bluuebunny/crossref_metadata_2025 huggingface dataset:
18F-FDG PET as a predictor of resectability and clinical outcomes in locally advanced pancreatic cancer patients treated with radiotherapy.
Authors: Tuli Richard , Yang Wensha , Tighiouart Mourad , Yue Yong , Fraass Benedick , Sandler Howard Mark , Hendifar Andrew Eugene , Nissen Nicholas N.
Published: February 2017

378

Background: Surgical resection is the preferred approach for localized pancreatic adenocarcinoma, yet likelihood of margin positive resection precludes its use in patients with locally advanced (LAPA) disease. Whereas CT imaging is the standard for defining resectability, studies suggest reduced accuracy following radiotherapy (RT). Given the potential clinical implications, improved methods to define resectability are needed. We investigate whether PET and other clinical factors can be used to predict likelihood of margin negative resection in LAPA patients. Methods: We reviewed LAPA patients treated with RT from 2011-2013 who also underwent pre- and 6-week post-RT PET/CT. Mann-Whitney test and Cox modeling were used to identify predictors of margin negative resection and progression-free survival (PFS), respectively. Variables assessed included: pre- and post-RT SUV max, mean, coefficient of variation (CV), total lesion glycolysis, CA19-9 and tumor size. Results: Eighteen LAPA patients treated with RT were identified. Median age was 66 years. Seven were considered resectable following RT. 6 patients underwent margin negative resection, while the 7thpatient refused surgery. An additional 2 patients were technically resectable, but developed metastatic disease. Mean value for post-RT SUV max was 3.5 in resected patients versus 4.9 in unresected patients. This difference was borderline significant (p=.08) for predicting resectability. Similarly, pre- to post-RT change in SUV max was -4.37 in resected patients and -1.26 in unresected patients, which was also not significant (p=.17). Median PFS was 13 months for resected patients and 8.5 months for unresected patients (p=.06). Predictors of PFS included post-RT SUV CV (p=.05) and pre-RT CA19-9 (p=.03). Conclusions: Mean post-RT SUV max was borderline significant for predicting which LAPA patients may undergo successful margin negative resection. Post-RT metabolic response was also predictive of improved PFS, further validating PET/CT as an important prognostic imaging tool. Studies are ongoing to further validate these predictors of resectability given the potential clinical significance.
Influence of histologic subtype on metastatic pattern in colorectal cancer.
Authors: Hugen Niek , Van De Velde Cornelis J. H. , de Wilt Johannes H. W. , Nagtegaal Iris D.
Published: February 2017

395

Background: In colorectal cancer (CRC) mucinous adenocarcinoma (MC) and signet-ring cell carcinoma (SRCC) have been associated with differences in metastatic patterns compared to the more common adenocarcinoma (AC). This study systematically evaluates metastatic patterns of different histological subtypes and analyses metastatic disease based upon primary tumor localization. Methods: A nationwide retrospective review of pathological records of 5,813 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch Pathology Registry (PALGA). To validate metastatic patterns in rectal cancer patients, data was compared to the prospective randomized multicentre TME-trial that investigated efficacy of preoperative radiotherapy. Results: In the autopsy study 1,675 patients with CRC had metastatic disease. Metastatic disease was more frequently found in MC and SRCC than in AC (33.9%, 61.2% and 27.5%; P< 0.0001) and more often had metastases at multiple sites (58.6% and 70.7% versus 49.9%; P=0.001). AC more commonly metastasized to the liver compared with MC and SRCC, 73.0% versus 52.2% and 31.7% (P<0.0001). The occurrence of metastases exclusively to the liver was less common in MC and SRCC patients. In SRCC patients, liver metastases were almost always observed in combination with other metastases. MC and SRCC metastasized to the peritoneal surface frequently, 48.2% and 51.2%, compared with 20.1% in AC (P<0.0001). Colon cancer patients presented more frequently with intra-abdominal metastases, than rectal cancer patients. Rectal cancer patients presented more often with extra-abdominal metastases. Results from the TME-trial confirmed findings in rectal cancer patients from the autopsy study. Conclusions: There are profound differences in metastatic patterns between different histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take histological subtype into account during pre-operative examination for metastases and during follow-up. Results also indicate that these factors should be considered a stratification factor in future research initiatives focusing on advanced disease.
Overlapping phenotypes with AFAP and FAP in patients with Lynch syndrome gene mutations.
Authors: Heckaman Erin , Moyes Kelsey , Arnell Christopher , Landon Michelle , Wenstrup Richard J.
Published: February 2017

