bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathologic features of patients with KRAS wild-type pancreatic adenocarcinoma.
Authors: Salem Mohamed E. , Al-hajeili Marwan R. , Dyson Gregory , Stanski Natalja , Jain Tania , Mahaseth Hemchandra , Choi Minsig , Shields Anthony Frank , Philip Philip Agop
Published: February 2017

192

Background: Pancreatic adenocarcinoma (PC) has the highest frequency of KRAS gene mutations among human cancers. A better understanding of disease biology may help improve targeted therapies for this disease. There is limited data about clinical, pathological features and treatment outcomes in patients (Pts) with wild type KRAS tumors (KRASwt). Methods: Retrospective review of 71 pts with histologically confirmed PC between 2009 and 2012 was undertaken. The KRAS codon 12 and 13 and BRAF codon 600 mutations were assessed in diagnostic tumor tissues (TrimGen Mutector II Shifted Termination Assay). Differences were evaluated with t-test and Fisher exact test. Results: KRAS mutations were identified in 50 tumors (70%), while 21 tumors (30%) had KRASwt genotype. Almost all (96%) mutations occurred at codon 12, there were no mutations in codon 13, and none of the KRASwt tumors harbored BRAF mutations. Pts with KRASwt tumors were mostly white (76%), females (57%), and did not have diabetes mellitus (80%). At diagnosis, pts with KRASwt tumors had a tendency to present at younger age (median age of 60 vs. 66 y; P = 0.1) and with lower CA19-9 values (median CA19-9: 392 vs. 3371 U/mL; P=0.042). Head of the pancreas was the primary site of disease in the majority of pts with KRAS wt tumors (58%), while body or tail was the primary site of disease in the majority of pts with KRAS mutant tumors (53%). There was no difference in the histologic differentiation. Although the majority of pts with KRAS wt (55%) and mutant tumors (57%) presented with distant metastases or locally advanced disease (40% and 39%; respectively), liver involvement was seen in only 55% of pts with KRAS wt tumors vs 92% in the pts with mutant tumors (p=0.016). In univariable analysis, age was an independent predictor of overall survival (HR 1.14, p=0.037) in pts with KRAS wt tumors, while level of bilirubin at presentation was a predictor of overall survival (HR 1.86 (0.77, 4.53); P <0.0001) in pts with KRAS wttumors who had distant metastasis. Conclusions: The frequency of pts with PC who had KRASwt tumors was higher than previously described. Pts with KRASwt tumors may have a disease that is biologically different than those with mutated KRAS. Further prospective characterization is warranted.
Comparison of a new prognostic system and five current staging systems in predicting the survival rate of patients with advanced hepatocellular carcinoma.
Authors: Chen Zhan-Hong , Li Xing , Dong Min , Ma Xiao-Kun , Wu Xiang-Yuan
Published: February 2017

193

Background: Prognosis of patients with advanced HCC is very poor, median overall survival varies from 3 to 6 months. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical tirals. We have established a new prognostic system called SYSU system (variables and risk classification criteria are listed below, reported in MASCC 2013) and now we want to compare this new prognostic system and 5 current staging systems in predicting the survival rate of patients with advanced HCC. Methods: From September 2008 to June 2010, a total of 253 patients with advanced HCC who were not amendable to locoregional therapy were analyzed. The median follow-up is 38.5 months and the median survival is 7 months. Data were collected to classify patients according to our new system(SYSU system), Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma (BCLC), Advanced Liver Cancer Prognostic System (ALCPS), Chinese University Prognostic Index staging system for HCC (CUPI), OKUDA score system and French scoring system(GETCH) at diagnosis. OS and 3-month OS were the end points used in the analysis. Results: When predicting 3-month survival, ROC analysis show AUC of SYSU system, ALCPS, CUPI,OKUDA, GETCH and BCLC is 0.822,0.821,0.777,0.756,0.688 and 0.621. AUC of SYSU system and ALCPS is similar and they are significantly better than the other four staging system (p<0.05). When predicting overall survival, likelihood ratio test show χ2 of SYSU system, ALCPS, CUPI,OKUDA, GETCH and BCLC is 97.7,85, 50.5, 46.4,22.6 and 8.4 and AIC of SYSU system, ALCPS, CUPI,OKUDA, GETCH and BCLC is 1939,1952,1986,1990,2014 and 2028. Our SYSU system has best performance in terms of discriminatory ability, homogeneity and monotonicity. Conclusions: Our SYSU system is the best score system in prediction of OS and 3-month OS among the 6 systems analyzed for Chinese advanced HCC patients. [Table: see text]
MicroRNA-27b as a prognostic marker in pancreatic neuroendocrine tumor.
Authors: Kang Bong Kyun , Hwang In kyeom , Lee Yoon Suk , Kim Jaihwan , Hwang Jin-Hyeok
Published: February 2017

