bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with colorectal cancer.
Authors: Kim Jae Hyun , Park Seun Ja
Published: March 2017

551

Background: Inflammatory response plays an important role in the pathogenesis of cancer. Some evidence has suggested that elevations in the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with decreased survival in various types of cancer. In this study, we aimed to evaluate the prognostic value of the NLR and PLR in patients with colorectal cancer (CRC). Methods: Between August 1995 and December 2010, medical records from a total of 2,004 patients with CRC were retrospectively reviewed. The values of simple inflammatory markers including NLR and PLR in predicting the long-term outcomes of these patients were evaluated using Kaplan-Meier curves and multivariate Cox regression models. Results: The median follow-up duration was 42 months (interquartile range, 19 – 69). The estimation of NLR and PLR was based on the time of diagnosis. In multivariate Cox regression analysis, high NLR ( ≥ 2.6) [hazard ratio (HR) 2.251, 95% confidence interval (CI) 1.570-3.228, p < 0.001] and high PLR ( ≥ 155) [HR 1.473, 95% CI 1.019 – 2.128, p = 0.039] were independent risk factors predicting poor overall survival (OS) in CRC patients. Combined high NLR and PLR was also an independent risk factor predicting poor OS in patients with CRC [HR 2.316, 95% CI 1.529 – 3.508, p < 0.001]. Conclusions: In this study, we identified that high NLR ( ≥ 2.6), high PLR ( ≥ 155), and combined high NLR and PLR are useful prognostic factors to predict OS in CRC patients.
Octogenarian patients with colorectal cancer: Characterizing an emerging clinical entity.
Authors: Goldvaser Hadar , Katz Shroitman Noa , Ben-Aharon Irit , Purim Ofer , Kundel Yulia , Shepshelovich Daniel , Shohat Tzippy , Brenner Baruch
Published: March 2017

552

Background: Colorectal cancer (CRC) in Octogenarians is an emerging clinical entity. It is currently unclear whether these patients have unique features and whether their treatment should differ from younger patients with CRC. The aim of this study was to better characterize this patients population. Methods: A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of ≥ 80 years between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Results: The study included 350 patients, followed for a median of 40.2 months (range 1.8-97.5). Several significant differences were noted. Elderly patients had a higher proportion of Ashkenazi ethnicity (p < 0.001), lower rates of family history of any cancer (p < 0.001) and family history of CRC (p = 0.006), and a higher rate of personal history of other malignancies (p = 0.035). CRC diagnosis by screening was less frequent in octogenarians (p < 0.001) and their performance status at presentation was worse. Octogenarians were more likely to have tumors located in the right colon (p = 0.029) and had a lower prevalence of well differentiated histology (p = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of performance status. Their 5-year cancer specific survival was worse (63.4% vs.77.6%, p = 0.009), both for metastatic (p = 0.03) and for non-metastatic disease (p = 0.028). Conclusions: Elderly patients with CRC presented several differences in clinical and tumor characteristics compared to their younger counterparts. They were less likely to receive treatment and they had worse outcome. Further research is needed to better define this growing patient population and to establish their optimal treatment.
Impact of extra-nodal metastasis on survival in gastric cancer patients with lymph node involvement.
Authors: Nishiwaki Noriyuki , Tokunaga Masanori , Furukawa Kenichiro , Fujiya Keiichi , Omori Hayato , Takagi Wataru , Hirata Fumiko , Kaji Sanae , Hikage Makoto , Makuuchi Rie , Tanizawa Yutaka , Irino Tomoyuki , Bando Etsuro , Kawamura Taiichi , Kinugasa Yusuke , Sugiura Teiichi , Uesaka Katsuhiko , Terashima Masanori
Published: March 2017

57

Background: Extra-nodal metastasis (ENM) is defined as a tumor nodule without lymph node structure, and distinguished from lymph node metastasis by histological findings. Despite the possible difference in metastatic mechanism, both are counted as metastasized lymph nodes according to the 3rd English edition of Japanese Classification of Gastric Carcinoma, and thus the prognostic value of ENM remains unclear. The aim of this study was to clarify the clinicopathogical characteristics and prognostic impact of ENM in gastric cancer patients with lymph node involvement. Methods: This study included 388 patients who underwent curative gastrectomy for primary gastric cancer between January 2009 and August 2013. A total of 2093 pathologically positive tumor nodules, including both metastatic lymph nodes and ENM, were examined. Clinicopathological characteristics and survival outcomes were compared between an ENM positive (ENMP) group (95 patients) and an ENM negative (ENMN) group (293 patients). In addition, multivariable analysis was performed to clarify the independent prognostic factors. Results: ENM was found in 269 of 2093 tumor nodules (12.9 percent). The incidence of ENM was significantly higher in patients with large tumor size, high pathological T stage (pT), high pathological N stage (pN) and in those with macroscopic infiltrative tumors, vascular and lymphatic invasion. Three-year relapse free survival was significantly worse in the ENMP group (56.5%) than in the ENMN group (82.4%, p < 0.001). Multivariable analysis revealed that ENM as well as age, pT and histological type was an independent prognostic factor. Conclusions: ENM is an independent prognostic factor in gastric cancer patients with lymph node involvement. A new N classification stratified by the presence of ENM might be considered.
Clinicopathological features and prognostic factors of colorectal neuroendocrine neoplasms.
Authors: Jiang Mengjie , Hu Hanguang , Yuan Ying
Published: March 2017