402

Background: Lynch syndrome is a well-described cause of hereditary colon cancer. A point of the Amsterdam II criteria, which defines Lynch syndrome, is to exclude familial adenomatous polyposis (FAP). FAP is caused by mutations in the APC gene and is defined as the presence of 100+ adenomas. The attenuated form of familial adenomatous polyposis (AFAP) can be considered when an individual has 10-99 adenomas. While adenomatous polyps may be a part of the Lynch syndrome phenotype (as a precursor to carcinoma), the assumption is that Lynch syndrome and APC-associated polyposis do not have overlapping phenotypes. Methods: A retrospective analysis was performed on 8,202 individuals with a personal history of adenomatous polyps that had clinical genetic testing for Lynch syndrome (including genes MLH1, MSH2, MSH6, PMS2, and EPCAM) between January 2006 and July 2013. Patient adenoma history was collected on the test request form. The inclusion criterion was limited to personal history of adenomatous polyps and did not depend on personal or family history of cancer. Patients were excluded if the test performed was either targeted mutation testing or single gene testing, presumably based on prior immunohistochemistry tumor testing. Results: Of 8,202 patients with a personal history of adenomatous polyps that underwent Lynch syndrome testing, 610 (7.4%) were positive for a mutation. Mutations were detected in patients with a wide distribution of cumulative adenomas (Table). Seventy-five of the patients with a Lynch syndrome mutation had an adenomatous polyp phenotype suggestive of either FAP (100+ adenomas) or AFAP (10-99 adenomas). Of these 75 patients, 19 underwent APCtesting, all of whom were negative for a mutation. Conclusions: Individuals with an adenoma history, who were tested for Lynch syndrome, had an overall 7.4% mutation positive rate, indicating an overlapping phenotype between Lynch syndrome and FAP/AFAP. This overlap supports consideration of a gene panel test approach. [Table: see text]
Identifying BRAF mutations in colorectal cancer (CRC) by initial immunohistochemical (IHC) staining for mismatched protein expression as part of a Lynch syndrome screening program: A distinct clinicopathologic entity.
Authors: Grote Thomas H. , Kilpatrick Scott E. , Webb Dena B. , Hughes Amy Herndon , Hughes Sarah
Published: February 2017

405

Background: Multiple genetic mutations resulting in different clinical phenotypes have been found in colorectal adenocarcinoma. Mutation in the BRAF oncogene is a key step in malignant transformation within the methylator pathway leading to colorectal cancer. There is little data regarding the identification of the subset of CRCs exhibiting mutations in the BRAF oncogene with initial IHC staining, as well as a paucity of information describing this unique subset of colorectal cancers Methods: Between 1/1/11 to 12/31/12, all newly diagnosed CRCs underwent IHC testing for MLH1, MSH2, MHS6, and PMS2 protein expression if sufficient pathologic material existed. If MLH1 protein expression was absent, BRAF V600E mutation analysis was preformed. Patient demographics, pathology and outcomes were examined through chart review. Statistical associations were determined by the TTest, Fisher’s exact probability test and Cox regression analysis of Kaplan-Meier curves. Results: 314 newly diagnosed CRC patients were identified and 278 (89%) underwent IHC staining (study population). 48 had absent MLH1 protein expression (15%) and underwent BRAF mutational analysis. 35/48 had the V600E mutation. Comparing the BRAF mutated group to the study population without BRAF mutation showed statistically significant differences. These differences included median age at diagnosis (78 vs. 65 years, p < 0.0001), female sex (77% vs. 51%, p = 0.0037), right colon location (77% vs. 42%, p = 0.0001) and significant mucinous component denoted pathologically (31% vs. 7%, p = 0.0001). There was no difference in stage of CRC at diagnosis between the groups. Survival rates at one year based on Kaplan Meier curves were 65% vs. 82% and results will be updated. Conclusions: BRAF mutations in CRC are associated with unique clinicopathologic characteristics and overall worse prognosis. This subgroup of CRC can be identified as part of a Lynch Screening program via ICH staining of the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2.
Il-8 as an underutilized prognostic factor in metastatic colorectal cancer.
Authors: Shah Manasi S , Fogelman David R. , Daniel-MacDougall Carrie , Raghav Kanwal Pratap Singh , Heymach John , Tran Hai T. , Jiang Zhi-Qin , Kopetz Scott
Published: February 2017

409

Background: Cancer-associated inflammation has been identified as a key determinant of disease progression and survival in colorectal cancer. We investigated the association between circulating inflammatory cytokines and survival in metastatic colorectal cancer (mCRC) patients. Methods: Plasma levels of 47 cytokines were measured using multiplex-bead assays in a cohort of 168 previously untreated mCRC patients. Demographic, clinical-pathological features, body mass index, and mortality data were abstracted from patient medical records. Overall survival (OS) was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. Results: Using principal component analysis, we identified a subset of cytokines explaining the maximum variance in OS; and found interleukin (IL)-1b, IL-5, IL-8, IL-12 and VEGF to be significantly associated with OS. However, only IL-8 was significantly and independently associated with OS in multivariable-adjusted models. For each 100 pg/ml increase in the level of circulating IL-8, hazard rate for death increased by 1.6 (95% CI 1.24-1.97). IL-8 measurements ranged from <1 to 413 pg/ml with a median value of 22 pg/ml. Median uncensored survival was 26.5 and 15.5 months among patients with IL-8 levels below and above this value, respectively. ROC analysis of IL-8 demonstrated an AUC of 0.69 (95% CI 0.60-0.76), as compared to 0.52 for CEA (95% CI 0.46-0.59). Conclusions: We identified an association between IL-8 and OS in previously untreated mCRC patients, suggesting its potential role as a prognostic inflammatory biomarker. In this dataset, IL-8 outperformed CEA as a prognostic biomarker, a finding which requires validation in subsequent work. Appropriately identifying, monitoring and managing chronic inflammation and the host inflammatory response during colorectal cancer treatment may be important for improving long-term survival.
Coamplification of receptor tyrosine kinases and downstream targets in Japanese gastric cancers.
Authors: Silva Arnaldo Neves Santos , Coffa Jordy , Miyagi Yohei , Menon Varsha , Bottomley Daniel , Ward Lindsay C. , Aoyama Toru , Hayden Jeremy D. , Arai Tomio , Tan Iain BeeHuat , Deng NianTao , Chan Xiu Bin , Lin Suling Joyce , Tan Patrick , Yoshikawa Takaki , Zondervan Ilse , Savola Suvi , Grabsch Heike I.
Published: February 2017