251

Background: Pancreatic neuroendocrine tumors (PNETs) are heterogeneous group of tumors with a wide spectrum of behavioral characteristics. PNET generally behaves in an indolent fashion. However, when metastasis occurs, it is difficult to be treated. Little is known about prognostic biomarker in PNET. The aim of this study was to elucidate prognostic biomarker in PNET using nanostring microRNA (miRNA) array technology. Methods: We had already selected several candidate miRNAs (miR-27b, miR-122, miR-142-5p, miR-196a, miR-223, miR-590-5p, miR-630 and miR-944), which indicated 3 folds expression differences between primary tumor and metastatic tumor on the basis of nanostring-based microarray in two PNET patients. Further 39 PNET patients were enrolled for clinical validation (recurrence group includes patients who had metastasis subsequently; no-recurrence group includes the others) of 8 miRNAs. Surrounding pancreas and tumor miRNA were isolated separately from formalin-fixed paraffin-embedded tissues. Expression of candidate miRNAs was measured by quantitative real-time PCR using U6 as an internal control. Mann-Whitney U test and Spearman rank correlation analysis were used for statistical evaluation at p < 0.05 level. Results: miR-27b expression was elevated in recurrence group compared to no-recurrence group (p = 0.019). And also, miR-27b expression was statistically significant correlated positively with CA 19-9 level (p = 0.015). The Hierarchical cluster analysis of eight miRNAs showed miR-27b linked functionally to miR-142-5p and miR-196a. Furthermore, miR-196 expression was associated with Ki-67 index with a statistical significance (p = 0.035). Conclusions: The miR-27b would be a prognostic marker of recurrence in resected PNET and link to miR-142-5p and miR-196a, which correlated with Ki-67 index. Further experimental investigation would be required to demonstrate the role of these miRNAs in PNET.
Capecitabine plus temozolomide (CAP-TEM) in patients with advanced neuroendocrine neoplasms (NEN): An Italian multicenter retrospective analysis.
Authors: Spada Francesca , Fumagalli Caterina , Antonuzzo Lorenzo , Messerini Luca , Radice Davide , Di Rocco Roberta , Galdy Salvatore , Barucca Viola , PISA Eleonora , Barberis Massimo , Di Costanzo Francesco , Fazio Nicola
Published: February 2017

281

Background: A combination of capecitabine (CAP) and temozolomide (TEM) has been successfully used as first-line treatment in low-grade pancreatic neuroendocrine neoplasms (PNEN). We reviewed activity and toxicity of the same regimen in patients with advanced NEN with different primary and grading. Methods: Clinical data of patients who had received oral CAP 1500 mg/m2/day over 14 days bid plus oral TEM 150-200 mg/m2/day on days 10-14 of each 28-day cycle, were retrospectively reviewed. The methylenguanilmetiltransferase (MGMT) methylation-status (MGMT-gene >5% = responders) and TS-polymorphisms (2R/2R, 2R/3R = responders, 3R/3R = non-responders) in tumor-tissue/peripheral-blood were evaluated by pyrosequencing. Results: Since March 2012, 29 patients were selected. The primary tumor was: pancreas in 14 patients (48%), gastrointestinal (GI) in 5 (17%), unknown in 2 (7%), lung in 8 (28%). According to 2010 WHO classification, Ki67 was <2% (G1) in 3%, 3-20% (G2) in 45% patients, >20% (G3) in 21% with two "low G3" (Ki67 21-30%), and unknown in 3%. Among lung: 7% typical and 21% atypical (Travis’ classification). 72% patients (21/29) were progressive on different therapies: peptide-receptor-radiotherapy (38%), chemotherapy (38%), everolimus (14%). Partial-response (PR) occurred in 14% (4/29) of patients (95% CI: 4-32), stable-disease (SD) in 59% (17/29) (95% CI: 39-77) mainly PNET. The two "low G3" responded. Disease control rate (PR+SD): 72% (95% CI: 53-87). Median TTP: 9 months (95% CI: 5.6-N.E.). Thrombocytopenia was the most frequent grade 3 toxicity, always temporary. All 4 PR patients had genotype 2R/3R-2R/2R investigated for the 28 base-pair (bp) variable number of tandem repeats (VNTR) in the 5'UTR of the TS-gene, and MGMT-gene inactivation by epigenetic silencing. Conclusions: This analysis suggests that CAP-TEM chemotherapy could be active and well tolerated in pretreated patients with advanced NEN of different origins and grading. This warrants a prospective investigation in a more homogeneous population (G2 and “low-G3” GEP NEN or lung carcinoids), in order to validate the predictive value of MGMT methylation-status and TS-polymorphisms.
Independent predictors of overall survival and recurrence in biphenotypic hepatocellular cancer.
Authors: Amin Manik , Chen Ling , Vachhajarani Neeta , Brunt Elizabeth , Doyle Maria Majella , Tan Benjamin R.
Published: February 2017

