Citations

508 Background: Severe adverse events (AEs) to 5-fluorouracil (5-FU) constitute a major dilemma in CC treatment. We recently demonstrated that specific deleterious DPYD variants in the coding region were highly predictive of grade >3 (G3+) AEs in stage III CC pts receiving adjuvant 5-FU based combination chemotherapy [Lee et al. JNCI. In press]. Other studies have suggested potential associations between AEs and non-coding DPYD variants: a novel haplotype (HapB3) containing three intronic variants (c.483+18 G>A, c.680+139 G>A, and c.959-51 T>C), one synonymous variant (c.1236 G>A, E412E), and a deep intronic variant (c.1129-5923 C>G) that affects pre-mRNA splicing. However, these studies included a diversity of cancer types, stages and treatments. The findings require further evaluation in a refined population. Methods: A total of 2,134 Caucasian stage III CC pts without DPYD*2A, D949V, and I560S variants from NCCTG N0147 trial who received adjuvant FOLFOX or FOLFIRI +/- cetuximab were genotyped by multiplexed single-base extension assays on the Sequenom MassARRAY. G3+ AEs were recorded (CTCAE v3) and classified as common to 5-FU treatment (5FU-AEs). Logistic regressions were used to assess the univariate and multivariate associations. Results: Analyzed pts displayed the following characteristics: 54.3% male, median age 59 [19-85], proficient MMR 87.5%, PS-0 76.5%, + irinotecan 8.5%, and + cetuximab 46.5%. Pts carrying c.1129-5923 C>G were significantly associated with higher risk of G3+ 5FU-AEs (Odds Ratio [OR]=1.539, 95% confidence interval [CI]=1.001 – 2.367, p=0.049). Only marginal association was observed for one of the HapB3 variants, c.1236 G>A (p=0.058). A linearly increasing risk of G3+ 5FU-AEs was identified for HapB3, comparing pts with no, one or >1 variant present (unadjusted OR=1.539, 95% CI=1.001 – 2.367, p=0.041; adjusted OR=1.198, 95% CI=0.998-1.437, p=0.052). Conclusions: In the largest study to date, c.1129-5923 C>G and HapB3 were predictive of 5FU-AE risk in stage III CC patients without DPYD*2A, D949V, and I560S variants receiving 5-FU-based combination chemotherapy.

383 Background: Sorafenib was approved by FDA for treatment of advanced unresectable hepatocellular carcinoma (HCC) patients in November 2007. In this study, we update survival trends in advanced HCC using Surveillance, Epidemiology, and End Results (SEER) data. Methods: We selected patients with advanced HCC diagnosed from January 2001 to December 2010 from SEER 18 registries. We excluded diagnosed at autopsy, from death certificate only, or those without survival date. We calculated 1- and 2- year relative survival rates in pre-sorafenib (2001-2007) and post-sorafenib (2008-2010) era by age, sex and ethnicity among using SEER*stat software. Results: The total number of advanced HCC patients during 2001-2010, 2001-2007 and 2008-2010 were 5,092, 2,747 and 2,345 respectively. The 1- and 2- year survival rates of patients improved significantly from pre-sorafenib era to post-sorafenib era (1 year RS: 17.20±0.7% to 19.90±0.80%, Z=2.63; 2 year RS: 8.00±0.5% to 8.7±0.60%, Z=2.31). Survival rates of male patients improved significantly in post-sorafenib era (1 year RS: 16.4±0.80 to 19.4±0.90%, Z=2.18; 1 year RS: 7.4±0.60% to 8.6±0.70%, Z=2.18). There was no improvement in survival rates of female patients. Similarly, younger patients had improvement in survival rates in post-sorafenib era compared to pre-sorafenib era (1 year Z value 2.46; 2 year Z value 2.23). There was no improvement in survival rates of older patients. Conclusions: Since FDA approval of sorafenib, survival rates of patients with advanced hepatocellular carcinoma have improved. The improvement in survival rates is limited to males and younger patients