41

Background: Amplifications of receptor tyrosine kinases genes (RTKs), EGFR, ERBB2, FGFR2, MET, have been associated with the pathogenesis and progression of gastric cancer (GC). Recent studies have found that coamplifications of RTKs are rare in GC. Two phase III trials using RTK targeted therapy have failed to achieve survival benefit in GC patients. Co-amplification of RTKs and downstream targets genes (DSTs), PIK3CA, KRAS, MYC, CCNE1 may be related to resistance to RTK targeted therapy. We tested the hypothesis whether RTKs and DSTs genes are coamplified in GC. Methods: DNA and RNA were extracted from 221 GC from the Kanagawa Cancer Center Hospital (Yokohama, Japan). Copy number of EGFR, ERBB2, FGFR2, PIK3CA, KRAS, MYC, CCNE1 was investigated by a newly developed multiplex ligation dependent probe amplification (MLPA) assay. RNA expression of the same genes was measured using the NanoString platform and compared to DNA copy number status. The frequency of RTK and DST co-amplifications was established and related to KRAS mutation status. Results: RTK amplification was associated with high levels of RNA expression except MYC (all p<0.05). 68% of GC had no RTK amplification. 9% of GC had RTK amplification and no DST amplification. 10% of GC had RTKs co-amplified. 23% of GC had RTK and DST co-amplified. There was no overlap between KRAS mutations and amplifications of KRAS, PIK3CA, FGFR2 or MET. Conclusions: This is the first study reporting that RTK and DST co-amplification are more frequent than RTK co-amplification in GC. These results indicate that GC patients considered for RTK targeting therapy might require DNA copy number assessment of RTKs as well as key DSTs and KRAS mutation testing in order to identify those patients who benefit most from treatment.
Patient-reported sleep disruption as an independent prognostic factor for overall survival in metastatic colorectal cancer.
Authors: Ulusakarya Ayhan , Palesh Oxana , Bjarnason Georg A. , Deguzman Carl , Haitz Karyn , Giacchetti Sylvie , Spiegel David , Levi Francis , Innominato Pasquale F.
Published: February 2017

410

Background: Sleep disruption is a prevalent problem among cancer patients and survivors, but clinical correlates of poor sleep are understudied, especially in colorectal cancer. We recently showed that metastatic breast cancer patients with poor sleep efficiency have a shorter overall survival. The primary study objective is to clarify the relationship between subjective sleep disruption and survival in patients with metastatic colorectal cancer (MCC). Methods: 240 pts (63% male, mean age=59; SD=11.0) treated for MCC in 1st to 5th line of 5-fluorouracil based chemotherapy completed the QOL Questionnaire (EORTC QLQ-C30). We considered sleep to be disrupted if patients reported little to severe trouble sleeping (scores >0 ). Multivariate Cox models included age, gender, site of primary tumor, stage at diagnosis, number of metastatic sites, performance status and prior chemotherapy. Results: 65.4% of the patients reported mild to severe sleep disruption according to EORTC QLQ-C30. Patients with trouble sleeping had poorer overall survival as compared to those without sleep disruption (HR: 1.47 [1.11 to 1.95]; p=0.008). Respective median survival times (months) were 14.2 [95% CI: 12.3 to 16.1] and 17.7 [10.0 to 25.3]. The survival benefit observed in patients without sleep disruption remained statistically significant after adjustment for other prognostic factors. The final multivariate prognostic model included subjective sleep disruption (HR: 1.49 [1.11 to 2.00]; p=0.009), number of metastatic sites (p<0.001), performance status (p=0.023), and prior chemotherapy (p<0.001). Conclusions: Our findings show that patients reported sleep disruption is an independent prognostic factor for overall survival in MCC. Future research is needed to determine the mechanisms of sleep disruption and its effect on survival, and whether treatment of sleep disruption can improve survival in MCC.
Genomic determinants of prognosis in esophageal adenocarcinoma: Using computational methods to account for gene-gene interactions.
Authors: Morgen Eric , Shen Xiaowei , Vaughan Thomas L. , Whiteman David , Wu Anna H. , Gammon Marilie D. , Chow Wong Ho , Stram Daniel O. , Romero Yvonne , Xu Wei , Liu Geoffrey ,   on behalf of the BEAGESS Investigators
Published: February 2017

42

Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.
Predicting the risk of gastrointestinal (GI) toxicity in early colon cancer (CC) patients (pts) treated with adjuvant chemotherapy: Developing a GI toxicity scoring system.
Authors: Gresham Gillian , Sidhu Jasleen , Malhi Navraj , Cheung Winson Y.
Published: February 2017

