bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions.
Authors: Pishvaian Michael J. , Rolfo Christian Diego , Liu Stephen V. , Multani Pratik S. , Chow Maneval Edna , Garrido-Laguna Ignacio
Published: January 2019

521

Background: Despite recent improvements in chemotherapy for pancreatic cancer that have demonstrated improvements in survival, response rates remain at less than 50%. Distinct molecular subgroups of pancreatic cancer that harbor specific actionable molecular alterations have recently been identified. These include gene fusions of the receptor tyrosine kinases NTRK and ROS1. Entrectinib is a CNS-active, potent, and selective TRK and ROS1 inhibitor that has shown substantial clinical activity in patients with locally advanced or metastatic solid tumors that have NTRK or ROS1 fusions (Drilon A, et al. Cancer Discov. 2017;7[4]:400-409). Methods: We examined 3 cases of pancreatic cancer where an actionable gene rearrangement was identified: 2 with a TPR-NTRK gene fusion, and 1 with an SCL4-ROS1 gene fusion. All 3 patients were treated with entrectinib 600 mg daily in a phase 2 trial (NCT02568267). Results: Entrectinib was well tolerated with mostly grade 1-2 adverse events consisting primarily of arthralgias, myalgias, and fatigue. All 3 patients showed evidence of clinical improvement, with normalization of the tumor biomarker CA19-9 and confirmed partial responses as per RECIST v1.1 in the 2 patients with a TPR-NTRK fusion, 1 of which was associated with a significant decrease in metabolic activity as assessed by PET/CT scan. The patient with the SCL4-ROS1 fusion had stable disease for at least 6 months. All 3 patients had an improvement to, or maintenance of, a high quality of life while on study. At the time of data cutoff, 1 of the patients with a TPR-NTRK fusion remained on treatment > 1 year. Conclusions: Entrectinib treatment was associated with response and prolonged disease control in these 3 patients with NTRK or ROS1 fusion-positive pancreatic cancer. NTRK and ROS1 gene fusions are rare in pancreatic cancer. The true incidence is unknown, as routine testing for gene fusions in pancreatic cancer is not yet standard practice. Given the benefit seen here with entrectinib and the clinical need for improved therapeutics, there may be value in broader and earlier molecular testing of patients with pancreatic cancer for these actionable fusions. Clinical trial information: NCT02568267.
Effect of epigallocatechin-3-gallate from green tea on 5-flurouracil-induced intestinal mucositis.
Authors: Lee Jung Min , Yoon Kichul , Min Geeho , Kim Woojung , Choi Seong ji , Kim Seung Han , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Chun Hoon Jai , Lee Hong Sik , Kim Chang Duck
Published: January 2019

522

Background: Chemotherapy-induced mucositis is a common complication during anticancer treatment. Epigallocatechin-3-gallate (EGCG), derived from green tea, has been shown to have antioxidant effects and immunomodulatory activities. However, studies on EGCG for chemotherapy-induced mucositis have been scarce. In this study, we aimed to prove the protective effect of EGCG in murine chemotherapy-induced mucositis model Methods: Twenty-four 8-wk-old male C57BL/6 mice were randomized to 4 groups : control, EGCG, 5-Flurouracil (5-FU), EGCG plus 5-FU. Mucositis was induced by intraperitoneal injection of 5-FU (400mg/kg). EGCG (50mg/kg) was administered orally for 5 days from the day before administration of 5-FU. After 6 days of 5-FU injection, the mice were sacrificed and intestinal tissue was obtained. WBC count was performed with whole blood from Inferior vena cava of mice. The end points were villus height, villus/crypt ratio, histologic characteristics, and mRNA expression of tumor necrosis factor ( TNF)-α, and interleukin ( IL)-6. Results: In 5-FU group, neutropenia was confirmed by laboratory test (5-FU, 0.650 K/μL; Control, 5.317 K/μL), indicating sufficient 5-FU effect. Histologic findings showed that crypt dilatation, villus stunting, and villus atrophy were reduced in EGCG plus 5-FU group than in 5-FU group. Quantitatively, mean villus height (EGCG plus 5-FU, 352 μm; 5-FU, 319 μm) and villus/crypt ratio (EGCG plus 5-FU, 3.28; 5-FU, 2.31) in EGCG plus 5-FU group, compared with 5-FU treated group, were significantly higher. mRNA expression of TNF-α was significantly lower in EGCG plus 5-FU group compared with 5-FU group (P < 0.05) (Figure 2). Conclusions: EGCG derived from green tea reduced 5-FU induced intestinal mucositis, suggesting a possibility for novel treatment of chemotherapy-induced mucositis.
Age distribution of tumor gene expression in patients with stage II/III colon cancer.
Authors: Hochster Howard S. , Lau Anna , Turner Michelle , Russell Christy Ann
Published: January 2019

