instead, absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to PFS in all patients, and in patients with an IPI score of 1–3.

Prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver-only metastasis

PurposeLiver resection may offer the only chance of cure in patients with colorectal cancer with liver metastases. In the unresectable cases, neoadjuvant chemotherapy could render curability if resectability could be achieved.MethodsNewly diagnosed K-RAS wild-type colorectal cancer patients with unresectable liver-only metastases were treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) plus cetuximab every 2xa0weeks for a maximum of 12 cycles. Clinical response was evaluated every 6xa0weeks, and surgery was performed at the physician’s discretion in patients with sufficient tumor shrinkage, followed by chemotherapy with the same regimen, to complete a total of 12 cycles. The primary endpoint was an overall R0 resection rate.ResultsBetween July 2008 and December 2009, 73 patients were registered from 11 Korean centers. Among 53 (73xa0%) patients who showed at least partial response, surgery with curative intent was attempted in 36 (49xa0%) patients. Intention-to-treat analysis revealed a R0 resection rate of 27xa0% (20/73) including 8 patients whose unresectable liver metastases were successfully treated with radiofrequency ablation (RFA). The most common grade 3 and 4 toxicity was neutropenia (50/462 cycles, 10.7xa0%). Median time to progression (TTP) was 9.8xa0months (range 0.5–31.8) in all patients, but we observed TTP of 14.1xa0months (range 1.3 to −30.8) in patients who received R0 resection and RFAxa0+xa0R0 resection.ConclusionsNeoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increased the resectability in colorectal patients with non-resectable liver-only metastases.

Small cell lung cancer detection in never-smokers: clinical characteristics and multigene mutation profiling using targeted next-generation sequencing

BACKGROUNDnOnce regarded as a smokers disease, small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers.nnnPATIENTS AND METHODSnPatients diagnosed with SCLC were grouped into smokers and never-smokers. The clinical outcomes of the two groups were compared. For SCLC in never-smokers, somatic mutation profiling was carried out using the AmpliSeq™ Cancer Hotspot Panel v2 and semiconductor sequencing technology. Epidermal growth factor receptor (EGFR) mutation was confirmed by PNAClamp™.nnnRESULTSnIn total, 391 SCLC patients treated over a 5-year period were analyzed. Fifty patients (13%) were never-smokers. The median overall survival was 18.2 months in never-smokers and 13.1 months in smokers (P = 0.054). Never-smoking history was independently a good prognostic factor [hazard ratio = 0.645, 95% confidence interval (CI) 0.456-0.914], as were limited disease (HR = 0.372, 95% CI 0.294-0.471), and lower age (HR = 0.709, 95% CI 0.566-0.888). The objective response rates to first-line etoposide/cisplatin therapy were similar between never-smokers and smokers (75% versus 81%). Of 28 genetically evaluable never-smokers, EGFR mutations were detected in four cases (two L858R, one deletion in exon 19, and one G719A). Other mutations were in TP53 (n = 26), RB1 (n = 7), PTEN (n = 5), MET (n = 4), and SMAD4 (n = 3).nnnCONCLUSIONSnNever-smokers with SCLC are increasingly prevalent and have a better prognosis than smokers with SCLC in Korea. Our study warrants further investigation in this group.BACKGROUNDnOnce regarded as a smokers disease, small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers.nnnPATIENTS AND METHODSnPatients diagnosed with SCLC were grouped into smokers and never-smokers. The clinical outcomes of the two groups were compared. For SCLC in never-smokers, somatic mutation profiling was carried out using the AmpliSeq™ Cancer Hotspot Panel v2 and semiconductor sequencing technology. Epidermal growth factor receptor (EGFR) mutation was confirmed by PNAClamp™.nnnRESULTSnIn total, 391 SCLC patients treated over a 5-year period were analyzed. Fifty patients (13%) were never-smokers. The median overall survival was 18.2 months in never-smokers and 13.1 months in smokers (P = 0.054). Never-smoking history was independently a good prognostic factor [hazard ratio = 0.645, 95% confidence interval (CI) 0.456-0.914], as were limited disease (HR = 0.372, 95% CI 0.294-0.471), and lower age (HR = 0.709, 95% CI 0.566-0.888). The objective response rates to first-line etoposide/cisplatin therapy were similar between never-smokers and smokers (75% versus 81%). Of 28 genetically evaluable never-smokers, EGFR mutations were detected in four cases (two L858R, one deletion in exon 19, and one G719A). Other mutations were in TP53 (n = 26), RB1 (n = 7), PTEN (n = 5), MET (n = 4), and SMAD4 (n = 3).nnnCONCLUSIONSnNever-smokers with SCLC are increasingly prevalent and have a better prognosis than smokers with SCLC in Korea. Our study warrants further investigation in this group.