420

Background: Baseline demographics and clinical factors may contribute to a pt’s overall risk for developing chemotherapy-related GI toxicity, such as nausea, vomiting, and diarrhea. We aimed to develop a GI toxicity scoring system to better stratify early CC pts who may be at higher risk of developing GI toxicity from adjuvant FOLFOX chemotherapy. Methods: Pts diagnosed with early CC from 2005 to 2008 and treated with FOLFOX at the British Columbia Cancer Agency were reviewed. GI toxicities of interest included (1) nausea/vomiting, (2) diarrhea, and (3) any GI side effects. Baseline variables that were analyzed consisted of age, sex, ECOG, time to adjuvant chemotherapy (TTAC), and laboratory parameters. Stepwise regression was used to develop a multivariate model for each toxicity and a weighted risk scoring system was subsequently devised based on the magnitude of the parameter estimates in the multivariate model. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged >70 years, and 54.5% were men. The majority (90.1%) was ECOG 0/1. Independent predictors for nausea/vomiting included age >70 years (OR 2.46, 95%CI 1.3-4.8, p=0.011), GFR <50 (OR 1.68, 95% CI 1.1-2.7, p=0.025), and TTAC >8 weeks (OR 1.33, 95% CI 0.9-2.1, p=0.14) whereas independent predictors for diarrhea included age >70 years (OR 1.44, 95% CI 0.79-2.62, p=0.12) and GFR <50 (OR 1.67, 95% CI 1.1-2.6, p=0.018). The multivariate model for the risk of any GI toxicity included age >70 years (OR: 2.61, 95% CI 1.1-6.1, p=0.049), GFR <50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038), and TTAC >8 weeks (OR 1.79, 95% CI 1.2-2.7, p=0.0059). Points were assigned: 2 points for long TTAC and poor GFR and 1 point for advanced age. The study cohort was classified into their risk groups based on their score (Table). Conclusions: We developed a simple 5-point scoring system to stratify early CC pts receiving adjuvant FOLFOX into low and high risk groups for GI toxicity based on baseline clinical factors. Further validation of this scoring system is required. [Table: see text]
Dose intensity and survival outcomes with adjuvant FOLFOX for colon cancer.
Authors: Smoragiewicz Martin , Rasool Javaheri Khodadad , Yin Yaling , Gill Sharlene
Published: February 2017

423

Background: Adjuvant FOLFOX chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Nonetheless, neutropenia is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose limiting toxicities (DLT), relative dose intensity (RDI) of oxaliplatin and 5-FU, on relapse-free (RFS) and overall survival (OS) in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer. Methods: A chart review was conducted on patients treated at the British Columbia Cancer Agency with ≥ 1 cycle of FOLFOX chemotherapy for resected stage II or III colon cancer between January 1, 2006 and December 31, 2007. RFS and OS were analyzed by the Kaplan-Meier method and multivariate Cox proportional-hazards models. Results: 114 patients (median age 59.2 years, 43.8% male, 98% stage III, median follow-up 5.2 years) were included. 90% of patients experienced any DLT, while 58% of patients had a neutropenia related DLT. There were no documented episodes of FN. G-CSF was used in 9.6% of patients. Median RDI was 81% and 85% for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variable or categorically (Table). Conclusions: DLTs affect the majority of patients on adjuvant FOLFOX for high-risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU. [Table: see text]
Are the cardiovascular side effects of bevacizumab caused by autonomic nervous system toxicity?
Authors: Oqab Zardasht , McIntyre William , Hammad Nazik , Biagi James Joseph , Seaborn Geoffrey , Hopman Wilma , Pal Raveen , Simpson Christopher , Baranchuk Adrian
Published: February 2017

429

Background: Bevacizumab, a monoclonal antibody that inhibits the activity of vascular endothelial growth factor, has demonstrated activity against several malignancies. Reported adverse effects include hypertension, endothelial dysfunction, and heart failure. Animal models have suggested ANS toxicity as the mechanism. This pilot study investigates the effects of bevacizumab on short and long-term ANS function using a pre-post intervention design protocol. We report on the acute effects herein. Methods: Patients were recruited among those starting bevacizumab for colon cancer. A 10-minute ECG was recorded prior to, during, and following a first dose and analysed for heart rate variability (HRV), a marker of ANS dysfunction. The HRV values were compared using paired t-tests and repeated measures ANOVA. Plasma hormones were drawn before and after infusion and compared using paired t-tests. Results: Nine patients without a cardiac history were tested. Mean age was 63 years and 5 were male. All were in sinus rhythm with normal systolic function by echo. The Table reports changes in HRV indices and plasma hormones. Conclusions: Acute administration of bevacizumab produced a statistically significant decrease in plasma aldosterone and was associated with a trend towards decreases in plasma norepinephrine and the low/high frequency domain ratio of HRV. These changes may be signs of an early ANS imbalance. Both a larger patient series and longer follow-up are planned to characterize the effects of bevacizumab on the ANS. [Table: see text]
Expression of proliferation markers in colonic mucosa in normal volunteers with a high arginine-containing diet and effect of dietary grape ingestion.
Authors: Holcombe Randall F. , Martinez Micaela , Planutis Kestutis , Planutiene Marina
Published: February 2017