291

Background: Biphenotypic hepatocellular cancer (BPHCC), which is a combined hepatocellular cancer (HCC) and cholangiocarcinoma (CC), is a rare form of primary liver cancer, whose long term prognosis is extremely poor as compared to either HCC or CC alone. Little is known about the recurrence rates and predictors of recurrence in BPHCC. Our objective was to 1) identify both overall survival and recurrence rates after primary resection or systemic and liver directed therapies and 2) to evaluate the independent predictors of survival and recurrence. Methods: Our Hepatobiliary Registry identified 65 patients with BPHCC from February 1999 till April 2013 at Siteman Cancer Center, Washington University, St. Louis MO. We conducted univariate Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression to identify factors independently associated with overall survival. We also conducted multivariable logistic regression analysis to identify factors independently associated with recurrence. Results: Of the 65 patients in our study, 18 (28 %) with prior resection, 2 (3 %) after OLT, 45 (69 %) ineligible for surgery, 40 (62 %) were treated with chemotherapy, 17 (26%) with liver directed therapies. Overall survival was 39.2 % at 1 year. Independent factors associated with survival were: smoking (HR 2.84, 95% CI 1.29-6.23, p = 0.0089), tumor thrombus (HR 5.45, 95% CI 2.05-14.50, p = 0.0007), any liver directed treatment (HR 3.01, 95% CI 1.21-7.48, p = 0.0175), multiple satellite lesions (HR 3.17, 95% CI 1.71-8.58, p = 0.025) and prior tumor resection (HR 2.65, 95% CI 1.16-6.03, p = 0.020). Risk of recurrence was independently predicted by male sex (OR 3.98, 95% CI 1.30-12.15, p = 0.015) and multiple satellite lesions (OR 15.42, 95% CI 2.68-88.62, p = 0.0076). Conclusions: Patients with biphenotypic cancers have a devastating overall survival. Tumor thrombus and satellite lesions were the strongest predictors of poor survival; satellite lesions also strongly predicted recurrence. In this rare form of cancer, this is the largest study to identify factors associated with overall survival and recurrence. These factors should help guide clinical care of patients with BPHCC.
Outcomes of neoadjuvant chemotherapy with FOLFOX/FOLFIRINOX and chemoradiotherapy in borderline resectable pancreatic cancer: Single-institution experience.
Authors: Son Chang O , Pai Sachin Gopalkrishn , Satti Suma , Dornelles Adriana , Bolton John S. , Conway W. Charles , Fuloria Jyotsna
Published: February 2017

327

Background: The clinical benefit of neoadjuvant treatment in locally advanced pancreatic adenocarcinoma (borderline/unresectable) has not been well established. However, the challenge of managing locally advanced pancreatic adenocarcinoma has led to the incorporation of neoadjuvant treatment into clinical practice. FOLFIRINOX has been increasingly used as neoadjuvant chemotherapy, but may not be well tolerated especially in older patients due to adverse effect profile. In our institution, we have used FOLFOX as an alternative for older patients and patients with poor performance status based on our retrospective observation of FOLFOX in metastatic/advanced pancreatic adenocarcinoma. Methods: We conducted a retrospective analysis of locally advanced pancreatic cancer patients from January 1, 2011 to February 28, 2013 treated with neoadjuvant chemotherapy (FOLFOX/FOLFIRINOX) with the intention of future resection. In addition patients also received neoadjuvant chemo-radiotherapy. Imaging studies, operative notes and Pathology reports were reviewed. Results: 27 patients were analyzed, 10 received FOLFIRINOX and 17 received FOLFOX regimen. Mean age of patients were 57.28 ± 11.68 SD and 68.66± 11.21 SD in the two groups respectively. Patients received 4.2 ± 0.92 SD and 3.59 ±1.06 SD cycles of chemotherapy in FOLFIRINOX and FOLFOX groups respectively. Mean duration of follow up was similar in both groups. 5 patients on FOLFOX and 1 patient on FOLFIRINOX had disease progression thereby precluding surgery. The Rate of R0 resections was 64.7 % and 60% (P 0.27) in the two groups respectively. Overall survival was not statistically significant between the two groups. (Kaplan Meier survival graphs will accompany final presentation). Conclusions: In our study, FOLFIRINOX was administered in younger patients. However the R0 resection rates were similar in both the groups. FOLFOX may be acceptable neoadjuvant chemotherapy of choice in patients with borderline functional status. Randomized trials are needed to define this better.
Clinical outcomes and prognostic factors of adjuvant treatment in resectable biliary tract cancer.
Authors: Hong Ji Hyung
Published: February 2017