347 Background: 9,704 was the first phase 3 pancreatic cancer trial to validate the prognostic value of postresection CA19-9 for overall survival (OS), with values > 90/180 associated with worse OS. All pts received adjuvant gemcitabine or 5-FU and chemo-radiotherapy (RT). This analysis evaluates patterns of disease failure. Methods: SMS was negative, positive, or unknown. CA19-9 was analyzed at cut points 90, 180 and continuously. LRF and DF were estimated by cumulative incidence and Gray’s test compared. Cox hazard models were used for multivariate analyses (MVA) and included treatment, tumor site, size and nodal status. To adjust for multiple comparisons a p-value < 0.01 is statistically significant and 0.01 to < 0.05 a trend. Results: 538 pts accrued, with 451 eligible and analyzable for SMS and 385 for CA19-9. For CA19-9, 132 (34%) were Lewis Antigen negative (no CA19-9 expression), 200 (52%) < 90 and 220 (57%) < 180. 188 (42%) had negative margins, 152 (34%) positive and 111 (25%) unknown (i.e., no margin comment in path report; shown to have outcomes similar to negative margin pts). Pts with CA19-9 ≥ 180 were more likely to have tumors ≥ 3 cm and pts with positive SMS more likely to have KPS 60 - 80, T3/T4, or N1 disease. On univariate analysis (UVA) CA19-9 cut at 90 was associated with significant increases in both LRF (trend) and DF; in the gemcitabine arm this was seen in DF, not in LRF; in the 5-FU arm it was seen in both. Results were similar at the 180 cut point and continuously. SMS on UVA was not associated with increase in LRF/DF; see Table. On MVA, CA19-9 > 90 was significantly associated with LRF and DF; positive SMS showed only a trend for DF. Conclusions: Postresection CA19-9 has significant association with both LRF and DF not seen with SMS. These findings support continued use of RT in trials and consideration of dose intensification among pts with elevated postresection CA19-9. Grants: NCI U10, CA21661, CA37422, CA180868, CA180822. Clinical trial information: 0000000. [Table: see text]

211 Background: The current standard of care for locally advanced esophageal cancer includes chemoradiotherapy with or without surgery. Radiation is usually delivered via a 3D technique. IMRT has been utilized in the treatment of multiple tumors and demonstrated similar efficacy while offering the possibility of decreased toxicity. Methods: Thirty-six patients were treated with IMRT and chemotherapy. Twenty-one patients underwent surgical resection. Eleven underwent open surgery and the remainder underwent minimally invasive surgery. Chemotherapy consisted primarily of 5-FU with oxaliplatin or cisplatin. All but two patients received 50.4 Gy; one patient received 41.4 Gy without surgery and one patient discontinued treatment after 25.2 Gy. Eleven patients required a treatment break during radiotherapy. The median age was 69 (range 46-87). Approximately two-thirds of tumors were adenocarcinomas located in the lower thorax. Two thirds of patients were staged as T3 and had positive lymph nodes. The median tumor size was 5 cm (range 2-13). Results: With a median follow-up of 21.3 months (range 2.4-44.8) and 33.9 months for survivors (range 3.7-44.8), overall survival at 24 months was 55%. The 24 month overall survival was 75% vs 24% for surgical and non-surgical patients, respectively. Seven patients had a complete pathologic response. Twenty-four patients experienced grade 3 or higher acute toxicity and there was one grade 5 toxicity. Acute toxicity was similar between surgery and non-surgery patients. Fourteen patients experienced grade 3 or higher late toxicity; 9 surgery and 5 non-surgery patients. The most frequent late toxicity was grade 3 stricture (21%). On multivariate analysis, advanced age (RR [10 year increase] 2.01, p=0.032) and heart maximum dose >55 Gy (RR 3.73, p=0.011) were associated with decreased survival. Conclusions: Patients who undergo surgery after chemoradiotherapy demonstrate improved survival; however, this may be related to underlying comorbidities that preclude surgery. IMRT appears to be a reasonable treatment option that may reduce complications from radiotherapy. Careful attention should be given to heart dose during treatment planning.

20 Background: Esophageal adenocarcinoma (EAC) incidence is rising and prognosis is uniformly poor, even with early stage disease. Barrett esophagus (BE) serves as a premalignant marker for EAC, with an estimated progression of 0.5% per year. Low-grade (LGD) and high-grade dysplasia (HGD) confer a higher risk of progression, providing an opportunity for intervention and surveillance. Aims: To evaluate a large cohort of patients undergoing endoscopic evaluation of BE and thereby better understand the natural history of BE and dysplasia. Methods: A retrospective review of endoscopic databases was conducted for all patients with the diagnosis of BE undergoing upper endoscopy at a tertiary academic medical center from 1991-2010. All endoscopy and accompanying pathology reports were reviewed. Only those patients with 2 biopsies documenting specialized intestinal metaplasia were analyzed. Results: 848 patients underwent upper endoscopy for evaluation of BE. Of these, 674 patients met inclusion criteria, at a mean follow up of 66.6 months. Table 1 depicts the distribution of patients according to their histology at presentation. 22 (3.2%) patients presented with established EAC, while EAC developed in 51 (7.6%). Of patients with HGD, LGD, or no dysplasia (ND) at presentation, EAC ultimately developed in 30.6%, 6.6%, and 2.7%, respectively. EAC developed in 4 patients despite RFA treatment for ND (2) or LGD (2). HGD developed in 6 such patients after treatment for ND (3) and LGD (3). Only 1 patient in each RFA-treated cohort required esophagectomy, while the others cleared dysplasia or EAC with continuous treatment. Conclusions: In this large cohort of patients with Barrett’s esophagus, higher grade of dysplasia at first endoscopy was associated with development of EAC. Continuous surveillance during and after endoscopic treatment is necessary and often results in clearance of dysplasia and EAC. [Table: see text]