572

Background: Limited research is available regarding colorectal neuroendocrine neoplasms (NENs), especially in China. The prognostic factors of colorectal NENs remain controversial. Methods: A total of 68 patients with colorectal NENs were studied retrospectively. Clinical characteristics and prognosis between colonic and rectal NENs were compared. The Kaplan-Meier method and Cox regression models were used to evaluate the capacity of various factors to predict the outcome. Results: Of the 68 colorectal NENs patients, 43 (63.2%) had rectal NENs, and 25 (36.8%) had colonic NENs. Compared with rectal NENs, colonic NENs more frequently exhibited larger tumor size ( P < 0.0001) and distant metastasis ( P < 0.0001). Colonic NENs had a worse prognosis ( P= 0.027), with 5-year overall survival rates of 66.7% vs. 88.1% compared with rectal NENs. Neuroendocrine tumors, neuroendocrine carcinomas and mixed adenoendocrine carcinomaswere noted in 61.8%, 23.5% and 14.7% of patients, respectively. According to the available data (n = 49), Ki-67 index values were ≤ 2% in 27 (39.7%) patients, ranged from 3 to 20% in 6 patients (8.8%) and were > 20% in 16 patients (23.5%). Multivariate analyses revealed that tumor location was not an independent prognostic factor ( P= 0.081), but tumor size ( P= 0.037) and pathological classification ( P= 0.012) were independent prognostic factors. Conclusions: Significant differences in clinicopathological feature and outcome exist between colonic and rectal NENs. Multivariate analysis indicated that tumor size and pathological classification were associated with the prognosis. However, tumor location was not an independent factor. The worse outcome of colonic NENs observed in clinical practice might be due not only to the biological differences, but also to larger tumor size in colonic NENs caused by the delayed diagnosis.
Systemic inflammation score (SIS) to predict the effect of the postoperative adjuvant chemotherapy for patients with stage III colorectal cancer.
Authors: Suzuki Yoshiyuki , Okabayashi Koji , Hasegawa Hirotoshi , Tsuruta Masashi , Ishida Takashi , Kitagawa Yuko
Published: March 2017

575

Background: Postoperative adjuvant chemotherapy (CTx) is a standardized treatment for patients with Stage III colorectal cancer (CRC). Since previous studies reported that the benefit of adjuvant CTx is estimated up to only 15% in Stage III patients, it is necessary to establish an appropriate patient selection for adjuvant CTx. Recently, systemic inflammation is reported to play a critical role in the progression of cancer and several studies demonstrate the impact of inflammation-based score, such as mGPS and SIS. There however is a lack of evidence for the influence of inflammation on patient requiring adjuvant CTx. The aim of this study is to evaluate the impact of SIS on patient selection of adjuvant CTx for Stage III CRC. Methods: Between 2004 and 2012 a total of 295 patients with Stage III CRC who underwent curative resection were included. The SIS was developed based on serum albumin and lymphocyte-to-monocyte ratio (LMR) levels (SIS = 0; albumin > 4.0 g/dl and LMR > 4.44, SIS = 1; albumin < 4.0 g/dl or LMR < 4.44, SIS = 2; albumin < 4.0 g/dl and LMR < 4.44). Primary endpoint was defined as disease free survival (DFS). DFS rates were compared using Kaplan-Meier curves and Prognostic factors were assessed by Cox proportional hazard model. Results: The median follow-up period was 5.99 years. 75.9% of patients received adjuvant CTx. The distribution of SIS was SIS = 0; 32.6 %, SIS = 1; 43.3 %, and SIS = 2; 24.1 %. In multivariate analysis for overall patients, SIS was not a significant prognostic factor. Subgroup analysis according to each SIS score demonstrated that adjuvant CTx significantly prevented postoperative recurrence just only in patients with SIS = 0 (5-year DFS rate; adjuvant CTx (+) 85.5 % vs. CTx (-) 33.7 %, p < 0.001 ). In Cox proportional hazard model, protective effect of adjuvant CTx decreased in proportion to the increase of SIS (HR of adjuvant CTx (95 % CI): SIS = 0; 0.187 (0.089-0.393), SIS = 1; 0.601 (0.311–1.162), SIS = 2; 0.747 (0.319–1.752)). Conclusions: The SIS can provide an appropriate patient selection for patients with stage III CRC who can benefit from adjuvant CTx. The results from this study might enhance precision medicine for adjuvant CTx for Stage III CRC.
Relationship between tumor location and oncogenes mutations (RAS, BRAF, and PIK3CA) in colorectal cancer.
Authors: Inagaki Daisuke , Shiozawa Manabu , Satoyoshi Tetta , Atsumi Yousuke , Murakawa Masaaki , Kazama Keisuke , Aoyama Toru , Higuchi Akio , Morinaga Soichiro , Rino Yasushi , Masuda Munetaka , Miyagi Yohei
Published: March 2017