552

Background: Colorectal cancer (CRC) incidence and mortality have been rising in the US among adults <55 y. Younger patients with CRC are more likely than older patients to receive postoperative systemic chemotherapy, despite lack of consensus on the prognostic value of age in this disease. CRC diagnosed in younger patients may be biologically different from that in older patients, but characteristics are unknown. Thus, we examined whether age-specific differences were measurable by tumor gene expression using the 12-gene Oncotype DX Colon Recurrence Score (RS) test (Genomic Health, Inc. [GHI]; Redwood City, CA). The Colon RS test is validated to predict risk of recurrence in patients with stage II/III colon cancer. Methods: We analyzed Colon RS test results and single-gene results for the 12 genes by age group (age <40, 40-54, 55-64, and ≥65) using data from the GHI clinical laboratory dated 1/2010 to 7/2017. Results: As of 7/2017, 21,925 Colon RS reports have been delivered. Median age was 63 y; 50% were male. About 23% of patients were <55 y (Table). Mean (SD) RS result was 25 (11). Colon RS result distributions were similar by age group (Table). Expression of individual tumor genes measured in the Colon RS test were also similar by age group (data to be presented). Conclusions: The etiology of the increase in both incidence and mortality from CRC in adults <55 y is poorly understood. Our findings suggest that colon cancer in younger patients is not biologically different from that in older patients, as measured by the Colon RS test in a large cohort referred for testing. As shown by this test in the GHI clinical laboratory experience, most patients with stage II/III colon cancer have low-risk disease, including patients <55 years. Our findings support a biology-driven approach to disease management of patients with stage II/III colon cancer regardless of age. This well-validated genomic assay may identify a group of younger patients for whom adjuvant chemotherapy might represent overtreatment. [Table: see text]
Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142.
Authors: Overman Michael J. , Bergamo Francesca , McDermott Raymond S. , Aglietta Massimo , Chen Franklin , Gelsomino Fabio , Wong Mark , Morse Michael , Van Cutsem Eric , Hendlisz Alain , Neyns Bart , Moss Rebecca Anne , Zhao Huanyu , Cao Z. Alexander , Kamble Shital , Kopetz Scott , Andre Thierry
Published: January 2019

554

Background: Nivolumab (NIVO) provided durable responses (ORR, 32% per central assessment) and disease control (DCR, 64%) in pre-treated pts with dMMR/MSI-H mCRC (NCT02060188; Overman MJ et al Lancet Oncol 2017). NIVO was approved in the US for pts with dMMR/MSI-H mCRC who progress after standard chemotherapy (SC) with a fluoropyrimidine (F), oxaliplatin (Ox), and irinotecan (Iri). Here we present long-term survival and outcomes by prior chemotherapy with NIVO in CheckMate-142. Methods: Pts with dMMR/MSI-H mCRC received NIVO 3 mg/kg Q2W. The primary endpoint was ORR per RECIST 1.1. Other endpoints were DCR, DOR, PFS, OS, and safety/tolerability. Results: Of 74 pts evaluated, 53 had received F, Ox and Iri (group A); 21 pts had ≤ 2 SC regimens (group B). Median follow-up was 21 mo. Efficacy by central assessment is shown in the Table. In the 74 pts, ORR was 34%; CRs increased from 3% in prior database lock (DBL) to 9%. Numerically higher responses were noted in group B vs group A (Table). Grade 3–4 TRAEs were reported in 20% (all pts), 25% (group A), and 10% (group B) of pts. No treatment-related deaths were reported. Conclusions: NIVO continued to provide clinically meaningful durable responses and long-term overall survival in pts with dMMR/MSI-H mCRC. Of note, CR rate increased with longer follow-up. No new safety signals were reported with long-term follow-up. Enhanced responses in pts with ≤ 2 SC regimens support ongoing evaluation of NIVO combinations in first-line setting. Clinical trial information: NCT02060188. [Table: see text]
Genetic profile of polyps and risk of advanced metachronous lesions.
Authors: Murcia Oscar , Juárez Miriam , Rodriguez-Soler Maria , Hernández-Illán Eva , Egoavil Cecilia , Giner-Calabuig Mar , Alustiza Miren , Alenda Cristina , Mangas Carolina , García Araceli , Aparicio José Ramón , Ruiz Francisco Antonio , Martínez Juan Francisco , Casellas Juan Antonio , Soto José Luís , Zapater Pedro , Jover Rodrigo
Published: January 2019