431

Background: Resveratrol, which inhibits ODC and Wnt signaling, has colon cancer prevention activity in animal models. To assess the effects of a resveratrol-rich diet on the colon, 30 normal volunteers enrolled on a cancer prevention clinical trial (NCT00578396) involving the ingestion of 1/3, 2/3, or 1 pound of grapes per day for 14 days. Data analysis was stratified based on arginine intake because meat and dietary arginine have been linked to colon carcinogenesis. Methods: Patients were placed on a low-resveratrol diet 14 days prior to and during the grape ingestion period. Detailed dietary information and colonic biopsies were obtained before and after the grape intervention in a single-subject design. Tissue was processed for RNA for qRT- PCR analysis of genes implicated in colonic proliferation, Wnt signaling and colon carcinogenesis. The % of cells expressing Ki67 in the lower 1/3 of colonic crypts was determined by IHC. Results: Mean arginine consumption for the study population was 4.5 ± 2.27 gm/day. Participants with higher initial dietary arginine consumption (> 4.5gm) had higher levels of cyclinD1 (p = 0.022), c-myc (p = 0.0002), axin2 (p = 0.0065) and CD133 (p = 0.041) mRNA in the colonic mucosa than participants with lower initial arginine consumption. No differences in the % of base of the colonic crypt cells staining for Ki67 were seen. Grape ingestion led to a significant reduction in cyclinD1 expression in participants with higher initial arginine consumption (p = 0.0039), with levels falling to those seen in low arginine consumption participants. Conclusions: Normal volunteers with a high amount of daily arginine ingestion had elevated levels of markers indicative of cell proliferation (cyclinD1, c-myc), Wnt signaling (axin2), and colonic stem cells (CD133). Expression of each of these markers was reduced following grape ingestion, though only the reduction in cyclinD1 reached statistical significance. Significance: Dietary arginine adversely affects colonic mucosa and may predispose individuals to the development of colon cancer. The effects are reversed in part by a resveratrol-rich grape-containing diet. Clinical trial information: NCT00578396.
The influence of vitamin D and receptor status in colorectal cancer.
Authors: Paluri Ravi Kumar , Council Leona , Putcha Balananda Kumar , Jadav Trafina , Manne Upender , Posey James
Published: February 2017

435

Background: Since vitamin D is a modifiable factor, we have proposed to evaluate vitamin D levels and cognate receptor expression in patients presenting with colorectal cancer (CRC). Previously, we retrospectively assessed vitamin D receptor (VDR) level in 98 CRC tumor tissues and noted a variation of expression with tumor stage (GI ASCO 2009 abs # 371). Methods: We prospectively evaluated 38 cases of CRCs newly diagnosed during 3 consecutive summers and assessed demographics, pathological characteristics and long-term clinical outcomes. Skin color was determined by the Fitzpatrick photo typing scale. At the time of enrollment, vitamin D levels were assessed, and a twenty point lifestyle assessment questionnaire was administered. Descriptive statistics were performed. Tumor and corresponding normal tissues are being evaluated to identify the patterns of VDR expression and expression of the Wnt/B-catenin inhibitors-Dickkopft 1(DKK-1) and Dickkoft-4 (DKK-4), which have been implicated in development of CRCs. Results: 38 patients diagnosed with CRC 24 were men and 14 were women with median age at diagnosis was 59 yrs (range, 28-78 yrs). Median follow up after diagnosis was 2.1 yrs (range, 0.06, 3.68 yrs). Histological grades of adenocarcinomas were well differentiated as well (13%), moderately differentiated (66%), and poorly differentiated (7%), and mucinous types (11%). Patients were staged as I (8%), II (39%), III (34%), or IV (19%). 81% of patients were treated with chemotherapy in an adjuvant or neo-adjuvant setting. The median serum total 25-hydroxy vitamin D level was 23 ng/ml (range, 6-87 ng/ml). There was no substantial difference in median vitamin D levels between lower and higher stages (25 vs 21). Lower stages of CRC were associated with lighter skin types (Fitzpatrick scale types I and II) and advanced stages with darker skin types (IV-VI); this could be a reflection of variable VDR expression. Conclusions: We are analyzing VDR expression as a covariate to compare to vitamin D levels, skin color, and stage. Results will be reported at the time of presentation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.
Prevalence and clinicopathologic features of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in Chinese American patients in south Brooklyn, New York.
Authors: Xiao Ying-Yi , Sun Yan Yu , Desani Jatin Karsandas , Clark Bradley , Win Khin Than , Huang Yiwu , Xu Yiqing
Published: February 2017