580

Background: Several studies have reported that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) differ in several factors including genetic features. We investigated the difference in clinicopathological characteristics and oncogenic mutation status between patients with RCC and LCC in all stages. Methods: This study was a prospective, observational study. Patients were recruited from December 2014 to February 2016. Formalin-fixed paraffin-embedded tissue blocks were collected and DNA wes extracted from tissue sections from 158 cases. Mutations in KRAS, NRAS, HRAS, BRAF and PIK3CAwere detected by next-generation DNA sequencer. Tumors from cecum to transverse colon were defined as RCC, and tumors from descending colon to rectsigmoid were defined as LCC. Results: RCC was 66 patients and LCC was 92 patients. Poorly differentiated adenocarcinoma or mutinous adenocarcinoma were significantly more frequent in RCC compared to LCC (P = 0.047). KRAS mutations were detected in 35 patients with RCC (53.0%) and in 32 patients with LCC (34.8%). NRAS mutations were detected in 2 patients with RCC (3.0%) and in 3 patients with LCC (3.3%). There was no HRAS mutation in all patients. BRAF mutations were detected in 7 patient with RCC (10.6%) and in 2 patients with LCC (2.2%). PIK3CA mutations were detected in 8 patients with RCC (12.1%) and in 10 patients with LCC (10.9%). KRAS and BRAF mutation in RCC were significantly more frequent than in LCC (P = 0.022 and P = 0.024, respectively). These mutations were not significantly different according to tumor stage. In this study, both KRAS and BRAFmutations were exclusive. Conclusions: KRAS and BRAF mutation were more frequent in the patients with RCC compared to those with LCC in all stages. This study suggested that it was important to evaluate BRAF mutation in addition to KRAS in order to select more effective treatments, especially in RCC.
CT and PET-CT for detection of synchronous lesion in patients with colorectal cancer obstruction.
Authors: Choi Hyun Ho , Kim Sang Woo , Kim Hyung-Keun , Kim Sung Soo , Chae Hiun-Suk
Published: March 2017

581

Background: Full preoperative colonic evaluation is recommended to exclude synchronous lesions. In patients with occlusive colorectal cancers, preoperative colonoscopy may not be possible because of narrowing of the lumen. After colonic stent placement, colonoscopy to the proximal part of the obstruction is feasible. However, a complete preoperative colonoscopy was not possible in some cases. The aim of our study was to evaluate the efficacy of preoperative CT and PET-CT for detection of synchronous neoplasms compared with colonoscopy in colorectal cancer obstruction patients who underwent colonic stent. Methods: A retrospective chart review of 205 patients who performed endoscopic colon stent placement for acute malignant colorectal obstruction between January 2010 and October 2015. To find synchronous cancer and other precancerous lesion, we reviewed CT, PET-CT finding and colonoscopic image. The results of CT and PET-CT were compared with the finding of the colonoscopy, which was remains the most reliable method for the detection of synchronous neoplasm. Results: Of the 205 patients with colonic stent placement, 115 patients underwent CT, PET-CT and preoperative colonoscopy passing through the colonic stent. On preoperative colonoscopy, 3 of 115 patients (2.7%) had synchronous cancers and 11 of 115 patients (9.6%) had large polyps (tubulovillous adenoma with high grade dysplasia). On CT and PET-CT, all synchronous lesions were detected. But among the eleven polyps, nine polyps had not been seen at CT and PET-CT. Conclusions: Our study indicates that CT and PET-CT were feasible and useful method of evaluating the entire colon to exclude synchronous colonic lesions in patients with acute colon obstruction after an effective stent placement. But colonoscopy should be performed shortly to find out precancerous lesion especially adenoma with high grade dysplasia.
The impact of pulmnary emphysema evaluated by CT on lung metastasis in rectal cancer.
Authors: Toyota Naoyuki , Tsuruta Masashi , Hasegawa Hirotoshi , Okabayashi Koji , Ishida Takashi , Kondo Takayuki , Kitagawa Yuko
Published: March 2017

582

Background: Our previous study suggested that smoking history could be a risk factor for pulmonary metastasis following rectal cancer surgery. Smoking causes emphysematous change in the lung, however, it remains unclear how much impact of pulmonary emphysema (PE) on the pathogenesis of pulmonary metastasis in rectal cancer. The objective of this study is to clarify the influence of PE on the pulmonary metastasis. Methods: Patients with rectal cancer who underwent curative resection from September 2005 to May 2014 in our institution were enrolled and their medical records were reviewed including the percentage volume of low attenuation area in the whole lung (LAA%), which were calculated from their preoperative chest CT by using AZE virtual place. PE was defined as more than 10% in LAA% and statistically evaluated the correlation with relapse free survival for pulmonary metastasis (RFSP). Results: A total of 286 patients, who consists of 7 in stage0,102 in StageⅠ, 75 in StageⅡ, and 102 in stageⅢ, were enrolled. The median LAA% was 3.16±3.78% and 14 patients (4.9%) were diagnosed PE by LAA%. Postoperative pulmonary metastasis was observed in 22 patients, including 3 patients in PE. Five-year RFSP rate in PE was significantly poorer than non-PE (25.4% vs 7.7%, p=0.02) by log-rank test. Multivariate survival analysis using Cox’s regression model revealed that PE was an independent risk factor for RFSP (Hazard Ratio = 19.14 [3.18 – 115.20], p < 0.001). Conclusions: Pulmonary emphysema may have a robust impact on pulmonary relapse after curative surgical resection of rectal cancer.
Long-chain omega-3 fatty acid and fish intake after colon cancer diagnosis and disease-free, recurrence-free, and overall survival in CALGB 89803 (Alliance).
Authors: Van Blarigan Erin , Fuchs Charles S. , Niedzwiecki Donna , Ye Xing , Zhang Sui , Song Mingyang , Saltz Leonard , Mayer Robert J. , Mowat Rex B. , Whittom Renaud , Hantel Alexander , Benson Al Bowen , Atienza Daniel M. , Messino Michael J. , Kindler Hedy L. , Venook Alan P. , Ogino Shuji , Willett Walter C. , Giovannucci Edward L. , Meyerhardt Jeffrey A.
Published: March 2017