370

Background: The survival outcomes and prognostic factors of adjuvant treatment after resection for biliary tract cancer (BTC) has not been clearly established. We analyzed the clinical outcomes and prognostic factors of patients with resected BTCs between adjuvant treatment and non-adjuvant treatment group. Methods: A total 189 patients of BTC were treated with surgery followed by adjuvant chemotherapy or concurrent chemoradiotherapy between Jan. 2008 and Jan. 2013. We retrospectively analyzed the clinical characteristics and recurrence and survival outcomes with following variables: histologic grade, resected margin status, lymphatic/vascular/perineural invasion, T and N stage, treatment modality. Results: Median age at diagnosis was 64 years (range: 32-85). Of the total 189 patients, R0 resection was done in 152 patients (80.4%). Among the 73 patients with adjuvant treatment, forty-one patients (21.6%) were treated with adjuvant 5-FU based systemic chemotherapy and 31 patients with chemoradiotherapy (16.5%). Recurrence rate were 39.7%. Median disease free survival (DFS) time was 58.1 months (95% CI, 38.9-77.3) and median overall survival (OS) time was 87.8 months (95% CI, 79.5-96.0). Adjuvant treatment showed the tendency to improve DFS with 39.0 months (95% CI, 8.9-69.1) in the adjuvant group compared with 57.0 months (95% CI, 39.5-74.5) in the non-adjuvant group, however, without statistical significance (p=0.113). Between the recurrent and non-recurrent group, perineural invasion, lymphatic invasion and poorly differentiated histology showed statistical significant difference, respectively (65.3% vs 35% ; p <.001, 28% vs 14.9% ; p = .028, and 8.1% vs 7.1% ; p = .011). Presence of perineural invasion showed association with RFS (HR= 1.543; 95% CI 1.133-2.102, p=.006). There was no other significant correlation in R1 resection, poor histologic grade, lymphatic and vascular invasion, chemotherapy regimen, and treatment modality with survival outcome. Conclusions: Perineural invasion could be a potential prognostic factor for recurrence. Further prospective study should be warranted to confirm this data.
Preoperative (preop) chemosensitivity testing as predictor of treatment benefit in adjuvant stage III colon cancer (CC): Interim analysis of the PEPITA study.
Authors: Hendlisz Alain , Deleporte Amélie , Van Laethem Jean-Luc , Vergauwe Philippe , Van Den Eynde Marc , Deboever Guido , Janssens Jos , Demolin Gauthier , Holbrechts Stephane , Clausse Marylene , Vermeij Joanna , D'Hondt Lionel A. , Laurent Stéphanie , Efira André , Gomez Galdon Maria , Buggenhout Alexis , Paesmans Marianne , Garcia Camilo , Piccart-Gebhart Martine J. , Flamen Patrick ,   Belgian Group for Digestive Oncology (BGDO)
Published: February 2017

385

Background: Adjuvant chemotherapy (CT) improves stage III CC outcome but is not effective for all patients (pts). PePiTA’s main hypothesis is that absence of metabolic response (MR) of the primary tumor after 1 preop CT course predicts absence of benefit from adjuvant CT (at 3-year DFS). This strategy's aim is to spare pts from useless toxicities, improve healthcare resource allocation, and guide translational research. This interim analysis was performed for safety and feasibility of MR assessment (MRA). Methods: Pts ≥ 18 years, with PS ≤ 1, diagnosed with CC considered for curative resection are eligible, after signed consent. Baseline PET is repeated after 1 CT cycle, followed by surgery. PET quality insurance and MRA are performed centrally and the result is blinded for investigators. Results: From 2010 to 2013, 114 pts—M/F (55%/45%), median age 66 (26-81), ECOG 0/1(92%/8%)—were included in 15 Belgian centers. 11 pts were excluded from analysis: 2 hyperglycemia at baseline PET; 2 withdrew consent; 6 PET-revealed stage IV CC; and 1 second cancer. Preop CT was associated with 5% grade (gr) 3-4 neutropenia, 1% gr 3 diarrhea, 1% gr 3 hypokaliemia, 1% peritonitis and 1% gr 3 thromboembolic events. Colectomies were performed in all pts after a median of 20 days (interquartile interval 18-21): 32 right (31%), 69 left (67%), and 2 procedures not detailed. Pathology showed stages 0 (1%), I (13%), II (34%), III (47%), IV (7%), without lymph node downstaging. Postoperative morbidity is 9% (95%CI 5-16%) and includes fistulas (4%), transient ischemic attack (1%), ileus (2%), and evisceration (1%), but no death. Technical or methodological reasons prevented MRA in 19/103 pts. Median SUVmax was 14.4 (4.9-47.8) at baseline, and 10.9 (0-39.3) on day 14. 2 pts presented with complete MR. For the others, median delta SUVmax was -22% (-60 to +31%). MR was observed in 60% of pts, and was absent in 40%, with equal distribution for stages II and III (p = 1.00). Conclusions: 1 course of CT is feasible before curative surgery for CC, without inducing excessive toxicity, delay or surgical morbidity. MRA indicated metabolic signs of chemoresistance in 40% of the primary tumors. Clinical trial information: NCT00994864.
Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04.
Authors: Allegra Carmen Joseph , Yothers Greg , O'Connell Michael J , Roh Mark S. , Beart Robert W. , Petrelli Nicholas J. , Lopa Samia H. , Sharif Saima , Wolmark Norman
Published: February 2017

390

Background: The primary aims were to: 1) compare capecitabine (Cape) and continuous intravenous infusion (CVI) 5-FU combined with pelvic radiation therapy (RT) given preoperatively for patients (pts) with stage II or III rectal cancer; 2) determine whether the addition of oxaliplatin (Ox) would improve pt outcomes. Preliminary results focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity were presented at ASCO 2011 (Roh: J Clin Oncol 29: 2011 Ab 3503). Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without intravenous Ox (50mg/m2 /wk x 5) or oral Cape (825 mg/m2 BID 5 days/wk), with or without Ox (50mg/m2/wk x 5). The primary endpoint of local-regional (L-R) tumor control included L-R tumor recurrence, less than an R0 resection (complete surgical resection), and no surgery. Results: From July 2004 to August 2010, 1608 patients were randomly assigned and 99.2% were eligible. There were no significant differences in L-R tumor control, DFS, or OS between regimens for either the 5-FU-Cape (L-R p=0.98) or the Ox-none (L-R p=0.70) comparisons. The addition of Ox was associated with significantly more grade 3-4 diarrhea (p<0.0001). Analysis of the primary endpoint showed 3-yr rates of L-R tumor control ranged from 87.4%-88.2%. 3-yr rates of L-R recurrence among pts who underwent R0 resection ranged from 2-4 % for stage II pts, and from 4-11% for stage III pts. 16% of stage II and 26% of stage III pts developed distant metastases by 5 yrs. From 84% to 97% of pts received >80% of the ideal chemotherapy dose in combination with preoperative RT. Conclusions: CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity. Clinical trial information: NCT00058474.
DCC and RET pathway analysis to identify factors associated with advanced colorectal cancer.
Authors: Shiovitz Stacey , Hsu Li , Qu Conghui , Harrison Tabitha A. , Berndt Sonja , Brenner Hermann , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Le Marchand Loic , Newcomb Polly A. , Potter John D. , Schoen Robert E. , Slattery Martha L. , White Emily , Peters Ulrike , Grady William M. ,   GECCO Consortium
Published: February 2017