441

Background: HNPCC is a hereditary disorder that predisposes to colorectal and other cancers before 50 years old and in multiple generations, with a prevalence of 2 to 5% in Caucasians. It is associated with mutations in DNA mismatch repair genes (MMR). The gold standard for diagnosis is genomic DNA sequencing. Immunohistochemical staining (IHC) is sensitive to predict but not diagnostic for HNPCC, as acquired hypermethylation of MLH1 promoter can present with negative IHC staining. We aimed to study the prevalence and clinicopathological features of HNPCC in Asian patients. Methods: IHC for 4 MMR protein expressions on tumor specimens, commercial MLH1 methylation studies and genomic sequencings were performed on eligible and selected patients diagnosed of colon, gastric or endometrial cancers. Results: 117 patients were identified (2000 to 2012), 55 M and 62 F, ranges from 23 to 92 years old. Seven cases of MMR deficiency were found: 5 with colon cancer (81 patients), 2 with gastric cancer (31 patients) and 0 with endometrial cancer (5 patients). Among the 81 colon cancer patients, 20 had cancer younger than 50 years old; and among them, 3 cases of MMR deficiency were confirmed by DNA sequencing. One patient was found to have a unique previously unreported suspected deleterious mutation. The other 2 patients had MLH1 promoter hypermethylation indicating acquired abnormality. 31 patients had gastric cancer, and 2 cases of MMR deficiency were found, including 1 MLH1 promoter hypermethylation and another isolated PMS2 deficiency by IHC. Conclusions: The prevalence of HNPCC in Chinese colon cancer patients in South Brooklyn is 3.7% (3/81). All cases were found in patients younger than 50 years old with a prevalence of 15% (3/20). Hypermethylation in MLH1 can be seen in both colon and gastric cancers. The screening in Chinese Americans for HNPCC is as important as in Caucasian population, and should be done also in Asian gastric cancer patients as well.
Relationship of RAS and TP53 predictive value for cetuximab (C) benefit: Results of the EXPERT-C trial.
Authors: Sclafani Francesco , Gonzalez David , Cunningham David , Hullki Wilson Sanna , Peckitt Clare , Tabernero Josep , Glimelius Bengt , Cervantes Andres , Wotherspoon Andrew , Dewdney Alice , Brown Gina , Tait Diana M. , Oates Jacqueline Rose , Chau Ian
Published: February 2017

447

Background: We previously reported that TP53 status may predict C benefit in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy and chemoradiotherapy (CRT) and this effect appeared to be independent of KRAS. Recent studies indicate that NRAS mutations and KRAS mutations beyond exons 2-3 may also preclude benefit from anti-EGFRs. We analyzed whether the predictive value of TP53 in EXPERT-C was independent of RAS. Methods: 164 patients received 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83) and were analyzed for KRAS (exons 2-3) and NRAS (exon 3). TP53 mutations (exons 4-9) were screened for by CE-SSCA. KRAS (exon 4) and NRAS (exons 2 and 4) mutations were screened for by bi-directional Sanger sequencing. Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier methods and log-rank analysis was used to compare the treatment arms. The interaction between treatment and TP53 was adjusted for prognostic variables and RAS in a multivariate model. Results: 75/144 (52%) eligible patients had a TP53 mutation. 81/86 patients with known KRAS (exons 2-3) and NRAS (exon 3) wild-type (WT) status were analyzed for the remaining RAS mutations. Of these, 11 (13%) had tumours with mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 75/144 (52%) patients were RAS WT (CAPOX, n=39; CAPOX-C, n=36). After a median follow-up of 65 months, no difference in PFS (HR 1.21, p=0.59) and OS (HR 0.97, p=0.94) was observed between TP53 mutant patients treated with CAPOX or CAPOX-C. In TP53 WT patients, the addition of C was associated with a statistically significant improvement in PFS (HR 0.23, p=0.02) and OS (HR 0.16, p=0.02). A significant interaction between TP53 status and C effect was found (PFS, p=0.029; OS, p=0.036). In multivariate analyses, this interaction remained significant even after adjusting for RAS status (PFS, p=0.026; OS, p=0.033). Conclusions: In EXPERT-C, the value of TP53 as predictive biomarker for C benefit was independent of RAS. The value of monoallelic vs. biallelic TP53 inactivation will be presented at the meeting.
Efficiency of biomarker screening for enriched metastatic colorectal cancer trials: The ATTACC program experience.
Authors: Morris Van Karlyle , Overman Michael J. , Kee Bryan K. , Fogelman David R. , Eng Cathy , Dasari Arvind , Shroff Rachna T. , Deaton Laurel , Manuel Shanequa , Garrett Chris R. , Vilar Sanchez Eduardo , Pini Tunghi May , Shureiqi Imad , Mills Gordon B. , Hamilton Stanley R. , Wolff Robert A. , Meric-Bernstam Funda , Abbruzzese James L. , Maru Dipen M. , Kopetz Scott
Published: February 2017