585

Background: Long-chain omega-3 fatty acids (LCN-3 FA) may prevent colon cancer (CC) progression, but data in humans are lacking. We hypothesized that LCN-3 FA and dark meat fish intake after CC diagnosis would be associated with longer disease-free survival (DFS), particularly among patients (pts) whose tumors expressed COX2. Methods: We conducted a prospective study among 1011 stage III CC pts enrolled in an adjuvant chemotherapy trial in 1999-2001. Intakes of dark meat fish; canned tuna; breaded fish; shrimp, lobster, scallops, clams; other fish; and fish oil supplements were assessed via food frequency questionnaire during and 6 months (mo) after therapy. Less than 5% of pts reported fish oil supplements. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for disease-free, recurrence-free (RFS), and overall (OS) survival, adjusting for clinical, sociodemographic, and lifestyle factors. In a subset of 510 pts, we examined whether tumor COX2 expression modified the association between LCN-3 FA intake and DFS. Results: We observed 343 CC recurrences and 305 deaths (7 y median follow-up). Higher LCN-3 FA intake after CC diagnosis was associated with 28% improved DFS [HR highest (Q4) vs. lowest (Q1) quartile: 0.72 (0.54, 0.97); p: 0.03]. The association was driven by CC recurrence [RFS - HR Q4 vs. Q1: 0.68 (0.50, 0.94); p: 0.01; OS - HR Q4 vs. Q1: 0.79 (0.56, 1.13); p: 0.17]. Among pts with moderate/high COX2 expression tumors, LCN-3 FA intake was associated with 80% improved DFS [HR Q4 vs. Q1: 0.2 (0.06-0.76); p: 0.006]; there was no association among pts with absent/low COX2 expression ( p-interaction: 0.13). When we examined dietary sources of LCN-3 FA, pts who consumed dark meat fish ≥ 2 times/mo vs. none had longer DFS [HR: 0.64 (0.48, 0.86); p: 0.007), RFS [HR: 0.61 (0.44, 0.83); p: 0.005], and OS [HR: 0.68 (0.48, 0.97); p: 0.05]. No other fish or seafood after CC diagnosis was associated with DFS, RFS, or OS. Conclusions: LCN-3 FA and dark meat fish intake after CC diagnosis may be associated with improved DFS, especially among pts with high COX2 expression tumors. Support: K07CA197077, U10CA180821, U10CA180882. ClinicalTrials.gov: NCT00003835.
Clinical and molecular landscape of metastatic colorectal cancer (mCRC) harboring ALK, ROS1, or NTRK 1, 2, 3 (NTRKs) rearrangements.
Authors: Pietrantonio Filippo , Di Nicolantonio Federica , Schrock Alexa Betzig , Lee Jeeyun , Tejpar Sabine , Siena Salvatore , Christiansen Jason H. , Hechtman Jaclyn Frances , Fucà Giovanni , Antoniotti Carlotta , Kim Seung Tae , Min Bosun , Murphy Danielle , Tebbutt Niall C. , Ross Jeffrey S. , Bardelli Alberto , Ali Siraj Mahamed , Falcone Alfredo , De Braud Filippo G. , Cremolini Chiara
Published: March 2017

589

Background: ALK, ROS1, and NTRKs fusions occur in 0.2-2.4% of CRCs, and represent therapeutic targets, as indicated by promising reports of individual patients treated with tyrosine kinase inhibitors. Clinical and molecular features of mCRCs harboring these fusions have not been elucidated. Methods: mCRC harboring ALK, ROS1 and NTRKs fusions were identified taking advantage of screening programs worldwide (Ignyta STARTRK trials; Foundation Medicine Database; Memorial Sloan Kettering-IMPACT; Australian MAX trial post-hoc analysis). Clinicopathological and molecular characteristics of ALK, ROS1, NTRKs rearranged cases were compared with those of non-rearranged cases, included in Ignyta’s STARTRK trials program. Results: 27 ALK, ROS1 or NTRKs rearranged (including a novel SCYL3-NTRK1 fusion) and 319 not rearranged mCRCs patients were included. Rearrangements were more frequent in older patients (p = 0.024), and tumors that were right-sided (80% vs 30%; p < 0.001), RAS wild-type (93% vs 52%; p < 0.001), MSI-high (48% vs 8%; p < 0.001) and spread more frequently to lymph nodes (46% vs 25%; p = 0.03) and less frequently to the liver (42% vs 66%; p = 0.026). At a median follow-up of 28.5 months, patients bearing rearranged tumors had a shorter overall survival (OS) when compared to non-rearranged (15.6 vs 33.7 mos; HR: 2.17, 95% CI 1.03-4.57; p < 0.001). In the multivariable model including significant prognostic variables (primary site, primary resection, BRAF and MMR status), rearrangements were still associated with shorter OS (HR: 2.78, 95% CI 1.27-6.07; p = 0.011). All of the 4 patients with rearranged tumors evaluable for benefit from anti-EGFRs experienced disease progression as best response. One patient with an MSI-high EML4-ALK rearranged tumor experienced durable response to PD-1 blockade. Conclusions: ALK, ROS1 and NTRKs rearrangements define a new molecular subtype of mCRCs associated with unfavorable prognosis, and specific clinicopathological and molecular features. Since sensitivity to available treatment options, including anti-EGFRs, is very limited, targeted approaches with or without immunotherapy should be investigated in these patients.
ABCG2 and TOP1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.
Authors: Brunner Nils , Nygaard Sune Boris , Budinska Eva , Stenvang Jan
Published: March 2017

591

Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were disease free survival (DFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, which is the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.
Role of genetic polymorphisms in CCL5/CCR5 axis to predict efficacy of regorafenib in patients with refractory metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Schirripa Marta , Cao Shu , Zhang Wu , Yang Dongyun , Marmorino Federica , Bergamo Francesca , Antoniotti Carlotta , Rossini Daniele , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Mashima Tetsuo , Yamaguchi Toshiharu , Loupakis Fotios , Lenz Heinz-Josef
Published: March 2017

