J.O. Park

Moderate Hyperhomocyst(e)inemia Is Associated with the Presence of Coronary Artery Disease and the Severity of Coronary Atherosclerosis in Koreans

To examine whether moderate hyperhomocyst(e)inemia is associated with coronary artery disease and the number of diseased coronary vessels in Koreans, we investigated 201 patients with angiographically documented coronary artery disease and 187 healthy subjects without evidence of stroke and coronary artery disease. The mean plasma total homocysteine in patients was higher than in controls (10.3 micromol/L; 95% confidence interval, 7.0-13.6 vs. 8.9 micromol/L; 6.0-11.8) (p=0.005). The prevalence of moderate hyperhomocyst(e)inemia, defined as the top 90th percentile in controls (13.2 micromol/L), was higher in patients than in controls (23.9% vs. 10.2%, p=0.001). Plasma homocyst(e)ine levels were not correlated to age, body mass index, levels of serum cholesterol, creatinine, and uric acid. Based on multiple logistic regression analyses with adjustment for total cholesterol, hypertension, smoking status, diabetes, age, and body mass index, the adjusted odds ratio of moderate hyperhomocyst(e)inemia for coronary artery disease was 1.53 (95% confidence interval: 1.39-1.65, p=0.0001). Moderate hyperhomocyst(e)inemia, diabetes mellitus, and old age were more prevalent in patients with triple-vessel disease than in single- or double-vessel disease (p=0.02). Multiple logistic regression analysis revealed that moderate hyperhomocyst(e)inemia was a significant predictor of triple-vessel disease with odds ratio of 2.78 (95% confidence interval: 1.08-7.10, p=0.02). We conclude that moderate hyperhomocyst(e)inemia is an independent risk factor for coronary artery disease, and also related significantly to the presence of triple-vessel disease.

719PTUMOUR SHRINKAGE AT 6 WEEKS PREDICTS FAVORABLE CLINICAL OUTCOMES IN A PHASE III STUDY OF GEMCITABINE AND OXALIPLATIN WITH OR WITHOUT ERLOTINIB FOR ADVANCED BILIARY TRACT CANCER

Background: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. Methods: This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. Results: Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p= 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p= 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p< 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p< 0.01) and OS (10.7 vs. 5.8 months, p< 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p< 0.01). Conclusions: ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated.

722PMOLECULAR SUBGROUP ANALYSIS OF CLINICAL OUTCOMES IN A PHASE 3 STUDY OF GEMCITABINE AND OXALIPLATIN WITH OR WITHOUT ERLOTINIB IN ADVANCED BILIARY TRACT CANCER

ABSTRACT Aim: We previously reported that the addition of erlotinib to gemcitabine and oxaliplatin (GEMOX) resulted in greater antitumor activity and might be a treatment option for patients with biliary tract cancers. Molecular subgroup analysis of treatment outcomes in patients who had tumor specimens available for analysis was undertaken. Methods: EGFR, KRAS, and PIK3CA mutations were evaluated using peptide nucleic acid-locked nucleic acid (PNA–LNA) PCR clamp reactions. Survival and response rates were analyzed according to the mutational status. Results: 64 patients (48.1%) were available for mutational analysis in the chemotherapy alone group and 61 (45.1%) in the chemotherapy plus erlotinib group. 1.6% (2/116) harboured an EGFR mutation (2 patients; exon 20), 9.6% (12/121) harboured a KRAS mutation (12 patients; exon 2), and 9.6% (12/118) a PIK3CA mutation (10 patients; exon 9 and 2 patients; exon 20). The addition of erlotinib to GEMOX in patients with KRAS wild type disease (n = 109) resulted in significant improvements in overall response compared with GEMOX alone (30.2% vs. 12.5%, p = 0.024). In 95 patients with both wild type KRAS and PIK3CA, there was evidence of a benefit associated with the addition of erlotinib to GEMOX with respect to response rate (RR) as compared with GEMOX alone (p = 0.04). Conclusions: This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in biliary tract cancers (BTCs). Additionally, the mutation status of PIK3CA may be a determinant for adding erlotinib to chemotherapy in KRAS wild type BTCs. Disclosure: All authors have declared no conflicts of interest.

726PNATURAL HISTORY OF UNTREATED PATIENTS WHO HAD METASTATIC BILIARY TRACT CANCER (BTC) WITH GOOD PERFORMANCE STATUS (PS)

ABSTRACT Aim: Although chemotherapy is widely recommended for patients with metastatic biliary tract cancer (BTC), the natural course of these patients, especially those with good performance status (PS) who are indicated for chemotherapy, is not known. Methods: We retrospectively reviewed patients with metastatic or locally advanced BTC who were examined between January 2005 and September 2013 at six cancer centers. Patients were eligible if they had good PS (Eastern Cooperative Oncology Group score 0-2) and no history of any treatment for cancer. The primary objective was to evaluate the survival time of patients with advanced BTC with good PS who were untreated. Results: Of the 1,677 screened patients, 204 met the inclusion criteria. The median age was 70.1 years and median overall survival (OS) was 7.1 months. OS by disease location was 4.7 months for intrahepatic, 9.7 months for extrahepatic, 4.4 months for gallbladder, and 11.2 months for ampulla of Vater cancer. In subgroup analysis, OS of locally advanced BTC was 13.8 months and that of patients with normal CEA/CA 19-9 was 10.6 months. In multivariate analysis, variables that were associated with poor prognosis were disease extent (metastatic disease) [HR 2.19 (95% CI 1.39-3.45 p = 0.001)], high baseline CEA level (defined as > 4.0 ng/mL) [HR 1.51 (95% CI 1.06-2.17 p = 0.024)], and high baseline CA 19-9 level (defined as > 100 U/mL) [HR 1.93 (95% CI 1.33-2.91 p = 0.001)]. Conclusions: Metastatic BTC with good PS showed modest survival without any treatment for primary cancer. Furthermore, subgroup analysis showed that patients with normal CA19-9 or CEA level or locally advanced status had favorable survival. Further studies comparing the outcome of chemotherapy with that of best supportive care in patients with unresectable BTC are warranted. Disclosure: All authors have declared no conflicts of interest.