450

Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials for metastatic colorectal cancer (mCRC) has been proposed or initiated by NSABP, EORTC, NCI Colon Task Force, and UK MRC. The feasibility of large scale screening efforts in mCRC has not been previously assessed. Methods: Patients (pts) with 5-FU refractory mCRC at MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion clinical trials with a therapy targeted to an aberration detected in the patient. Results: Between 8/2010 and 8/2013, 400 heavily pretreated mCRC pts were enrolled onto ATTACC for screening and allocation onto 10 separate Phase I or II companion trials based on banked FFPE tumor testing by IHC, gene sequencing, and CpG island methylation phenotype (CIMP) assay. Outside tissue was obtained with a median of 6 calendar days (8% had insufficient tumor). IHC, sequencing, and CIMP results required a median of 11, 12, and 20 days, respectively. In this population, 53% tumors had KRAS mutations, with BRAF, NRAS, and PI3KCA mutations, and complete PTEN loss present in 8.1%, 8.6%, 21%, and 12%, respectively. CIMP-high status (≥2 markers) was noted in 38% of pts. Given molecular results, trial-specific eligibility, and intermittent study openings, fewer than 25% of screened pts were eligible for enrollment onto a companion protocol. Of these eligible patients, approximately half (13%) enrolled onto a companion trial. Within the entire cohort, 19% enrolled in unenriched trials, and 51% received standard-of-care therapies. ATTACC screening, with an expanding biomarker panel, remains ongoing at a rate of 25-30 patients per month. Conclusions: Universal screening programs such as ATTACC represent an optimal strategy for enrolling patients in multiple biomarker enrichment studies. Even in the setting of multiple companion treatment studies, motivated patients/physicians, and a dedicated screening infrastructure, a majority of patients did not ultimately participate on a companion trial, emphasizing the lack of drugs targeting a number of common aberrations.
Molecular subtypes of colorectal cancer in relation to disease survival.
Authors: Phipps Amanda I. , Limburg Paul J. , Baron John A. , Burnett-Hartman Andrea N. , Weisenberger Daniel J , Laird Peter W. , Sinicrope Frank A. , Rosty Christophe , Buchanan Daniel D. , Potter John D. , Newcomb Polly A.
Published: February 2017

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Background: Classifications for molecular subtypes of colorectal cancer based on microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and somatic mutations in BRAFV600E and KRAS have been proposed to reflect distinct pathways of colorectal tumorigenesis. We assessed the relationship between these subtype classifications and colorectal cancer survival in a population-based study. Methods: Tumor-markers were evaluated in incident colorectal cancer cases diagnosed between 1997-2007 in western Washington State. Cases were classified into pathway-based subtypes according to the following tumor-marker combinations: (1) traditional pathway [microsatellite stable / low MSI (MSS/MSI-L), non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 631]; (2) MSI-high serrated (MSI-high, CIMP-positive, BRAF-mutated, KRAS-wildtype, N=100); (3) MSS/MSI-L serrated (MSS/MSI-L, CIMP-positive, BRAF-mutated, KRAS-wildtype, n = 55); (4) alternate pathway (MSS/MSI-L, non-CIMP, BRAF-wildtype, KRAS-mutated, n = 353); and (5) MSI-high familial (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 50). Multiple-imputation was used to classify tumor-marker status for cases with missing data on one to three markers. Differences in survival across subtypes were assessed through multivariable-adjusted Cox regression. Results: Relative to cases of the predominant traditional pathway subtype, cases with MSS/MSI-L serrated and alternate pathway tumor subtypes experienced statistically significantly worse disease-specific survival [hazard ratio (HR) = 2.25, 95% confidence interval (CI): 1.50-3.36 and HR = 1.39, 95% CI: 1.12-1.71, respectively]; cases with MSI-high familial tumors had the most favorable disease-specific prognosis (HR = 0.28, 95% CI: 0.12-0.64). With respect to overall survival, associations were similar but slightly attenuated. Conclusions: In this large, population-based study, colorectal cancer subtype classifications based on integrated pathways were associated with marked differences in survival, highlighting the significance of molecular heterogeneity in colorectal cancer.
Association of prior treatment with anti-EGFR monoclonal antibodies with downregulation of circulating TRAIL and upregulation of EGFR and VEGF family ligands in metastatic colorectal cancer.
Authors: Lee Michael Sangmin , Lieu Christopher Hanyoung , Overman Michael J. , Eng Cathy , Morris Jeffrey , Jiang Zhi-Qin , Morelli Maria , Heymach John , Tran Hai T. , Kopetz Scott
Published: February 2017

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Background: Inhibition of growth factor receptor signaling leads to unintended compensatory pathway activation in preclinical models, which may impact the success of subsequent therapies. We hypothesized that increased circulating levels of receptor ligands after anti-EGFR monoclonal antibody (mAb) therapy, including VEGF ligands or EGFR family ligands, may provide insights into clinically relevant feedback mechanisms. Methods: Plasma was obtained from 96 metastatic colorectal cancer (mCRC) patients: 48 previously treated with anti-EGFR mAbs and 48 mCRC patients previously treated without prior anti-EGFR therapy who were matched for total months of prior chemotherapy and interval since last chemotherapy treatment. Plasma levels of circulating cytokines with emphasis on EGFR and VEGF ligands were determined using suspension bead multiplex assay (BioRad). Comparisons were done by the two-sided nonparametric Wilcoxon signed rank test. Multivariate linear regression analysis was done with forward selection at p<0.1. Results: By Wilcoxon signed rank test, prior anti-EGFR mAb treatment was associated with differences in EGF (3.5-fold increase, p=0.0001), epiregulin (1.6-fold increase, p=0.02), and TGF-alpha (1.4-fold increase, p=0.04). There was no significant association with amphiregulin, betacellulin, or HB-EGF. Prior anti-EGFR mAb treatment was also associated with differences in TRAIL (1.4-fold decrease, p=0.001) and with differences in VEGF-C (1.4-fold increase, p=0.01), and FGF-basic (1.8-fold increase, p=0.02). After multivariate analysis, prior anti-EGFR mAb treatment remained significantly associated with differences in EGF (p=0.003), TRAIL (p=0.045), VEGF-C (p=0.02), and FGF-basic (p=0.02). Conclusions: Prior treatment with anti-EGFR mAbs is associated with an apparent compensatory increase in EGFR ligands and pro-angiogenic factors, and lower levels of the pro-apoptotic cytokine TRAIL. These differences in circulating growth factor receptor ligands may provide insights on resistance mechanisms and optimal treatment sequencing.
A new prognostic staging system for pulmonary metastases from colorectal cancer.
Authors: Hirosawa Tomoichiro , Itabashi Michio , Bamba Yoshiko , Ogawa Shimpei , Sugihara Kenichi , Kameoka Shingo
Published: February 2017

