Citations

767 Background: The CORRECT trial (NCT01103323) showed that REG improves overall survival (OS) vs placebo (PBO) in patients with mCRC who failed approved therapies (OS HR 0.77; 1-sided p=0.0052; Grothey 2013). A total of 760 patients were randomized to REG (n=505) or PBO (n=255) in more than 100 centers across North America, Europe, Asia, and Australia. We conducted a post-hoc exploratory subgroup analysis of the 83 (11%) patients from 18 US centers. Methods: Eligible patients had an ECOG PS ≤1 and had received approved therapies, including a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, and if KRAS wild-type cetuximab and/or panitumumab. Data from the overall cohort, including US patients, are provided for perspective. Descriptive statistics are shown. Results: Of the 83 US patients, 36 (43%) were randomized to PBO and 47 (57%) to REG. Baseline characteristics of the US group were consistent with the overall cohort: median age in the US was 58 yr (range, 34 – 85) vs 61 (22 – 85) overall, 49% of US patients were ECOG PS1 (vs 46%), and 46% received ≤ 3 treatments for mCRC (vs 52%). KRAS status mutant/wild-type was 57%/34% in the US vs 57%/39% overall. All patients in the trial had prior bevacizumab and 57% of US patients also had prior cetuximab and/or panitumumab (vs 51% overall). However, higher proportion of patients in the US were Black (11% vs 2%), KRAS status unknown (10% vs 4%), and had colon as the primary disease site (82% vs 65%). Mean percentages of planned REG dose were similar (76% US vs 79% overall) and mean REG treatment duration was 3.1 mos in US vs 2.8 mos overall. Rates of dose modifications REG/PBO were 87%/47% in the US vs 76%/38% overall and grade ≥3 adverse events REG/PBO were 74%/64% vs 78%/49%, respectively. Based on 44 total death events, the HR for OS in the US subgroup was 0.46 (95%CI 0.25 – 0.84) favoring REG; median OS was 4.7 mos for PBO, but could not be estimated for REG due to censored data. However, this analysis was based on a relatively small sample size and event count. Conclusions: Patients treated in the CORRECT study in the US appear similar to the overall cohort and results are generally consistent with the overall findings of the trial. Clinical trial information: NCT01103323.

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.

326 Background: The Survival Prediction After Radical Cystectomy (SPARC) score (Eisenberg et al, J Urol 2013) incorporates clinical and pathologic features to predict cancer specific survival (CSS) for urothelial carcinoma of the bladder. Validation of this model would improve its generalizability. Methods: Using the IRB-approved bladder cancer database at the University of Southern California (USC), we identified patients who underwent radical cystectomy (RC) for urothelial carcinoma of the bladder for curative intent from 1971-2009. Clinical factors (Charlson comorbidity index, ECOG performance status, hydronephrosis, adjuvant chemotherapy, smoking status) and pathologic factors (pathologic T stage, nodal status, multifocality, and lymphovascular invasion) included in the SPARC score were obtained. Patients were excluded if there were missing variables or if they underwent neoadjuvant chemotherapy. Associations between clinicopathologic factors and CSS were evaluated using Cox proportional hazards. Calibration plots were generated comparing actuarial CSS with SPARC predicted CSS by deciles. A c-index was generated to determine accuracy of the prediction. Kaplan Meier curves estimated CSS stratified by SPARC score and were compared with the log rank test. Results: A total of 2,045 patients underwent RC and 1,123 (55%) met inclusion criteria with a median follow-up of 4.7 years (IQR 2.0-8.9 years). Of the 1,123 patients, 332 (30%) died of bladder cancer. All the clinical and pathologic variables used in the SPARC scoring model were associated with CSS except for smoking status and tumor multifocality. Calibration plots demonstrated concordance between the SPARC-predicted and actuarial CSS with a c-index of 0.75. Kaplan Meier curves demonstrated significant differences in CSS based upon SPARC score, p<0.001. Conclusions: The SPARC score represents a valid instrument for predicting bladder CSS after RC. The model can be utilized to better tailor adjuvant therapy and surveillance.