555

Background: The role of genetic profile of polyps to predict advanced metachronous lesions (AML) remains unknown. The aim is to study the relation between genetic profile of polyps and both risk of AMLs and time to develop them in surveillance. Methods: 308 patients with colonic polyps were consecutively enrolled between 2007 and 2009 for this cohort study, and followed up to 2014 (median 26 months, range 63). Variables as age, sex, smoking, weight, number of colonoscopies and number and characteristics of polyps were collected. 995 polyps were analyzed for somatic mutations on BRAF and KRAS genes using allelic discrimination by real-time PCR and direct DNA sequenciation, respectively. High level of methylation on CpG islands (CIMP-H) was also tested using MS-MLPA. AML was defined by a size higher than 9mm, high grade dysplasia or villous component. Risk of developing AML for individual genetic markers was studied using Chi-square tests and logistic regression. Log-rank test with Kaplan Meier survival curves and Cox-regression model were also performed. Multivariate analysis were adjusted by sex, age, familial colorectal cancer, smoking and features of AML in first colonoscopy. Results: 21% of polyps in first colonoscopy were CIMP-H. KRAS and BRAF mutations accounted for 25% and 17% of polyps, respectively. In univariate analysis, KRAS-mutated polyps were related to higher risk of AML in surveillance (52% KRAS-mutated polyps vs 31% non-mutated; p = 0.01). Similar results were obtained regarding CIMP-H (77% CIMP-H polyps vs 38% non-CIMP; p = 0.005). Logistic regression showed CIMP-H as the unique genetic marker of risk for AML (OR 11.41, 95% CI 2.04-63.70; p = 0.006). Regarding time to develop AML, shorter intervals were found related to CIMP-H (median of 31 vs 48 months in non-CIMP-H; p = 0.002) and KRAS-mutations (median of 36 vs 49 months in non-mutated; p = 0.029) in univariate analysis. Multivariate analysis highlighted CIMP-H as the unique independent marker associated to shorter time to develop AML (HR 4.01, 95% CI 1.36-10.46; p = 0.01). Conclusions: Presence of CIMP-H in polyps associates higher risk of subsequent AML and shorter interval to their development. Genetic profile of polyps emerges as useful tool for colonoscopy surveillance.
Prospective clinical study of circulating tumor cells for colorectal cancer screening.
Authors: Tsai Wen-Sy , Nimgaonkar Ashish , Segurado Oscar , Chang Ying , Hsieh Ben , Shao Hung-Jen , Wu Jen-chia , Lai Jr-Ming , Javey Mana , Watson Drew , Mei Rui
Published: January 2019

556

Background: Colorectal cancer (CRC) is among the most preventable cancers when precancerous lesions are detected at an early stage. Current screening methods for CRC require bowel prep or stool-based testing that are inconvenient, resulting in low compliance. Stool based tests have limited sensitivity for the detection of precancerous lesions. We have conducted a prospective clinical study over a period of > 3 years to assess a novel assay to detect and enumerate circulating tumor cells (CTCs) in a blood sample for early CRC detection. Methods: A single-center, IRB-approved, prospective and blinded clinical study was conducted in 620 subjects including 438 with adenoma, polyps or stage I-IV CRC and 182 healthy controls. For each subject, 2mL peripheral whole blood collected through a routine blood draw was processed using the CellMax biomimetic platform (CMx). The CMx test is a proprietary microfluidic biochip that minimizes non-specific binding and accurately enumerates CTCs. A multivariate analysis was performed to assess the clinical performance characteristics of the CMx test. Results: Disease status was evaluated by a standard clinical protocol which included colonoscopy and biopsy results. Probability of CRC risk was assessed by an age-adjusted regression model which correlated CTCs to clinical status. The CMx test’s overall accuracy was 88% for all stages of colorectal illness, including precancerous lesions. Conclusions: The study has demonstrated high accuracy for the detection of CRC using a novel CTC assay. It is the first study to show high sensitivity in the detection of precancerous colorectal lesions. The simple blood draw required can be easily integrated into a patient’s routine physical, increasing test compliance.[Table: see text]
Reverce: Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan.
Authors: Shitara Kohei , Yamanaka Takeharu , Denda Tadamichi , Tsuji Yasushi , Shinozaki Katsunori , Komatsu Yoshito , Kobayashi Yoshimitsu , Furuse Junji , Okuda Hiroyuki , Asayama Masako , Akiyoshi Kohei , Kagawa Yoshinori , Kato Takeshi , Oki Eiji , Ando Takashi , Ohashi Yasuo , Yoshino Takayuki
Published: January 2019

557

Background: The optimal treatment sequence in current standard care for patients (pts) with anti-EGFR antibodies-naïve metastatic colorectal cancer (mCRC) is cetuximab (C) followed by regorafenib (R). The objective of this randomized phase II trial is to evaluate efficacy and safety of the therapeutic sequence of R followed by C compared with that of C followed by R for mCRC pts. Methods: Pts with KRAS exon 2 wild-type mCRC after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with R followed by C ± irinotecan (R-C arm) or reverse sequence (C ± irinotecan followed by R; C-R arm). The primary endpoint was OS. Key secondary endpoints included PFS with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and QOL. The exploratory endpoint was serial biomarker analyses including oncogenic alterations from ctDNA or multiple serum proteins. Results: Between November 2013 and September 2016, 101 pts (51 in the R-C arm and 50 in the C-R arm) were randomized and eligible for efficacy analysis. Baseline characteristics were well-balanced in both arms. Bevacizumab had been previously administered in 96% and 98% pts in R-C and C-R, respectively. Sequential treatment was succeeded in 86% pts in both arms. After a median follow-up of 29.0 months with 81 death events, median OS in R-C and C-R were 17.4 and 11.6 months, respectively (stratified logrank P = 0.0293), with a hazard ratio (HR) of 0.61 for OS (95% CI, 0.39–0.96). HR for PFS1 (R in R-C versus C in C-R) was 0.97 (95% CI, 0.61–1.54), whereas that for PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI, 0.17–0.50). No unexpected safety signals were observed in both arms. OS results in RAS/RAF wild type populations with ctDNA analysis at study entry (n = 86) were similar to those of overall population. Conclusions: This was the first randomized study to compare the two therapeutic sequences of R and C for mCRC, suggesting R followed by C is the preferred sequence. Comparable PFS1 and remarkable PFS2 improvement may lead to a longer OS in R-C sequence. The results of detailed biomarker analysis would be also reported. Clinical trial information: UMIN000011294.
Effect of physical activity trackers and daily text messages on quality-of-life in colorectal survivors (Smart Pace): A pilot randomized controlled trial.
Authors: Chan Hilary , Van Loon Katherine , Kenfield Stacey A. , Chan June M. , Mitchell Emily , Zhang Li , Paciorek Alan , Joseph Galen , Laffan Angela , Fukuoka Yoshimi , Miaskowski Christine , Meyerhardt Jeffrey A. , Venook Alan P. , Van Blarigan Erin
Published: January 2019