457

Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10-6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10-3. SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10-3. SNPs in NTN1 and RET reached significance only at p = 1.73x10-2 and 1.53x10-2, respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.
Molecular profiling of patients (pts) with advanced colorectal cancer (CRC): Princess Margaret Cancer Centre experience.
Authors: Chiu Joanne W. , Bedard Philippe L. , Roehrl Michael H. , Serra Stefano , Kryzanowska Monika K. , Knox Jennifer J. , Mackay Helen , Hedley David W. , Moore Malcolm J. , Liu Geoffrey , Dhani Neesha C. , Kamel-Reid Suzanne , Torlakovic Emina , Wang Tao , Tsao Ming-Sound , Chadwick Dianne , Zhang Tong , Yu Celeste , Chen Eric Xueyu , Sakashita Shingo
Published: February 2017

459

Background: The prevalence of somatic mutations other than KRAS, PIK3CA and BRAF in CRC has not been well described. This study reports molecular profiling of pts with advanced CRC in clinical practice. Methods: Pts with advanced CRC are enrolled in an ongoing institution-wide screening program. Molecular profiling is performed on FFPE archival tissues using a customized Sequenom panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥ 500x coverage) in our CLIA-certified laboratory. PTEN negative tumor is defined by IHC with H score <1. Demographic and clinical data are collected. Data was analyzed by chi-square test. Results: From March 2012 to August 2013, 132 pts were enrolled. One or more mutations were found in 50% (58/117) and 93%(14/15) of pts using Sequenom and MiSeq platforms respectively. Mutation rate was 40% for KRAS, 9% for PIK3CA, 2% for BRAF, 4% for NRAS, and 1% for each of CTNNB1, ERBB2, FGFR3, and EGFR. Mutations outside of codons 12/13 were found in 8% (4/53) of tumors with KRAS mutations. MiSeq showed additional mutations including ERBB4 (1/15), SMAD4 (1/15), FRXW7 (1/5), APC (5/15), and TP53 (12/15) in CRC. Co-mutation with KRAS was found in 58% (7/12) of pts with PIK3CA mutation and 80% (4/5) of pts with APC mutation. PTEN negative tumor was present in 20% (11/55) of pts. Presence of any mutation was significantly more common for pts with right-sided CRC (73%) compared to those with left-sided CRC (47%) and rectal CRC (38%) (p < 0.01). There was a trend toward increased proportion of KRAS mutation in right-sided CRC (p=0.06). There was no difference in age, ethnicity, gender, smoking status, stage at presentation, pathology grade, and response to first-line chemotherapy between right and left-sided CRC. Conclusions: Somatic alterations are common in advanced CRC. Targeted next-generation DNA sequencing identifies additional clinically relevant alterations than multiplex genotyping. Differences in the mutation profile of right and left-sided CRC tumors should be further investigated. Updated results will be presented at the meeting.
LDH serum levels as a predictive factor for global outcome in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.
Authors: Del Prete Michela , Scartozzi Mario , Prochilo Tiziana , Faloppi Luca , Giampieri Riccardo , Bianconi Maristella , Berardi Rossana , Onofri Azzurra , Bittoni Alessandro , Zaniboni Alberto , Cascinu Stefano
Published: February 2017

497

Background: Although a demonstrated clinical efficacy, a non negligible proportion of colorectal cancer patients does not seem to benefit from regorafenib and are consequently exposed to unnecessary toxicity. LDH serum levels represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis in many tumour types. In colorectal cancer LDH showed a correlation with treatment outcome for patients receiving antiangiogenetic treatment, thus suggesting a possible interaction with the activity profile of these drugs. We analyzed the role of LDH serum levels in predicting clinical outcome for pre-treated metastatic colorectal cancer patients receiving regorafenib. The final aim was to individuate a potentially reliable and easy to use marker for patients stratification. Methods: 118 colorectal cancer patients treated with regorafenib were available for our analysis. For all patients, LDH values were collected within one month before the procedure and after treatment end. LDH cutoff value was determined by ROC curve analysis, patients were then divided into two groups (A and B, below and above cut-off level respectively). Patients were also classified according to the variation in LDH serum levels pre- and post-treatment (increased patients vs. decreased patients). Results: Patients in group A and B proved homogeneous for all clinical characteristics analyzed. In group A patients median progression free survival (PFS) was 3.18 months, whereas it was 1.87 months in group B patients (p = 0.0018). Median overall survival (OS) was 6.23 months and 3.28 months in group A and B respectively (p = 0.048). Significant differences were not noted among the 2 groups for response rate. All the other clinical variables analyzed failed to show any correlation with patients outcome. Conclusions: Our observations seem to suggest a role of LDH as a marker of clinical outcome in colorectal cancer patients receiving regorafenib. We can then speculate that high LDH patients may not be optimal candidates for regorafenib. After further confirmation in larger trial, these findings may be relevant for a better patients stratification and selection.
The impact of chemotherapy use on financial strain among stage III colorectal cancer patients: A population-based survey.
Authors: Veenstra Christine Marie , Regenbogen Scott E. , Hawley Sarah T. , Banerjee Mousumi , Kato Ikuko , Ward Kevin C. , Morris Arden M.
Published: February 2017