119 Background: Radiotherapy (RT) interruptions have a negative impact on outcomes in many epithelial malignancies treated with definitive RT. The purpose of this study was to analyze the impact of RT duration on outcomes in patients (pts) with esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Pts treated with definitive CRT on RTOG trials 8501 and 9405 were included. Separate analyses were performed in pts receiving standard dose (SD-CRT; 50 Gy + 5FU + cisplatin) and high dose (HD-CRT; 64.8 Gy + 5FU + cisplatin) CRT. Local (LF) and regional (RF) failure were estimated by the cumulative incidence method. Disease-free (DFS) and overall (OS) survival were estimated by the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were utilized to examine for correlation between RT duration (< vs. ≥ median) with LF, RF, DFS and OS. Results: In the SD-CRT cohort (n=235), 96 pts (41%) had ≥ 1 RT interruption for a median of 3 (IQR 1-6) days. The median RT duration was 39 (IQR 37-43) days. In UVA and MVA, RT duration was not associated with LF, RF, DFS, or OS. Estimated outcome rates are in the table. In the HD-CRT cohort (n=107), 64 pts (60%) had ≥ 1 RT interruption for a median of 3.5 (IQR 2-7.5) days. The median RT duration was 52 (IQR 50-57) days. In UVA, RT duration ≥ 52 days was associated with a 33% reduction in risk of DFS failure (HR=0.66, 95% CI [0.44-0.98], p=0.039) and a 29% reduction in risk of death (HR=0.71, 95% CI [0.48-1.06], p=0.09). When excluding the 25 pts with RT dose < 64.8 Gy, RT duration was not associated with DFS or OS. Conclusions: In pts with esophageal cancer receiving definitive SD-CRT, an association between RT duration and outcomes was not observed. In pts receiving HD-CRT, longer RT duration was associated with improved DFS, which may have been due to a significant number of deaths at RT dose < 64.8 Gy. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422. Clinical trial information: NCT00002631. [Table: see text]

9 Background: Prostate cancer molecular subtypes based on ETS gene fusions and SPINK1 were originally identified through outlier gene expression profiling analysis. Such molecular subtypes may have utility in disease stratification and clonality assessment, complementing available purely prognostic tests. Hence, we determined the analytical validity of molecular subtyping in a large sample of PCa treated with radical prostatectomy. Methods: We analyzed Affymetrix Human Exon 1.0ST GeneChip expression profiles for 1,577 patients from 8 radical prostatectomy (RP) cohorts. Multi-feature random forest classifiers and outlier analysis were used to define microarray-based molecular subtypes. Results: A random forest (RF) classifier was trained and validated to predict ERG fusion status using a subset with known ERG rearrangement status defined by FISH, achieving >95% sensitivity and specificity in the validation subset. Less frequent rearrangements involving other ETS genes or SPINK1 over-expression were predicted based on gene expression outlier analysis. Across cohorts, 45%, 9% 8% and 38% of PCa were classified as ERG+, ETS+, SPINK+, and Triple Negative, respectively. Global gene expression analysis shows that the four subtypes could be collapsed into three entities (ERG+, ETS+ and SPINK+/Triple Negative) based on expression patterns and clinical characteristics similarity. A series of multivariable analyses further revealed, ERG+ to be associated with lower pre PSA and Gleason scores but more likely to have EPE and occur in patients with European American ancestry compared to the ETS+, SPINK+/Triple Negative tumors (p<0.001). In contrast, patients with ETS+ were more likely to have SVI compared to both ERG+ and SPINK/Triple Negative (p=0.01), while SPINK+/Triple Negative had higher Gleason scores and were more likely to occur in African Americans (p<0.001). Conclusions: The Decipher platform can accurately determine ERG rearrangement status and PCa molecular subtypes. Inclusion of molecular subtyping, such as m-ERG status, may enable additional precision medicine opportunities in prognostic tests