559

Background: There are over 1.3 million colorectal cancer (CRC) survivors in the United States, and many of whom suffer from lower health-related quality-of-life (HRQoL) years after diagnosis and treatment. Physical activity may improve survival outcomes and HRQoL for CRC survivors. Feasible interventions to support physical activity after CRC diagnosis are needed. Methods: We conducted a two-arm randomized controlled trial of 41 men and women who had completed treatment for CRC. Participants in the intervention arm were given a Fitbit Flex™ and received daily text messages for 12 weeks. HRQoL was assessed in both arms at baseline and 12 weeks using the RAND Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy – Colorectal (FACT-C). Survey score changes from baseline to 12 weeks were compared between the two arms using independent t-tests, and scores at baseline and 12 weeks were compared using paired t-tests. SAS was used for analysis, and statistical significance was declared at p < 0.05. Results: We observed a statistically significant increase in the FACT-C functional well-being sub-scale in individuals in the intervention arm pre- and post- intervention (mean ∆ 1.81 ± 2.76; p: 0.02). There was no change in functional well-being in the control arm (mean ∆ -0.35 ± 4.12; p: 0.71). The between-arm comparison of change from baseline to 12 weeks was not statistically significantly ( p: 0.08). There was a statistically significant increase in the FACT-C emotional well-being sub-scale in the control arm (mean ∆ 1.20 ± 2.48; p: 0.04) and in the SF-36 role physical sub-scale in the control arm (mean ∆ 22.5 ± 38.8; p: 0.02). No other measures of HRQoL were statistically significantly different within groups, across time points, or between groups. Conclusions: A 12-week physical activity intervention using a Fitbit Flex™ and daily text messages may improve functional well-being among CRC survivors. Larger randomized studies are needed to definitively determine if a digital physical activity intervention improves functional well-being among CRC survivors, and if the improvement can be sustained over time. Clinical trial information: NCT02966054.
A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Bang Yung-Jue , Chee Cheng Ean , Ryan David P. , McRee Autumn Jackson , Chow Laura Q. , Desai Jayesh , Wongchenko Matthew , Yan Yibing , Pitcher Bethany , Foster Paul , Cha Edward , Grossman William , Kim Tae Won
Published: January 2019

560

Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation of combined anti–PD-L1 (A) plus MEKi (C) in pts with mCRC. Methods: Pts with chemotherapy-refractory or locally advanced mCRC were evaluated. A was administered IV q2w at 800 mg. C was dosed PO daily at 20 to 60 mg during dose escalation and 60 mg during dose expansion (14/14 or 21/7 d on/off schedule). Primary endpoints were safety and tolerability. Investigator-assessed ORR and PFS by RECIST v1.1 and OS were secondary endpoints. Microsatellite instability (MSI) status was locally reported and centrally confirmed by NGS-based scoring. Results: As of May 10, 2017, 84 pts (57 KRASmt, 25 KRASwt, 2 unknown) were enrolled and evaluable. 66 pts had received 5+ prior therapies; 38 had known MSI status at baseline (MSS [n = 29], MSI-low [n = 8], MSI-H [n = 1]). A + C combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 37%, respectively. The most frequent related Gr 3-4 AEs were increased blood CPK, rash, diarrhea and fatigue (5% each). No treatment-related Gr 5 AEs occurred. 13% and 24% of pts experienced AEs leading to A and C withdrawal, respectively. Median follow-up was 14.3 mo (range, 0.5-29.8). Confirmed PR was observed in 7 pts (8%; locally reported MSS [n = 3], MSI-low [n = 1], MSI unknown [n = 3]). Median DOR was 14.8 mo (95% CI: 6.0, NE); DCR (PR + SD) was 31%. Median PFS was 1.9 mo (95% CI: 1.8, 2.3); median OS was 10.0 mo (95% CI: 6.2, 14.1). The 6-mo and 1-y OS rates were 65% (95% CI: 54, 76) and 46% (95% CI: 34, 58), respectively. Molecular determinants and immune biomarkers of response will be presented. Conclusions: A + C demonstrated a tolerable safety profile and improvements in OS vs those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts with MSS/MSI-low mCRC were durable, suggesting benefit of this novel combination in a pt population refractory to immune therapies. Clinical trial information: NCT01988896.
Second primary cancers and recurrence in patients after resection of colorectal cancer: An integrated analysis of trials by Japan Clinical Oncology Group: JCOG0205, JCOG0212, JCOG0404 (JCOG1702A).
Authors: Tanaka Kiyo , Ogawa Gakuto , Mizusawa Junki , Eba Junko , Katayama Hiroshi , Nakamura Kenichi , Shimada Yasuhiro , Hamaguchi Tetsuya , Moriya Yoshihiro , Fujita Shin , Kitano Seigo , Inomata Masafumi , Kanemitsu Yukihide , Fukuda Haruhiko
Published: January 2019