596

Background: CCL5/CCR5 pathway is known to mediate VEGF-A production. A recent study reported that serum VEGF-A and CCL5 levels predict efficacy of regorafenib in metastatic colorectal cancer (mCRC). We tested whether genetic polymorphisms in the CCL5/CCR5 pathway are associated with outcomes in patients with refractory mCRC treated with regorafenib. Methods: We analyzed genomic DNA extracted from 229 samples of two cohorts receiving regorafenib: an evaluation cohort of 79 patients (median age 62 years, male 47%, median follow-up time 15.3 months); and a validation cohort of 150 patients (median age 62 years, male 54%, median follow-up time 36.4 months). Nine single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway ( CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were analyzed by PCR-based direct sequencing. Associations between SNPs with progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Multivariable analyses including SNP and baseline characteristics were performed using the Cox proportional hazard regression model. Results: In the evaluation cohort, patients with any A allele in CCL4 rs1634517 had a significant shorter PFS compared to those with the C/C variant (2.0 vs. 2.5 months, HR 1.54, P= 0.043). Patients carrying any A allele in CCL3 rs1130371 had marginally significant shorter PFS (2.0 vs. 2.5 months, HR 1.48, P= 0.064) than those with the G/G variant. In the validation cohort, Patients with any A allele in CCL4 rs1634517 had a shorter PFS (1.8 vs. 2.3 months, HR 1.74, P= 0.001) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) compared to those with the C/C variant. It remained significant in multivariable analysis for PFS and OS ( P= 0.012 and 0.041). Patients carrying any A allele in CCL3 rs1130371 had a shorter PFS (1.8 vs. 2.3 months, HR 1.66, P= 0.002) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) than those with the G/G variant; these effects were significant in multivariable model (PFS: P= 0.027; OS: P= 0.047). Conclusions: Genetic variants in the CCL5/CCR5 pathway, CCL4 rs1634517 and CCL3 rs1130371, may serve as predictive and prognostic markers in refractory mCRC patients receiving regorafenib.
Comprehensive genomic sequencing of appendiceal cancer tumors to identify different genomic alterations by subtype, novel treatment opportunities, and improved outcomes.
Authors: Ang Celina , Singhi Aatur D. , Schrock Alexa Betzig , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Ali Siraj Mahamed , Millis Sherri Z.
Published: March 2017

599

Background: Appendiceal cancers are rare and consist of mucinous (M), adenocarcinoma (A), goblet cell carcinoma (GCC), pseudomyxoma peritonei (PMP), and several even rarer histologies. Current treatment involves surgical resection or debulking; no standard exists for adjuvant chemotherapy or metastatic disease treatment. Systemic treatment is often based on chemotherapy regimens used in colorectal cancer. Methods: Tissue from 518 appendiceal cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling across all appendiceal cancer histological subtypes identified different patterns in GAs across subtypes (table), most notably in GNAS, KRAS, and TP53. No PMP exhibited microsatellite instability (MSI-H) or high TMB ( > 20 mutations/Mb); MSI-H cases included 3 M, 4 A, 1 GCC; 3-7% 12% A and 6% m had high TMB. Case reports of patients with tumors harboring GNAS alterations showed response to MEK inhibitors. Conclusions: Genomic profiles of tumors from patients with appendiceal cancers reveal differing profiles from colorectal cancers (CRC) and considerable heterogeneity between subtypes, suggesting an individualized approach to treatment. Therapeutic options include clinical trials targeting pathways involving KRAS, BRAF, GNAS, PIK3CA, FBXW7, SMAD4, APC, and ATM. Recent case reports indicate that GNAS is a clinical target for MEK inhibitors. Overall, given the poor prognosis of advanced stage appendiceal carcinoma patients, CGP may identify novel, unanticipated therapeutic targets in a significant subset of patients, including immunotherapy for high TMB patients. [Table: see text]
Anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma.
Authors: Maron Steven Brad , Alpert Lindsay , Xu David , Rendak Rachel , O'Day Emily , Setia Namrata , Catenacci Daniel V.T.
Published: March 2017

60

Background: Gastroesophageal cancer (GEC) is a global health problem. Multiple phase III anti-EGFR trials of unselected metastatic GEC patients (pts) were negative, yet subset analyses suggested potential benefit in pts with EGFR amplification (amp). We sought to quantify the incidence of EGFR amp in metastatic/recurrent GEC pts compared to the locally advanced TCGA rate, treat them with EGFR antagonists, quantify response/duration, and assess for mechanisms of action and resistance (MOA, MOR). Methods: 106 stage IV GEC pts in any therapy (tx) line (L) were prospectively screened for EGFR amp between 9/1/14-8/31/16 at a single site using tumor next generation sequencing (NGS). EGFR amp samples were then assessed by FISH, immunohistochemistry (IHC) and mass spectroscopy (MS) to confirm. Pts received 1L ABT-806 (1/4) or 2L+ cetux (3/4) monoclonal anti-EGFR antibodies, in combination with chemotherapy if 1L or 2L (2/4), or as monotherapy for 3L+ (2/4). Pts were followed for response (ORR) and disease control (DCR). Pre and post-treatment NGS, serial ctDNA, and EGFR/PD-L1 FISH/IHC/MS were obtained to monitor for MOA and MOR to tx. Results: Six (5.7%) pts harbored EGFR amp tumors with copies/cell ranging 54-167. Four eligible pts received >1 dose of tx with monoclonal anti-EGFR therapy: 1 FOLFOX-ABT-806 (1L), 1 FOLFIRI-cetux (2L), and 2 cetux alone (3L, 4L); ORR was 100% (4/4) by RECIST, respectively (-70%, -65%, -77%, -43%). All 3 cetux treated pts developed classic rash, which disappeared when/if progression (2/3). The 4-month DCR was 75% (3/4). No pts showed PD-L1 staining pre/post therapy. Upon progression, the 2L pt acquired de novo PTEN exon 6 deletion after 10 months, while basal NRAS mutated and HER2 amp ctDNA clones had expanded in the 4L pt after 4 months of monotherapy. Conclusions: EGFR amp incidence was similar to TCGA. Despite large negative trials with EGFR antagonists for GEC, EGFR amp predicted benefit (100%) from anti-EGFR tx, including monotherapy in 50%, albeit until various resistance mechanisms emerged, including HER2, RAS, and PTEN/AKT pathway activation. No PD-L1 expression was observed pre/post treatment, consistent with our previous data showing that EGFR-amplified cases trend towards a ‘non-T cell-inflamed’ phenotype. Clinical trial information: NCT01416714 / NCT02213289.
Polymorphisms in adipokine-related genes to predict treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy.
Authors: Miyamoto Yuji , Stintzing Sebastian , Zhang Wu , Cao Shu , Ning Yan , Okazaki Satoshi , Berger Martin D. , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Matsusaka Satoshi , Yang Dongyun , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Baba Hideo , Heinemann Volker , Lenz Heinz-Josef
Published: March 2017