457 Background: Curative therapy for PDAC is currently achievable through resection only, but ≤ 15% of patients are candidates for surgery. FG-3019, a recombinant human mAb to connective tissue growth factor (CTGF), plus gemcitabine (G) significantly reduced tumor growth, increased apoptosis and improved survival vs G alone in the KPC mouse model. Higher FG-3019 exposure and lower baseline (BL) CTGF were independently and significantly associated with improved overall median and 1-year survival (OS) in a Ph2a trial with G and erlotinib in stage 3 or 4 PDAC. Neoadjuvant treatment of LAPC with FG-3019 combined with multidrug therapy may change the fibrotic character of LAPC and thus may make it amenable to surgical resection and potentially improve OS. Methods: Patients with unresectable LAPC (confirmed by laparoscopy) are randomized to G/NP ±FG-3019 for 6-cycle/24-week treatment. Safety, efficacy, PK and changes in CT, PET, & CA19.9 from BL through end of treatment (EOT) are assessed. Up to 4 endoscopic ultrasound (EUS) guided core biopsies are collected at BL. Protein microarrays of pre- and post-treatment biopsies are prepared from tumor and stromal cells isolated by laser capture microdissection. Surgical exploration is performed in subjects who achieved the protocol-defined criteria for possible resection. Results: To date, 11 subjects were enrolled with 5 randomized to +FG-3019 arm. There were no complications from laparoscopy or EUS core biopsies that were clinically significant or delayed dosing. Per investigator assessment, no FG-3019-related SAEs were reported, nor any identified toxicity suspected from combination of FG-3019 with chemotherapy. Overall, CA19.9 mean change from BL was −62.7% at Week 8 (n = 8), and target lesions were reduced by 20.6% (n = 6) at Week 16. Three out of 4 subjects had PET SUVmax reductions of ≥ 30% at EOT. Additional data from protein microarrays will be presented. Conclusions: Based on the limited data collected so far, this trial design is feasible and the G/NP +FG-3019 combination is well-tolerated and appears to be active. Summary results on surgical exploration of subjects will be provided later. Clinical trial information: NCT02210559.

445 Background: Radical cystectomy (RC) is the gold standard treatment for muscle-invasive and high-risk non-muscle invasive bladder cancer. However, the procedure has been associated with a high complication rate, including perioperative infection. In addition to resulting in patient morbidity, infections have been suggested as a quality metric. We sought to evaluate the incidence, risk factors, and timing of infection following RC. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried to identify patients undergoing RC for bladder cancer from 2005-2013 using CPT procedure and ICD-9 diagnosis codes. Infections (urinary tract infection (UTI), surgical site infection (SSI), and sepsis) within 30 days of RC were recorded. Characteristics including age, gender, ethnicity, body-mass index, diabetes, smoking status, renal function, steroid usage, albumin, receipt of perioperative transfusion, and operative time were abstracted, and relative risk of infection was assessed in univariate chi-squared analysis. Results: A total of 3,187 patients were identified, of whom 2604 (81.8%) were male, with a median age of 68.8 years (IQR 62, 77). Postoperative infection was diagnosed in 766 (24%) patients, at a median of 13 days (IQR 8, 19) after RC, with 44.4% occurring prior to hospital discharge. The most common type of infection was SSI (404; 12.7%), followed by sepsis (315; 9.9%), and UTI (309; 9.7%). Factors associated with increased overall infection risk were obesity (RR 1.32; 1.20-1.46; p < 0.001), receipt of a blood transfusion (RR 1.20; 1.10-1.31; p < 0.001), and increased operative time (RR for > 450 min 1.46; 1.26-1.70; p < 0.001). Risk factors for UTI in particular included obesity (RR 1.28; 1.11-1.47; p < 0.001), diabetes (RR 1.38; 1.09-1.75; p = 0.009), and increased operative time (RR for > 450 min 1.45; 1.18-1.78; p < 0.001). Conclusions: Approximately 25% of patients undergoing RC experience an infection within 30 days of surgery, most commonly SSI. Several modifiable risk factors were identified, including blood transfusion and prolonged operative time, that represent potential targets for care improvement.