561

Background: Improvements in early detection and treatment have resulted in an increasing number of long-term survivors of colorectal cancer (CRC). For the survivors, Second primary cancers and recurrence are important issues, but the evidence for appropriate surveillance strategy is limited. The aim of this study was to investigate the frequency and the timing of second primary cancers and recurrence in patients (pts) after surgery using 3 randomized trials (J0205, J0212 and J0404) conducted by Colorectal Cancer Study Group of JCOG. Methods: Eligibility criteria included histologically proven CRC and having received surgery. The timing, site and frequency of second primary cancer and recurrence were investigated. Risk factors associated with the events were explored. Standardized incidence ratio (SIR) about second primary cancer compared with national database of Japan Cancer Registry was estimated. Results: A total of 2,824 pts with a median follow-up time of 6 years were included. Median age was 62 years old (23-75), male/female was 58%/42%, and stage 0/I/II/III/IV was 0.2%/8.7%/25.4%/64.8%/0.9%. Pts with 5-FU based adjuvant chemotherapy were 63%. Cumulative incidence of second primary cancer increased constantly over time (Table). Among 240 pts, the most common site was lung (37), stomach (35) and colon (32). In multivariable analysis, age (over 64 years old) and sex (male) were risk factors (age HR: 1.60 (95% CI: 1.24-2.07), sex HR: 1.36 (95% CI: 1.04-1.78)). The SIR of any second primary cancers was 1.07 (95% CI: 0.94-1.21). The SIR for second primary cancers of colon was 1.09 (95% CI: 0.79-1.47). On the other hand, cumulative incidence of recurrence almost reached at 3 years. Conclusions: Common surveillance strategy can be applied even for curatively resected CRC pts after 3 years from surgery, because the risk of second primary cancer was almost same as general population over time. The necessity of intensive follow-up to detect recurrence decreases after 3 years. [Table: see text]
Tumor characteristics and treatment in early-onset colorectal cancer.
Authors: Burnett-Hartman Andrea , Powers John D. , Chubak Jessica , Corley Douglas , Ghai Nirupa R. , McMullen Carmit K. , Pawloski Pamala A. , Feiglelson Heather S.
Published: January 2019

566

Background: While overall incidence and mortality of colorectal cancer (CRC) has declined, incidence and mortality are increasing in those < 50 years old (early-onset CRC). Our objective was to better understand early-onset CRC by comparing tumor characteristics and initial treatment type between early-onset and normal/late-onset CRC. Methods: We used health system and national tumor registries to identify patients diagnosed with adenocarcinoma of the colon or rectum from 2010-2014 at 6 US integrated health systems in the Patient Outcomes To Advance Learning (PORTAL) network. Tumor registry data included: age at diagnosis, stage, grade, anatomic site, histology, number of lymph nodes examined, and receipt of initial systemic therapy (chemotherapy or immunotherapy). Demographics and other patient characteristics were obtained from the EHR. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset ( < 50 years old) vs. normal/late-onset CRC. Results: There were 1,424 early-onset and 10,810 normal/late onset CRC cases in our analyses. Compared to normal/late onset cases, patients with early-onset CRC were more likely to be Hispanic, obese, never smokers, and to have Charlson comorbidity scores < 3. After adjustment for patient characteristics, compared to normal/late onset CRC, early-onset CRC was associated with more advanced stage disease (OR for stage 4 vs. stage 1 = 2.8, CI: 2.4-3.4), high grade histology (OR for poorly differentiated/undifferentiated vs. well/moderately differentiated = 1.2, CI: 1.1-1.5), signet ring histology (OR for signet ring vs. non-mucinous adenocarcinoma = 1.7, CI: 1.1, 2.6), and rectal (OR for rectum vs. cecum = 2.4, CI: 1.9-2.9) or left colon location (OR for left colon vs. cecum = 2.2, CI: 1.8-2.8). After adjustment for patient and tumor characteristics, early-onset patients were more likely than normal/late onset patients to have > 12 lymph nodes examined (OR = 1.6, CI: 1.4-1.8) and to receive systemic therapy (OR = 2.8, CI: 2.4, 3.4). Conclusions: Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use.
Colorectal tumor patterns among adolescents, emerging adults, and young adults.
Authors: Holowatyj Andreana Natalie , Lewis Mark Andrew , Schmit Stephanie , Kirchhoff Anne C. , Figueiredo Jane , Ulrich Cornelia M
Published: January 2019