600

Background: The molecular effects of obesity are mediated by alterations in the levels of adipokines, which are produced mainly by adipose tissue. Adipokines have multiple effects, including insulin sensitivity, cell proliferation, inflammation, and angiogenesis. We previously reported that single-nucleotide polymorphisms (SNPs) in obesity-related genes were associated with the recurrence probability of CRC treated with 5-FU based adjuvant chemotherapy. This study aimed to evaluate whether SNPs in adipokine-related genes may predict clinical outcomes in bevacizumab treated mCRC pts. Methods: Genomic DNA was obtained from mCRC pts receiving bevacizumab plus FOLFIRI as first-line treatment and analyzed by using PCR-based direct sequencing. Eleven functional SNPs in 7 genes ( LEP, LEPR, ADIPOQ, ADIPOR1, RETN, TNFa and NAMPT) were tested in 291 pts in FIRE3 trial bevacizumab cohort (NCT00433927). Main characteristics were the following: male/female = 193/98; median age = 65; High BMI pts (BMI ≥ 25 Kg/m2)/low BMI pts (BMI < 25 Kg/m2) = 162/129; median PFS = 10.1 months; median OS = 24.2 months, median follow-up time = 40.8 months. Results: LEPR rs1137100 G/G variants (n = 24) showed worse PFS than any A variants (n = 246) in univariate (10.4 months (M) vs. 9.2 M, HR = 1.75, 95%CI = 1.12-2.74, P = 0.011) and multivariate analyses (HR = 1.75, 95%CI = 1.11-2.74, P = 0.016). NAMPT rs61330082 T/T (n = 24) showed worse PFS than any C variants (n = 243) in multivariate analysis (HR = 1.65, 95% = 1.02-2.67, P = 0.042). RETN rs1862513 C/C (n = 23) showed worse OS than any G variants (n = 246) in univariate analysis (14.1 m vs. 25.1 M, HR = 1.65, 95%CI = 1.04-2.60, P = 0.029). In subgroup analyses of high BMI pts, the prognostic effect of LEPR rs1137100 G/G and RETN rs1862513 C/C was confirmed and no association was observed among low BMI pts. Conclusions: Our study showed for the first time that genetic variations in adipokine-related genes are associated with prognosis of mCRC pts treated with bevacizumab based chemotherapy.
Mutation enrichment next-generation sequencing for quantitative detection of KRAS mutations in urine cell-free DNA from patients with advanced colorectal and other cancers.
Authors: Janku Filip , Barzi Afsaneh , Sartore-Bianchi Andrea , Fujii Takeo , Cassingena Andrea , Siravegna Giulia , Karp Daniel D. , Piha-Paul Sarina Anne , Subbiah Vivek , Tsimberidou Apostolia Maria , Huang Helen J. , Veronese Silvio , Di Nicolantonio Federica , Erlander Mark G. , Luthra Rajyalakshmi , Kopetz Scott , Meric-Bernstam Funda , Siena Salvatore , Lenz Heinz-Josef , Bardelli Alberto
Published: March 2017

602

Background: Molecular testing of cell-free (cf) DNA from urine is a completely non-invasive approach for detection of actionable mutations in cancer. Methods: A quantitative mutation enrichment next-generation sequencing (NGS) urine cell-free (cf) DNA KRASG12/G13mutation test was developed and results compared to clinical testing of archival tumor tissue and research testing of plasma cfDNA from patients with advanced colorectal (n=56, 79%) and other advanced cancers (n=15, 21%). Results: The analytical sensitivity of the KRASG12/G13 cfDNA test was 0.002%-0.006% mutant copies in wild-type background. In 71 patients, the agreement between urine cfDNA and tumor was 73% (sensitivity 63%; specificity 96%); the agreement increased to 89% for patients with recommended 90-110mL of urine. In 33 patients with available plasma samples, the agreement with tumor was 94% (sensitivity 92%; specificity 100%). In patients treated with systemic therapy there was lower number of KRASG12/G13 copies in urine and plasma cfDNA on therapy compared to baseline and progression ( P<0.003). Decrease in urine and plasma cfDNA KRASG12/G13 copies on therapy compared to no change/increase was associated with longer median time to treatment failure ( P<0.05). Conclusions: Mutation enrichment NGS detection of KRASG12/G13 mutations in urine cfDNA has good concordance with archival tumor tissue. Changes in urine cfDNA correspond with time to treatment failure.
Soluble CD87 (s-uPAR) predicts bevacizumab-based first line treatment of metastatic colorectal cancer (mCRC): Results from a prospective multi-center study.
Authors: Unseld Matthias , Kornek Gabriele , Gleiss Andreas , Demyantes Svitlana , Schwarzwald Jost , Bianconi Daniela , Andel Johannes , Tinchon Christoph , Pecherstorfer Martin , Eisterer Wolfgang , Jagdt Björn , Kretschmer Andreas , Gerger Armin , Greil Richard , Seebacher Adelheid , Krippl Peter , Laengle Friedrich , Zielinski Christoph , Scheithauer Werner , Prager Gerald W.
Published: March 2017