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Background: A number of studies have examined the prognostic factors associated with pulmonary metastases of colorectal carcinoma (CRC). However, it has not yet been clarified which factor to emphasize taking the treatment strategy into consideration. Methods: The baseline characteristics and outcomes on 352 CRC patients undergoing complete pulmonary resection were collected from 19 institutions by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Study Group (Group A). The clinical and pathological factors were entered into a multivariate analysis to identify independent variables that were helpful for accurately predicting the long-term prognoses after pulmonary resection. Using the prognostic factors of Group A and the following processes (1) to (3), we developed and examined a new prognostic staging system (PSS): (1) Pulmonary (PUL) staging was performed using only pulmonary metastases-related factors in order to further clarify the prognosis. (2) The PSS was created using the PUL staging, primary cancer-related factors and hepatic metastases-related factors. (3) The new PSS was examined in a validation study in a series of 944 patients from 110 institutions of the JSCCR by the 78th society of the JSCCR (Group B). Results: (1) PUL1a: No. of metastases (No.) = 1 and DFI > 2 years;(The 5-year OS: 66.7%, RFS rates: 52.8%). PUL1b: No. = 1 and DFI ≤ 2 years or No. = 2 or No. ≥ 3 and a unilateral distribution; (47.4%, 30.7%). PUL2:No. ≥ 3 and a bilateral distribution or the presence of lymph node metastases or pleural dissemination; (17.4%, 11.1%), (p<0.01). (2) Grade A: PUL1a and lymph node metastases of N0, N1 or N2, or PUL1b and N0; (75.4%, 55.1%). Grade B: PUL1a and N3 or hepatic metastases cases or PUL1b and N1 or N2; (52.0%, 30.8%). Grade C: PUL1b and N3 or hepatic metastases cases or PUL2; (18.2%, 9.0%), (p<0.01). (3) Grade A (n=324): 75.3%, 53.7%; Grade B (n=359): 60.8%, 41.5% and Grade C (n=261): 48.2%, 21.9%. (p<0.01). Conclusions: Our new PSS was useful for the selection of patients suitable for pulmonary resection.
Prognostic and predictive value of tumor-infiltrating immune cells in Japanese patients with stage II/III gastric cancer.
Authors: Earle Sophie , Aoyama Toru , Wright Alexander I. , Treanor Darren , Miyagi Yohei , Ward Lindsay C. , Arai Tomio , Hayden Jeremy D. , Yoshikawa Takaki , Thygesen Helene H. , Grabsch Heike I.
Published: February 2017

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Background: Since the ACTS-GC trial, Japanese patients with stage II/III gastric cancer (GC) receive adjuvant S1 chemotherapy. However, selection of patients (pts) by TNM stage does not predict benefit from adjuvant S1 with certainty. Thus, there is an urgent clinical need to identify predictive biomarkers. Increasing evidence suggests tumor immune cell infiltration may be related to GC pts prognosis. We tested the hypothesis that extent and type of immune cell infiltration in GC is related to benefit from adjuvant chemotherapy. Methods: Tissue microarrays from 252 GC resections (109 pts treated by surgery alone (S), 143 pts treated by surgery and adjuvant S1 chemotherapy (SC)) from the Kanagawa Cancer Center Hospital (Yokohama, Japan) were investigated by immunohistochemistry for common leucocytes antigen (CD45), neutrophils (CD66b), macrophages (CD68 and CD163), T-cell subtypes (CD45R0, CD8, CD3), B-cells (CD20) and Treg cells (FOXP3). Staining was quantified as percentage immunoreactivity/area by automated image analysis. Relationship with overall survival was analyzed. A Cox regression model was used to identify independent prognostic markers and treatment interaction effect. Results: The hazard ratio of S1 was 0.694 in this GC cohort which is similar to the results of the ACTS-GC trial. CD45 and CD45R0 were independent prognostic markers in the S group only (CD45 p=0.032, CD45R0 p=0.003). A treatment interaction effect was seen for CD45, CD45R0, and CD68 (p value for test of interaction: CD45 p=0.062, CD45R0 p=0.082, CD68 p=0.057). Survival in the SC group was significantly poorer compared to the S group for CD45>56% or CD68>7% (p<0.05). Conclusions: This is the first study to investigate the relationship between tumor immune cell infiltration at time of surgery and benefit from adjuvant chemotherapy. Our results indicate that GC patients with high intratumoral levels of CD68, CD45, or CD45R0 positive immune cells might not benefit from adjuvant S1 chemotherapy. These findings require validation in a second independent dataset before conducting a prospective study stratifying patients with stage II/III GC based upon extent of CD45, CD45R0, or CD68 immune cell infiltration for adjuvant treatment.