567

Background: Despite overall reductions in colorectal cancer (CRC) incidence, this trend has shifted among young individuals. Incidence rates continue to rise in this population, yet causes remain unknown. We examined CRC tumor patterns within the adolescent, emerging adult, and young adult (AYA) population in the United States. Methods: Using Surveillance, Epidemiology, and End Results program data, we identified individuals aged 15 to 39 years diagnosed with CRC from 2010-2014. Unadjusted and adjusted multinomial logistic regression models were used to quantify the associations between age of onset [adolescents (15-18 years), emerging adults (19-25 years) and young adults (26-29, 30-34, 35-39 years)] and CRC tumor site and sidedness. Results: We identified 4,417 AYA patients (33 adolescents; 298 emerging adults; 4,086 young adults) with CRC over the 5-year study period. The percentage of cases diagnosed with colon cancer decreased across all AYA groups compared to rectal cancer cases ( P-trend=0.03). Age group was associated with sidedness ( P-trend=0.01). Individuals aged 26 to 29 years remained more likely to be diagnosed with right-sided (Odds ratio, OR=1.35, 95% CI 1.08-1.69, P=0.009) and high-grade (OR=1.29, 95% CI 1.02-1.64, P=0.03) colorectal tumors compared to counterparts aged 35 to 39 years, after adjusting for sex, race/ethnicity, stage, grade, and county-level poverty. Conclusions: CRC site and sidedness were associated with age at diagnosis within the AYA population. These data are the first to define clinical patterns of CRC among AYAs. Elucidating etiologies underlying these patterns in young-onset CRCs are needed for tailoring CRC screening/surveillance and treatment.
Diagnostic colonoscopy following abnormal FIT results: A quality improvement analysis.
Authors: Heavener Trace , Jaeger Victoria , Stephenson Kristen , McStay Frank , Sing Tommy
Published: January 2019

568

Background: Published rates of colorectal cancer (CRC) screening with diagnostic colonoscopy after abnormal fecal immunochemical test (FIT) findings have varied substantially from 42% to 83% and median days to follow up colonoscopy have ranged from 41 to 184 days. Although data for lack of follow up exists for urban safety-net hospital systems, Veteran’s Affairs systems, and healthcare systems not located in the southern US to our knowledge no data exists for the Baylor Scott & White Health System (BSWH) which is the largest not-for-profit healthcare system in Texas. Methods: The initial retrospective chart review searched BSWH’s Central Texas division for whom a FIT was ordered during the following dates: June 1, 2014 to June 1, 2016. Eligible patients were between and including 50 and 75 years of age. The search results were manually screened by two resident Internal Medicine physicians. Results: The initial screen produced 232 patients with a positive FIT test. After excluding for testing reasons other than CRC screening, 94 patients were included in the final analysis. Most of those (70/94, 74.47%) received a gastroenterology clinic visit within one year, and most (62/94, 65.96%) received or were offered a colonoscopy. The most common reasons for not completing colonoscopy were patient no-show (14/32, 43.75%) and no documented reason (12/32, 37.5%). Of those receiving a colonoscopy at our institution, median time from positive FIT to colonoscopy was 64 days, a quarter (11/43, 25.58%) waited longer than 6 months, and 22/43 (51.16%) had an abnormal finding. The abnormal findings on colonoscopy included: 3/22 (13.64%) were dysplastic polyps, 13/22 (59.10%) were adenomatous polyps and 6/19 (31.58%) were hyperplastic polyps. Conclusions: Colonoscopy following an abnormal FIT is an important part of preventing and diagnosing CRC. Although fecal based screening tests are more convenient and affordable, it appears that poor follow up is not limited to government and indigent health systems. As one of the largest not-for-profit health systems in the nation, a 65.96% follow up colonoscopy rate after abnormal FIT testing leaves much room for improvement.
Comprehensive genomic profiling of ctDNA in patients with colon cancer and its fidelity to the genomics of the tumor biopsy.
Authors: Gregg Jeffrey P. , Li Gerald , Pavlick Dean , Chung Jon , Cooke Matthew , He Jie , Schrock Alexa Betzig , Lipson Doron , Forcier Brady , Clark Travis A , Nahas Michelle , Ali Siraj Mahamed , Stephens Phil , Miller Vincent A.
Published: January 2019

569

Background: The liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor (ct) DNA to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of the tumor. The clinical utility study (CUS) for FoundationACT (Foundation Medicine, Cambridge, MA; NCT02620527) is a large multi-center prospective clinical study to validate this ctDNA assay for multiple solid tumor types. In this subset of the CUS study, paired specimens from 98 patients with colon cancer were analyzed with comprehensive genomic profiling of the tumor (FoundationOne) and a blood sample (FoundationACT). Methods: Maximum somatic allele fraction (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both FoundationOne and FoundationACT were compared for each subject. Results: 60% were male; 73 had stage IV, 17 had stage III, and 8 had stage II disease. 16% of cases had an MSAF value of 0, indicating that no ctDNA were in these samples. For the cases with MSAF > 0, 153 insertion/deletions (indels)/substitutions were identified in the tumor, and 73% of these identical alterations were also identified in the ctDNA samples. As robust analytical performance for FoundationACT has been demonstrated at MSAF > 0.5% for indel/subs, further analysis was conducted using this threshold. 83% of the alterations identified with FoundationOne were identified with FoundationACT. Further, 90% of NRAS/KRAS and 75% BRAF alterations (NCCN guideline genes) were concordant between the two assays. Lastly, there were 11 patients with tumor biopsy and blood draw taken within 30 days of each other, and in these there was 100% concordant. Association of the genomics results with other clinical variables will be presented for the available subset of patients. Conclusions: In cases where tumor profiling is not possible, these results provide compelling evidence that comprehensive molecular profiling of ctDNA in colon cancer can be used to identify most clinically relevant alterations and has fidelity to the genomics of the tumor. Clinical trial information: NCT02620527.
High prevalence of pathogenic variants in individuals with colorectal cancer ≤ age 35.
Authors: Marshall Megan L. , Roberts Maegan , Susswein Lisa R. , McGill Anna K. , Xu Zhixiong , Klein Rachel T. , Hruska Kathleen S.
Published: January 2019