604

Background: Bevacizumab-combined chemotherapy is well established in the induction treatment of metastatic colorectal cancer (mCRC). Despite tremendous efforts, no valid predictive marker for anti-VEGF treatment has so far been defined. CD87, the urokinase plasminogen activator receptor (uPAR), is centrally regulating VEGF-induced angiogenesis via adapting endothelial cell migration and invasion (Unseld et al.; ThrombHaem,2015, Brunner et al.; Blood 2011, Prager et al; Blood 2009; Prager et al; Blood 2004). Preoperative plasma s-uPAR levels were shown to independently predicted survival of patients resectable colorectal cancer. This study aimed to identify any prognostic or predictive value of s-uPAR in front-line bevacizumab-treated mCRC patients. Methods: In this prospective multi-center trial (NCT02119026), patients were either treated with bevacizumab plus FOLFOX or bevacizumab plus FOLFIRI. Baseline s-uPAR levels were assessed in 80 patients (40 ea. group) using respective CE-certified electro-chemiluminescence immunoassay (ECLIA). Biomarkers were explored using Kaplan-Meier curves and were log transformed for survival analysis by Cox proportional hazards models. All P values reported are two-sided. Results: Data from eighty patients were available for analysis. Progression free survival (PFS) and overall survival (OS) were assessed. Data indicate significance for the angiogenic biomarker uPAR to determine prognostic (HR = 3.06, CI 1.45 - 6.53, p = 0.003) and predictive (HR = 3.41, CI 2.03 - 5.74, p < 0.001) value in the treatment of Bevacizumab. Conclusions: This is the first prospective analysis of baseline s-uPAR. High baseline-s-uPAR levels were an independent predictive marker for worse bevacizumab-based first-line treatment response.
Signet ring cell colorectal cancer: Genomic insights into a rare subpopulation of colorectal adenocarcinoma.
Authors: Korphaisarn Krittiya , Morris Van Karlyle , Overman Michael J. , Fogelman David R. , Shureiqui Imad , Kee Bryan K. , Wolff Robert A. , Eng Cathy , Menter David , Hamilton Stanley R. , Dasari A. , Raghav Kanwal Pratap Singh , Mehta Trupti R. , Manuel Shanequa , Kopetz Scott
Published: March 2017

606

Background: Colorectal signet ring cell carcinoma (SRCC) has been shown to be associated with advanced tumor stage at presentation and worse outcomes. Due to the rarity of this subtype, 1% of all colorectal adenocarcinoma (CRC), little is known about its molecular characteristics. We aimed to characterize the molecular alterations of this subgroup. Methods: Metastatic CRC (mCRC) patients (pts) with signet ring cell (SC) histology who had tumors evaluated with next generation sequencing between February 2009 and November 2015 were reviewed. SC mCRC were classified into 2 groups; SRCC (>50% of signet cells) and adenocarcinoma (AC) with SC component. Genomic alterations, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status noted in SC mCRC were compared to non-SC mCRC pts from the Assessment of Targeted Therapies Against Colorectal Cancer program at MD Anderson Cancer Center using Pearson’s χ 2 test. Results: A total of 665 mCRC pts were included in this study. 93 pts (14%) had SC histology of which 30 (32.3%) pts were SRCC. The Table below shows key cancer genes mutation frequencies. Conclusions: Colorectal SRCC has distinct molecular features compared with non-SC and AC with SC component CRC. The frequencies of KRAS, PIK3CA and APC mutations were lower than the frequencies reported in non-SC CRC. SRCC was not associated with MSI-H or CIMP-H tumor in this study. Further studies on identification of activated pathways underlying this worse prognosis and potential therapeutic targets are required. [Table: see text]
Rational combination therapy in young vs older patients with advanced colorectal cancer (CRC).
Authors: Capasso Anna , Pitts Todd M. , Tentler John J. , Klauck Peter J , Bagby Stacey M , Nguyen Anna , Arcaroli John , Cattaruzza Fiore , Meyer Joshua E. , Connelly Caitlin , Eckhardt S. Gail , Lieu Christopher Hanyoung
Published: March 2017