505

Background: Many colorectal cancer (CRC) patients suffer personal financial hardship from the disease and its treatment. We hypothesized that chemotherapy use is associated with even greater financial burden and worry. Methods: We analyzed data from a population-based survey of patients with stage III CRC in the Georgia and Detroit SEER catchment areas focusing on the effects of CRC and its treatment on personal finances. The primary outcomes were financial burden, assessed with a seven-component composite measure, and financial worry, assessed with a 5 point Likert scale. The primary independent variable was chemotherapy use. We evaluated relationships between chemotherapy use and individual components of financial burden, as well as composite financial burden and worry, using chi square analyses. Logistic regression was used to examine the effect of chemotherapy use on financial burden and worry, after controlling for patient characteristics. Results: Financial burden scores and financial worry were significantly higher among chemotherapy users (P<0.001). Financial burden and worry were associated with younger age, lack of insurance, and lower education. After controlling for these factors, chemotherapy use remained significantly associated with both financial burden and financial worry. 717/844 respondents (85%) reported chemotherapy use. Chemotherapy users were more likely to use savings (34% vs 20%, P=0.001), borrow money/take out loans (14% vs 4%, P=0.001), fail to make credit card payments (14% vs 5%, P=0.003), reduce spending for food and/or clothing (31% vs 14%, P<0.0001), decrease recreational activities (38% vs 15%, P<0.0001), and reduce general expenses (51% vs 24%, P<0.0001) than those who did not use chemotherapy. Conclusions: Adjuvant chemotherapy confers significant survival benefit in stage III colorectal cancer (CRC), but is associated with significantly increased personal financial burden and worry. Because financial stress has the potential to preclude adherence to recommended care, CRC patients who receive chemotherapy may require additional social services and economic support.
A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.
Authors: Janjigian Yelena Yuriy , Capanu Marinela , Imtiaz Tooba , Kelsen David Paul , Ku Geoffrey Yuyat , Schattner Mark , Brown Karen T. , Ilson David H. , Solit David B. , Berger Michael F. , Vakiani Efsevia
Published: February 2017

52

Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma –progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos). Median age 62, KPS 80, median 2 (1 to 4) prior T containing regimens, 64% of tumors IHC3+; 36% IHC2+/FISH>2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade 1/2:54%), rash (Grade 1/2:54%), mucositis (Grade 1:23%), paronychia (Grade 1/2:15%). To date, 13 pts evaluable for response, 3 of 13 pts (23%) had disease stabilization (PR or SD); 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. Next generation sequencing of matched pre-T and post-T progression tumors from 6 pts was performed and results will be reported. Conclusions: Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
Tolerability study of adjuvant modified FOLFOX6 treatment in curatively resected stage II/III colon cancer (JFMC41-1001-C2: JOIN trial).
Authors: Shinozaki Katsunori , Kotaka Masahito , Touyama Tetsuo , Manaka Dai , Matsui Takanori , Ishigure Kiyoshi , Hasegawa Junichi , Munemoto Yoshinori , Takagane Akinori , Ishikawa Hiroshi , Ishida Hideyuki , Ogata Yutaka , Tsuji Yasushi , Oba Koji , Goto Koichi , Sakamoto Junichi , Saji Shigetoyo , Watanabe Toshiaki , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2017