576

Background: Young age at onset is a hallmark feature of an inherited predisposition to cancer. Recent evidence suggests that the incidence of pathogenic/likely pathogenic variants (PV) in cancer predisposition genes among individuals diagnosed with colorectal cancer (CRC) ≤ age 35 is high, but few studies have examined the frequency identified by multi-gene hereditary cancer panel testing. We report on PV yield and clinical presentation of individuals diagnosed with CRC ≤ 35 years (y). Methods: We retrospectively reviewed test requisition forms and provided pathology reports for 4,727 individuals with CRC who underwent panel testing of, at a minimum, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH. Two-tailed Fisher’s exact tests were used to determine statistically significant differences between groups. Results: Of the 691 individuals diagnosed with CRC ≤35y, 137 PV were identified in 126 individuals (126/691, 18.2%), including 72 with Lynch syndrome, 16 with familial adenomatous polyposis (FAP), five with MUTYH-associated polyposis, four with constitutional mismatch repair deficiency, one with juvenile polyposis syndrome, and one with Peutz-Jeghers syndrome. Thirty-eight additional PVs were identified in other non-CRC genes. Microsatellite instability (MSI) and immunohistochemistry (IHC) results were reported for 277 individuals and were reportedly abnormal in 63. The yield of PV in individuals with abnormal tumor studies was 52.4% (33/63); PV in genes other than the Lynch syndrome-associated genes were identified, commonly in the MSI-H group. While statistical significance was not observed, the positive rate was higher for individuals with non-rectal cancers (colon cancer: 104/534, 19.5%; rectal cancer: 22/157, 14.0%, p = 0.13). Conclusions: In our cohort, 18.2% of individuals diagnosed with CRC ≤35y were found to harbor a PV. Yield increased in those with abnormal MSI/IHC as well as non-rectal tumor location. Hereditary predispositions in patients diagnosed with very early-onset CRC are not limited to Lynch syndrome and FAP. Therefore, individuals with very early-onset CRC may benefit from multi-gene panel testing rather than syndromic-based testing.
Differential utilization of preventive care among colon cancer survivors compared to non-cancer patients.
Authors: Lau Sally C , Lee-Ying Richard M. , Sam Davis , Cheung Winson Y.
Published: January 2019

577

Background: With advances in diagnosis and treatment, many cancer patients survive more than 5 years. The care of these cancer survivors (CS) represent an area of unmet need. We aim to characterize the patterns of preventive care in colon CS compared to non-cancer controls (NCC) and identify areas of deficiencies within the context of a universal health care system. Methods: Adult patients with non-metastatic colon cancer treated at the BC Cancer Agency between 2000-2012 were included. An age and gender matched cohort constructed from the provincial database served as NCC. Areas of preventive care examined include vaccinations, cancer, osteoporosis and cardiovascular diseases (CVD) screening. Multivariate regressions were done to test for associations between CS and preventive care. Results: In total, 9381 colon CS and 47187 NCC, matched at a ratio of 1:5, were analyzed. Among CS, median age of diagnosis was 68, 58% were male and 47% had stage 3 disease. The median overall survivals were 12/10/8 years for stages 1/2/3 disease respectively. 61% of these survivors died from colon cancer, 12% from other cancers and 25% from non-cancer causes. Deaths from colon cancer are more common within 5 years of diagnosis, particularly stage 3 disease. CS were more likely to receive any preventive care. In CS compared to NCC, 90% vs 85%, 47% vs 39% and 53% vs 46% of eligible patients had CVD screening, cancer screening and other preventive care respectively. This remained significant in multivariate analyses (Table). Patients who were female, had higher income and resided in urban areas were more likely to receive screening. Among CS, patients > 65 years (OR1.2, p = 0.04 95%CI 1.0-1.4), females (OR 1.5, p < 0.01 95%CI 1.3-1.8) and stages 1 or 2 disease (OR 1.3, p < 0.01 95%CI 1.1-1.5) had higher uptake of screening. Conclusions: Many colon cancer patients are long term survivors. CS are more likely to receive screening than NCC but uptake is suboptimal in certain areas. Targeted education towards certain sub-groups such as males, ≤65 years, low income and rural area patients may improve long term health outcomes. [Table: see text]
Prevalence of advanced colorectal neoplasia according to risk categories at screening colonoscopy in a tertiary referral center.
Authors: Negrete Carballo Eduardo , Huitzil Melendez Fidel David
Published: January 2019