612

Background: Although CRC is rare in young adults, the incidence has increased recently and patients present more commonly with Stage III or IV disease which may reflect differing biology. Prior analyses revealed a statistically significant increase in the risk of death in young patients with metastatic CRC compared to older patients. Methods: To assess age-dependent genetic changes, DNA and RNA from younger ( < 40) and older ( > 65) CRC were isolated, and whole exome and transcriptome sequencing analysis from 4699 FFPE CRC clinical specimens were performed. Hybridization capture was performed on up to 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Samples were sequenced to high (average 688X) uniform coverage. CRC PDXs were injected into athymic nude mice and randomized into vehicle control, refametinib (MEKi), OMP-18R5 (monoclonal Ab against FZD 1, 2, 5, 7, and 8), or the combination and treated for at least 28 days. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. Alterations in CTNNB1 [p < 0.001, False Discovery Rate (FDR) = 0.07] and MLH1 (p < 0.001, FDR = 0.017) were found to be more common in younger patients. Older patients were more likely to have alterations in APC (p < 0.01, FDR < 0.01) and FAM123B (p < 0.01, FDR = 0.03). The CTNNB1 data provided support to explore the WNT pathway as a potential target for younger patients. Therefore, we conducted an in vivo study of MEKi and OMP-18R5 to assess efficacy in molecularly defined young CRC PDX models. In a young PDX models, we observed enhanced combination effects with tumor growth inhibition index (treated/control) of 13% in the combination arm (compared to tumor growth of 150 %, and 116%, respectively with MEKi and OMP-18R5 alone). Interestingly, in this PDX models, RNA sequencing data showed baseline enrichment in the WNT and mTOR pathway, not observed in the older PDX models. Conclusions: The combination of refametinib and OMP-18R5 showed enhanced antitumor activity in combination compared to the single agent arms. Studies investigating predictive biomarkers of response are currently underway.
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced cancers of the GI tract and anus.
Authors: Schrock Alexa Betzig , Young Lauren , Klempner Samuel Jacob , Bordoni Rodolfo , Ross Jeffrey S. , Stephens Philip J. , Devoe Craig E. , Braiteh Fadi S. , Ali Siraj Mahamed , Miller Vincent A.
Published: March 2017

618

Background: The treatment of GI carcinomas (CA) is influenced by the presence or absence of prognostic and predictive genomic alterations (GA). Tissue sampling is the historical platform for genomic biomarker assessment, but non-invasive ctDNA assay provides an alternative when tissue is unavailable or cannot be safely obtained. Methods: Hybrid-capture based genomic profiling using a ctDNA assay (FoundationACT) was performed on blood samples from 82 consecutive pts with lower alimentary canal CA. Results: Median age was 62 (range 28-92) and 61% were male. Anatomic breakdown included CRC (n = 51), esophageal (n = 9), gastric (n = 8), gastroesophageal (n = 3) and small bowel adenoCA (SBA, n = 2), anus squamous cell CA (n = 5), and other GI CA (n = 4). At least one GA was reported in 72% of cases. In 23 cases with no GA reported, the average maximum somatic allele frequency was 0.17% (95% CI: 0-0.6%) vs. 16.7% (95% CI: 0-54.4%) for the 59 cases with GAs (P < 0.0001). For the 3 of 18 patients with both blood and tissue testing performed and samples collected within a 30-day interval, 8/9 (89%) GA detected in tissue were also detected in ctDNA. An average of 1.7 GA/sample were detected in ctDNA. The most commonly altered genes were TP53 (61%), KRAS (24%), BRAF (10%) and PIK3CA (10%). Comparative analysis using the tissue-based Foundation Core database showed a similar trend with overall slightly higher frequencies of GAs in individual genes . RAF and RAS short variants (SV) were exclusive to lower GI and anal CA. KRAS and RAF1 amplification (amp) occurred only in esophageal CA (4/11, 36%). FGFR SV or amp was identified in 3 cases across the cohort. Of CRC, 4 (8%) had ≥ 1 ERBB2 activating SV or amp, 2 (4%) had IDH1/2 hotspot SV, and 2 (4%) had BRCA2 inactivating alterations. ERBB2 activating SV and EGFR amp were found in a SBA and an esophagus CA, respectively. A kinase fusion was identified as the sole driver in 1 CRC ( STRN-ALK) and 1 SBA ( GOPC-ROS1). Outcomes to targeted therapies will be presented for the available subset of patients. Conclusions: Our results provide early clinical support and confirm that hybrid-capture based ctDNA testing can reliably detect all 4 classes of GA and provide a molecular profiling option for patients with GI CA.
Differences in mutation rates between right- and left-sided colorectal adenocarcinoma.
Authors: Jensen Christopher E. , Loaiza-Bonilla Arturo , Villanueva Jonathan Yap , Morrissette Jennifer J.
Published: March 2017

622

Background: Recent reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease (Schrag et al 2016, JCO 34 (suppl; abstr 3505)) as well as differences in treatment response based on disease sidedness (Venook et al 2016, JCO 34 (suppl; abstr 3504)). However, the biological and genetic underpinnings of these clinical differences are incompletely understood. Methods: We compared mutation rates among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. Primary location was identified via chart review. Right = cecum to transverse colon; Left = descending colon to rectum. Results: Among 293 samples (167 left-sided, 103 right, 23 synchronous or without clear primary), BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (CI: 1.6-8.0%) (p=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (p=0.01). Among right-sided CRC, there was a trend toward more KRAS mutations at 57.3% (CI: 47.7-66.8%) versus 44.9% (CI: 37.4-52.5%) and more PIK3CA mutations at 26.2% (CI:17.7-34.7%) versus 17.4% (CI: 11.6-23.1%), though these differences did not rise to the level of statistical significance. The overall rate of BRAF mutations in our sample (8.9%, CI: 5.5-12.3%) was consistent with the rate of BRAF mutations among large intestine adenocarcinomas in the COSMIC database (10.6%, CI: 10.4-10.8%), lending support to the external validity of these data. Conclusions: These differing mutation rates may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right and left-sided disease described in prior studies. Further work is needed to more clearly elucidate genetic difference between right and left-sided CRC, as well as the mechanistic relationship between these mutations and prognosis.