389 Background: Venous thromboembolism (VTE) has been reported in approximately 5-7% of patients undergoing radical cystectomy (RC). While extended-duration pharmacologic prophylaxis (EDPP) has been investigated following surgery for a variety of malignancies, limited data exist in bladder cancer. Herein, we evaluated the efficacy and safety of EDPP after RC. Methods: We instituted a change in our clinical practice beginning in May 2014 such that patients undergoing RC were prescribed 30 days of enoxaparin at discharge. We recorded symptomatic VTE and lymphocele rates within 30 days of RC among patients treated from 5/14-6/15, and compared these outcomes to the cohort of all patients who underwent RC at our institution in the year prior to EDPP implementation. Patients in both groups received subcutaneous unfractionated heparin and mechanical prophylaxis during hospitalization. Patients with a history of VTE prior to surgery (n = 24) were excluded from study. Unadjusted descriptive statistics and univariate analyses were performed using the Pearson or Fisher chi-square test for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: In total, 58 patients who received EDPP and 82 patients who had not received EDPP after RC were included for analysis. Baseline clinicopathologic demographics were similar between the cohorts. We found that only 1 patient (1.9%) discharged with EDPP was diagnosed with a VTE within 30 days of RC, compared to 5 (6.1%) who had not received EDPP. Mean time to VTE was 18.0 days after RC (range 9-28 days). Events consisted of DVT alone (n = 2), DVT and PE (n = 2), and PE alone (n = 2). The odds ratio for VTE in the absence of EDPP was 3.31 (95% CI 0.38, 29.2). Overall, 3 patients developed a symptomatic lymphocele within 30 days of RC: 1 (1.9%) who received EDPP and 2 (2.4%) who had not (p = 0.84). No patient in either cohort was rehospitalized for bleeding complications. Conclusions: Our initial experience suggests that EDPP was associated with a lower rate of VTE following RC, and does not increase the risks of bleeding or symptomatic lymphocele. Future evaluation in a larger-scale prospective clinical trial setting is needed to confirm the benefit of EDPP in RC patients.

255 Background: The purpose of this study was to identify site-specific recurrence patterns for patients (pts) with biochemical recurrence (BCR) after prostatectomy (RP) using C-11 Choline PET/CT (C11Ch) and 3T pelvic MRI with endorectal coil (pMRI). Methods: Between 2008 and 2006, 2,466 men underwent C11Ch and pMRI for BCR after RP. From this cohort, we identified 261 pts who received no adjuvant or salvage therapy (androgen deprivation or radiation). Suspected radiographic relapse was confirmed by biopsy (46%) or progression/response to treatment in concordance with subsequent rise/decline in PSA (54%). Results: Of the 261 men evaluated, 202 (75%) had positive pMRI, C11Ch or both. Seventy nine (39%), 105 (52%) and 18 (9%) pts had high, intermediate, and low risk CaP, respectively at RP. Median PSA at the time of positive scan was 2.3 ng/mL, with a median time from BCR to radiographic disease identification of 15 months. Of these 202 men, 67 (33%) harbored prostate fossa recurrence only, 44 (22%) had a combination of local and metastatic disease and 91 (45%) had metastatic disease without local recurrence. Forty (20%) pts had pelvic nodal recurrence only and 18 (9%) had perirectal nodal involvement. Median PSA for pts with local only recurrence, distant metastases only, and local + distant disease was 2.3, 2.7 and 2.2 ng/mL, respectively, with a median interval from BCR to positive scan of 16.7, 7.9 and 11 months. Imaging revealed that 33% to 66% of our cohort would have all sites of disease treated by salvage RT depending on the extent of the treatment field Conclusions: C11Ch and pMRI were used to identify recurrence patterns in pts with BCR after RP only. At median PSA of 2.3 ng/ml, our study demonstrates a low rate of local-only recurrence, higher than anticipated frequency of metastatic recurrence with peak frequency within the pelvic lymph nodes, and substantial perirectal recurrences. Despite the high rates of distant recurrences, 2/3 of our cohort had their disease limited to the pelvis and could be potential candidates for local therapies, including salvage radiation.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV 1 ], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV 1 , worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.