530

Background: Adjuvant FOLFOX is a widely accepted standard regimen for resected colon cancer. The incidence of grade ≥ 3 peripheral sensory neuropathy (PSN) was 12.4% and 5.7% in Western MOSAIC and Eastern MASCOT (outside Japan) trials, while that of grade ≥ 3 allergic reactions (AR) was 2.9% and 3.1%, respectively. JOIN Trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese patients (UMIN ID: 000004443). Methods: Twelve cycles of mFOLFOX6 were given to patients fitting the following criteria, which were the same as those of MOSAIC: stage II/III resected colon cancer, PS of 0-1, 20 years or older, starting FOLFOX within 7 weeks of surgery, and adequate organ function. The primary endpoint was the incidence of PSN persisting for at least 8 days that interfered with daily activities and that of grade ≥ 3 AR. Target sample size was 800, assuming the expected incidence of grade ≥ 3 PSN and grade ≥ 3 AR would be 12.0% and 3.0%, and the two-sided 95% confidence interval (CI) would not include the corresponding threshold levels (16.5% for PSN and 6.5% for AR) with a 95% probability. Results: From Nov 2010 to Mar 2012, 882 patients were enrolled at 198 institutions. The safety data was analyzed in 828 patients whose data were finalized out of 848 patients received mFOLFOX6, and patient characteristics included: median age of 64 years (21-83); Male/ Female: 444/384; PS 0/1: 776/52; colon/rectosigmoid: 633/195; and stage IIA/IIB/IIC/IIIA/IIIB/IIIC: 96/33/23/61/437/178. The incidence of persistent PSN was 3.3% (95% CI: 2.2%-4.7%), while that of grade ≥ 3 AR was 1.7% (95% CI: 1.0%-2.8%), and the primary endpoint was met. Only grade ≥ 3 neutropenia showed a ≥ 10% incidence (28.7%). The incidence of grade ≥ 3 PSN was 5.8% and interstitial pneumonitis was observed in one case. There was no treatment-related death. The median number of cycles of chemotherapy was 12, and the completion treatment rate was 67.0%. The median total dosage of oxaliplatin (L-OHP) was 811.1 mg/m2. The median relative dose intensity of L-OHP, fluorouracil (FU) bolus and FU infusion were 90.0%, 76.9% and 81.7%, respectively. Conclusions: Adjuvant mFOLFOX6 is tolerable in Japanese patients with colon cancer. Clinical trial information: UMIN000004443.
Predictors of clinically significant bleeding in colorectal cancer: Results from a global prospective cohort study.
Authors: Sohal Davendra , Kuderer Nicole Maria , Shepherd Frances A. , Pabinger Ingrid , Agnelli Giancarlo , Liebman Howard A. , Vicaut Eric , Meyer Guy , Lyman Gary H. , Khorana Alok A.
Published: February 2017

558

Background: Bleeding is an important complication among patients with colorectal cancer but its prevalence and predictors are incompletely understood. We evaluated data from a global prospective cohort study to define the incidence, predictors and consequences of bleeding in patients undergoing adjuvant or palliative treatment for colorectal cancer. Methods: CANTARISK was a prospective, non-interventional, international cohort study in patients with lung and colorectal cancer on chemotherapy, the patients were not on long term anticoagulation. Clinical data were collected at baseline, and at 2, 4, and 6 months. All data were compiled centrally and analyzed after the study had closed. Statistically significant univariable associations and a priori variables were tested in multivariable models; adjusted odds ratios (OR) with confidence intervals (CIs) are presented. Results: A total of 1,789 patients with colorectal cancer were enrolled from 2011-12. Median age was 62 years; 61% were male; 71% were Caucasian and 18% were Asian; 37% were from Europe, 28% from North America, 23% from Asia, and 12% from South America. Ninety-two (5.14%) patients experienced at least one bleeding episode during antineoplastic treatment, ranging from 1 to 5 episodes each, with a total of 109 episodes. The gastrointestinal tract was the source in 49 (45%) episodes. Approximately one-third of episodes (n=34, 31%) necessitated transfusion, but only 1 (0.9%) was fatal. In multivariate analysis, independent predictors of bleeding included presence of metastases (OR = 2.13, 95% CI=1.25-3.65) and surgery within prior 6 months (OR = 3.66, 95% CI=1.78-7.47) but not intact primary tumor (OR = 1.57, 95% CI=0.99-2.51). Notably, age, baseline blood counts, ECOG performance score, and anticoagulant use during study were not associated with bleeding. Conclusions: Bleeding is prevalent amongst patients with colorectal cancer receiving systemic chemotherapy. Post-surgical patients and those with metastatic disease appear to be at highest risk. Resection of the primary tumor does not appear to significantly alter risk.
An interim analysis of a phase II study using an epigenetic biomarker (CHFR methylation status) to personalize chemotherapy in patients with operable esophageal cancer.
Authors: Kelly Ronan Joseph , Wrangle John , Hales Russell K. , Molena Daniela , Yang Stephen C. , Rodgers Kristen , Lang Margaret , Reynolds Jeffrey , Beckman Tammy , Choflet Amanda , Brock Malcolm , Herman James Gordon
Published: February 2017

76

Background: Preoperative chemoradiotherapy using a platinum plus either a taxane or 5FU results in a pathological complete response rate (pCR) of approximately 25% to 30% in patients with operable esophageal cancer. A predictive biomarker to personalize chemotherapy in an effort to increase pCR would be a significant advance. Checkpoint with forkhead and ring finger domains (CHFR) is an E3 ligase which plays a role in response to mitotic stress. In our retrospective data, hypermethylation and silencing of CHFR, correlates with improved response and prolonged survival following therapy with taxanes. The primary endpoint of this study is to determine if there is a higher pCR rate when CHFR methylation status (MS) is used to decide if patients receive a taxane or 5FU. Methods: All patients presenting to Johns Hopkins with operable T2-T4/N0-N3 esophageal cancer are eligibile. A methylation-specific PCR which demonstrates CHFR MS has been developed by our lab. Methylated (M) patients receive weekly cisplatin (30mg/m2)/paclitaxel (50mg/m2) and unmethylated (U) patients receive previously described regimens of folfox or cisplatin/5FU. All patients receive concurrent radiation. Results: From July 2011 to September 2013, 35 patients have been assessed, 18 U (51%), 14 M (40%) and 3 unknown (9%). Twenty-four patients (22 males and 2 females) have been treated on study (age 48 – 74 years old, median 63.8) with 14 tumors U (58%) and 10 tumors M (42%) respectively. To date, 2/13 U patients (15%) have had a pCR and 3/8 M patients (38%) have had a pCR (p=0.32). Toxicities of each regimen are consistent with previous reports. Conclusions: Trimodality therapy is standard of care for operable esophageal cancer in the United States. Different chemotherapies have been combined with radiation prior to surgery to improve pCR rates but no biomarkers to personalize chemotherapy exist at present. Epigenetic biomarkers such as CHFR MS potentially may be used to decide which patients are more sensitive to taxane based regimens. Accrual to this study is ongoing. Clinical trial information: NCT01372202.
Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: New results from the OPUS study.
Authors: Tejpar Sabine , Lenz Heinz-Josef , Köhne Claus-Henning , Heinemann Volker , Ciardiello Fortunato , Esser Regina , Beier Frank , Stroh Christopher , Duecker Klaus , Bokemeyer Carsten
Published: February 2017