89 Background: Lymph node counts have been proposed as a quality metric for patients undergoing radical prostatectomy (RP) and pelvic lymph node dissection (PLND). It is unclear whether surgical approach and hospital characteristics independently determine the number of lymph nodes removed at PLND. Therefore, we assessed the variation in lymph node counts from a population-based cohort of patients undergoing surgery for intermediate and high-risk prostate cancer. Methods: Using the National Cancer Database, we identified all surgically treated patients diagnosed with pre-treatment intermediate or high-risk prostate cancer from 2010 to 2011. The primary outcome was the number of lymph nodes retrieved at the time of RP. Generalized estimating equations were used to assess for differences in the adjusted number of lymph nodes retrieved after accounting for patient and hospital characteristics and surgical approach. Results: Overall, 35,876 patients were diagnosed with intermediate (61.2%) and high-risk (38.8%) prostate cancer and underwent RP and PLND. On multivariable analysis, open radical prostatectomy (ORP) and high volume and academic hospitals were independently associated with greater lymph node counts compared to robotic-assisted radical prostatectomy (RARP) and medium/low and community hospitals, respectively (all p<0.001). After adjusting for patient and hospital variables, higher adjusted lymph nodes counts were observed for ORP compared to RARP (7.1 vs. 6.1; p<0.001). Adjusted counts were also higher for high volume compared to medium/low volume hospitals (7.8 vs. 5.9; p<0.001), and academic compared to community hospitals (7.3 vs. 5.6; p<0.001). Conclusions: Among patients with aggressive prostate cancer treated with RP and PLND, lymph node counts varied by surgical approach and hospital characteristics.

84 Background: In elderly patients, Charlson score among other features, might allow clinicians to limit the use of aggressive adjuvant treatment strategies or even primary surgical treatment to those who might not achieve benefit during their lifetime. Methods: Retrospective analysis, 7,650 case multicenter high-risk prostate cancer (Pca) radical prostatectomy database selecting >= 70 years old cases. We predicted death from all causes (DAC) and cancer related death (CRD) including all clinical and pathological data. Multivariable analysis were performed to identify independent predictors of DAC and CRD with binary logistic regression, using STATA® software, version 13.1. Results: 2,106 patients from 14 high-volume centers were included. Mean age was 72.8 years (SD 2.46). 206 (9.78%) patients were classified as ASA 3-4 and 497 (23.6%) as CS >=1. Mean PSA was 21.7 ng/ml (SD 50.5). At final histopathology, 800 (38%) had pT3b-T4 disease, GS was 8-10 in 589 (28%), LNI was found in 518 (24.6%) and 822 (39%) PSM. Adjuvant RT, ADT and RT+ADT were administered in 359 (17%), 391 (18.6%) and 437 (20.7%), respectively. Mean follow up was 5.18 years (DS 4.47). BCR occur in 649 (30.8%) and CF in 150 (7.1%) of which distant in 59 (2.8%). Total deaths accounted 341 (16.2%) and CRD for 100 (4.7%) cases. Conclusions: Multicenter data confirms that elderly patients survival harboring high risk prostate cancer will benefit from radical treatment if they are Charlson score 1 or less. [Table: see text] [Table: see text]

8 Background: A number of biomarkers related to cell cycle, angiogenesis or apoptosis have been found to be associated with patient outcome in tissue samples from men treated with first line radiation therapy in RTOG clinical trials using immunohistochemical staining and analysis. In a prior study, four biomarkers (Ki-67, MDM2, p16 and Cox-2) and clinical covariates were included in a model of distant metastasis (DM; Pollack et al, Clin Cancer Res, 2014 [epub ahead of print]) risk. The current study tested the hypothesis that these genes are prognostic for DM in men treated primarily with total prostatectomy using RNA expression profiling. Methods: RNA fromprostatectomy samples from Cleveland Clinic (CC, n=182); Mayo Clinic (MC)-I (n = 545) and II (n=235); Memorial Sloan Kettering Cancer Center (MSKCC, n=131); Erasmus Medical Center (EMC, n=48) and Thomas Jefferson University (TJU, n=130) were profiled using 1.4 million RNA features. A Cox proportional hazards model was built on the MC-I training set to combine the 4 biomarkers into a prognostic risk score (4BMSig). 4BMSig was subsequently evaluated for its prognostic significance separately and in combination with clinical risk factors (biopsy Gleason Score, cT-category and Preop-PSA) for DM. Results: 4BMSig was found to discriminate DM patients significantly for the MC-II (AUC = 0.66, p < 0.001), CCF (AUC = 0.68, p < 0.001), and MSKCC (AUC = 0.71, p = 0.04) datasets, and achieved borderline significance for EMC (AUC = 0.70, p = 0.06). 4BMSig did not discriminate DM in the TJU dataset (only 10 DM events). Pooled multivariable analysis (n = 726) with clinical covariates revealed that 4BMSig is a strong independent prognostic covariate for DM (p < 0.001) and prostate cancer specific mortality (p = 0.005). Conclusions: The four genes identified previously as being associated with DM in radiotherapy patients were incorporated herein into 4BMSig, which was found to have potential as a pretreatment prognostic DM risk assessment tool for men treated with prostatectomy. Further validation would consist of testing 4BMSig from RNA in diagnostic tissue from prostate cancer patients prior to prostatectomy.