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

PurposeThe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.MethodsWe retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.ResultsAmong 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4xa0%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (nxa0=xa06) or erlotinib (nxa0=xa06). The most common mutation was exon 19 deletion (nxa0=xa07). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75xa0%, respectively. The median PFS was 3.67xa0months (95xa0% CI: 1.34–5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53xa0months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83xa0months) who were treated with EGFR TKIs.ConclusionsThe results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.

Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma

BackgroundThe optimal treatment strategy for cholangiocarcinoma (CC) after curative resection remains controversial. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal CC.MethodsWe retrospectively reviewed the medical records of patients who underwent R0 resection for distal CC at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of the study were overall survival (OS) and recurrence-free survival (RFS).ResultsA total of 158 patients were included in the analysis; 47 patients (29.7xa0%) had lymph node involvement. Fifty-six patients (35.4xa0%) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (Pxa0<xa00.001), T3/T4 disease (Pxa0=xa00.009), positive lymph nodes (LN; Pxa0=xa00.052), and elevated baseline carbohydrate antigen 19-9 (Pxa0=xa00.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to treatment modality. A multivariable analysis showed a significant improvement in OS after CT [hazard ratio (HR) 0.21, 95xa0% confidence interval (CI) 0.08–0.53, Pxa0=xa00.001] and CRT (HR 0.25, 95xa0% CI 0.08–0.83, Pxa0=xa00.024). However, RT alone was associated with shorter OS (HR 2.38, Pxa0=xa00.040), along with T3/T4 disease (HR 2.12, Pxa0=xa00.012) and positive LN (HR 2.30, Pxa0=xa00.008). RFS benefited from adjuvant treatment with CT (HR 0.34, Pxa0=xa00.002) and CRT (HR 0.33, Pxa0=xa00.004), but not with RT alone (HR 1.42, Pxa0=xa00.361). In the subset analysis according to LN status, adjuvant therapy not including RT alone was associated with a significant OS and RFS advantage in both LN-negative and LN-positive patients.ConclusionsOur results show that patients receiving CT or CRT had significant improvements in OS and RFS. In addition, a benefit of adjuvant therapy (except RT alone) was observed even in LN-negative patients.

A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer

OBJECTIVESnMore than half of cases of gastric cancer (GC) are diagnosed in elderly patients (≥70years). While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in advanced GC, the main goal of chemotherapy remains palliation.nnnMATERIALS AND METHODSnIn a multi-center phase III trial, patients with chemotherapy-naïve, metastatic GC, aged 70years or older were randomized 1:1 to receive X monotherapy (capecitabine 1000mg/m2 bid po on days one to fourteen) or XELOX (X plus oxaliplatin 110mg/m2 iv on D1). Treatment was repeated every 21days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was overall survival (OS).nnnRESULTSnIn total, 50 patients with a median age of 77 (range, 70 to 84) were enrolled (X, n=26; XELOX, n=24). No treatment-related serious adverse events or unexpected toxicities were observed. The most frequently observed toxicities were nausea and hand-foot syndrome, with fatigue and peripheral neuropathy more common in XELOX than in X patients. Median OS was 11.1months for XELOX arm and 6.3months for X arm (HR 0.58, 95% CI 0.30-1.12, P=0.108). Although the difference was not significant, on the basis of evidence of superiority of XELOX seen in the first interim analysis, an independent data monitoring committee recommended early stopping of the trial. PFS was significantly longer (HR 0.32, 95% CI 0.17-0.61, P<0.001) with XELOX (7.1months) than with X (2.6months).nnnCONCLUSIONnPlatinum-based combination chemotherapy was associated with survival benefit, as compared with X monotherapy in elderly patients with GC.

A Retrospective Analysis for Patients with HER2-Positive Gastric Cancer Who Were Treated with Trastuzumab-Based Chemotherapy: In the Perspectives of Ethnicity and Histology.

Purpose While the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy. Materials and Methods Data of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively. Results A total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025). Conclusion While subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer.

Intrinsic resistance to sunitinib in patients with metastatic renal cell carcinoma

Although targeting angiogenesis with vascular endothelial growth factor receptor (VEGFR) inhibitors has demonstrated efficacy in the treatment of renal cell carcinoma, primary, intrinsic resistance to the VEGFR inhibitor sunitinib is not fully understood in a subset of metastatic RCC (mRCC) patients.