LBA444

Background: Patients with KRAS exon 2 codon 12/13 wild-type (wt) mCRC benefit significantly from the addition of cetuximab to first-line FOLFOX4 in relation to response and progression-free survival. Patients with KRAS exon 2 codon 12/13 mutations show no benefit with a trend to worse clinical outcomes. Methods: Tumors from OPUS study patients previously defined as KRAS codon 12/13 wt (n=179) were screened for specific mutations in KRAS exons 3 and 4 (8) and NRAS exons 2, 3, and 4 (18) using BEAMing technology. Treatment outcomes were assessed according to mutation status. Results: RAS tumor mutation status was evaluable for 118/179 (66%) patients. Mutations at the screened loci were detected in 36 (31%) patients. In the RAS wt population, there was benefit associated with the addition of cetuximab to FOLFOX4 (Table). In the overall RAS-mutant population, there was less favorable clinical outcome and no benefit from the addition of cetuximab to FOLFOX4. Conclusions: Patients with mCRC harboring any activating mutation of KRAS or NRAS are unlikely to benefit from the addition of cetuximab to FOLFOX4. Definitive conclusions for patients with new tumor mutations cannot be drawn due to low patient numbers. Restricting cetuximab administration to patients with tumors wt at all such loci might enable the further tailoring of therapy to maximize patient benefit. [Table: see text]
The initial report of RTOG 0436: A phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery.
Authors: Suntharalingam Mohan , Winter Kathryn , Ilson David H. , Dicker Adam , Kachnic Lisa A. , Konski Andre A. , Chakravarthy Bapsi , Gaffney David K. , Thakrar Harish V. , Horiba Margit Naomi , Deutsch Melvin , Kavadi Vivek , Raben Adam , Roof Kevin S. , Videtic Gregory M. M. , Pollock Jondavid , Safran Howard , Crane Christopher H.
Published: February 2017

LBA6

Background: RTOG 0436 is a randomized Ph III trial designed to evaluate the benefit of cetuximab added to the concurrent chemoradiation for patients undergoing non-operative management of esophageal carcinoma. Methods: Pts with biopsy-proven squamous cell or adenocarcinoma of the esophagus (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions ± weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2). Patients were stratified by histology, tumor size (< 5 cm vs > 5cm), and the status of celiac lymph nodal involvement. Overall survival (OS) was the primary endpoint, with a planned accrual of 420 pts to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided 0.025 alpha. An interim analysis of cCR was planned for the first 150 of each histology. Results: The study accrued 344 pts from 2008-2013 and 328 were eligible. Based on interim analyses, the study stopped accruing adeno pts in 5/2012 and SCC pts in 1/2013. Pts were well matched for pretreatment characteristics: 80% with T3/4 disease, 66% N1, and 19% with celiac nodal involvement. Incidence of grade 3/4/5 treatment (tx) related AEs was 45%, 22%, 4% in Arm 1 (cetuximab) and 49%, 17%, 1% in Arm 2 (no cetuximab). A cCR rate of 56% was observed in Arm 1 vs 59% in Arm 2 (p=0.72). No differences were seen in cCR between tx arms for either histology. The 12 and 24 mo OS rates for cCR pts were 79% and 58% vs 53% and 30% for those with residual disease (p<0.0001). Median follow-up for all pts is 15.4 mos. The 12 and 24 mo OS (95% CI) for Arm 1 is 64% (56%, 71%) and 44% (36%, 52%) vs 65% (57%, 72%) and 42% (34%, 50%) for Arm 2 (p=0.70). Adeno pts (n=203) had a 12 and 24 mo OS of 65% and 43% for Arm 1 vs 64% and 41% for Arm 2 (p=0.37). The 12 and 24 mo OS for the 125 SCC pts was 62% and 46% for Arm 1 vs 67% and 43% for Arm 2 (p=0.97). Conclusions: The addition of cetuximab to concurrent chemoradiation did not improve OS. There were no differences in cCR rates by tx arm. These Ph III results point to little benefit for current EGFR targeted agents in the tx of esophageal cancer. Supported by RTOG CA21661 and CCOP CA3742 NCI grants and Bristol Myers Squibb. Clinical trial information: NCT00655876.