578

Background: Colorectal cancer (CRC) is the third most common cancer in the world. There is strong evidence that screening for colorectal cancer improves survival in conutries with high incidence. Although Mexico is considered a country with a low incidence of CRC, 4694 potentially preventable deaths occur every year. There is no established CRC screening program in our country, risk stratification of the target populations to be screened may bring potential advantages, making the strategy more cost-effective. The Asia-Pacific Colorectal Screening (APCS) score, is a validated risk-stratification tool that helps identify individuals at risk for advanced colorectal neoplasm amongst the asymptomatic population. Methods: We performed a retrospective, cross-sectional analysis of database records from 1172 patients who underwent screening colonoscopy betwen january 2013 and november 2014. Results: The prevalence of advanced colorectal neoplasia was 2.9%. Applying the APCS stratification, 91 subjects (7.8%) were in the average risk tier, 849 subjects (72.4%) in the moderate risk tier and 232 (19.8%) subjects in the high risk tier. The prevalence of advanced neoplasia in the average risk, moderate risk and high risk groups was 0%, 2.6% and 5.1%, respectively. The subjects in the high risk tier had 2.21-fold (p = 0.021) increased prevalence of advanced neoplasia than those in the average-moderate tier. Conclusions: The APCS score is a simple risk stratification index for colorectal advanced neoplasm that uses elementary clinical information on age, gender, family history and smoking to stratify the risk of colorectal advanced neoplasm in asymptomatic subjects for priority of colorectal screening.
The prognostic value of systemic inflammation in patients undergoing surgery for rectal cancer: Comparison of composite ratios and cumulative scores.
Authors: Dolan Ross , McSorley Stephen Thomas , Park James Hugh , Roxburgh Campbell SD , Horgan Paul G. , McMillan Donald C
Published: January 2019

579

Background: Colorectal cancer is the second commonest cause of cancer death in Europe and North America with rectal cancer making up a third of this disease burden. Markers of the systemic inflammatory response (SIR) have been shown to be prognostic in cancer. These include ratio of different white blood cells/acute phase proteins such as NLR (neutrophil/lymphocytes), PLR (platelets/lymphocytes), LMR (lymphocytes/monocytes) and CAR (CRP/albumin) and cumulative prognostic scores such as NPS (Neutrophil Platelet Score)/mGPS (modified Glasgow Prognostic Score). The aim of the present study was to compare the prognostic value of SIR markers in patients undergoing surgery for rectal cancer. Methods: A prospectively maintained database of all patients undergoing elective curative rectal resection in our institution was examined. The SIR was measured by the ratios and scores NLR, PLR, LMR, CAR, NPS and mGPS using standard thresholds NLR (>5), PLR (>150), LMR (<2.4), CAR (>0.24), NPS (0, 1, 2) and mGPS (0, 1, 2). Statistical analysis was carried out in SPSS using ROC curve and Cox regression analysis for both cancer specific survival (CSS) and overall survival (OS). Results: Of the 393 patients included in the study, 237 (60%) were male, 91 (25.6%) had neoadjuvant therapy, 341 (87%) had open surgery, 285 (72.5%) had T3/4 disease and 155 (39.4%) and node positive disease. On ROC curve analysis, validated ratios and scores such as NLR (AUC: 0.534 95%CI 0.469-0.600), PLR (AUC: 0.526 95%CI 0.444-0.607), LMR (AUC: 0.574 95%CI 0.472-0.676), CAR (AUC: 0.551 95%CI 0.487-0.615), NPS (AUC: 0.578 95%CI 0.513-0.643) and mGPS (AUC: 0.571 95%CI 0.513-0.629) showed considerable similarities. On multivariate categorical analysis with TNM stage there was a significant relationship between CSS and NPS (HR: 2.09 95%CI 1.14-3.82, p=0.017), CAR > 0.22 (HR: 1.64 95%CI 1.09-2.47, p=0.018) and mGPS (HR: 3.06 95%CI 1.71-5.47, p < 0.001). Conclusions: The SIR as measured by a number of scores/ratios had prognostic value in patients with rectal cancer. Only the NPS and mGPS had prognostic value independent of TNM stage. These scores may be useful in stratifying treatment in patients with rectal cancer.
Correlation of VEGF with immune suppression involving MDSC, malnutrition, and prognosis in patients with gastric and colorectal cancer.
Authors: Gonda Kenji , Shibata Masahiko , Ujiie Daisuke , Ashizawa Mai , Okayama Hirokazu , Fujita Shoutarou , Sakamoto Wataru , Nakajima Takahiro , Endo Hisahito , Saito Motonobu , Saze Zenichiro , Monma Tomoyuki , Ohki Shinji , Kono Koji , Takenoshita Seiichi
Published: January 2019

582

Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Vascular endothelial growth factor (VEGF), previously known as vascular permeability factor. 45 kDa protein, belongs to a family of platelet-derived growth factors. VEGF, inflammation-related protein, could contribute to the accumulation of immunosuppressive cells (MDSC, Treg, TAM, and Tie-2-expressingmonocytes) in tumor-bearing hosts through direct or indirect mechanisms. Methods: We tested the serum levels of VEGF by ELISA in 106 patients including 43 with gastric and 63 with colorectal cancer, and they were increased in advanced stages of gastric and colorectal cancer. Production of IL-17, pro-inflammatory cytokine, with a stimulation of PHA was measured by ELISA and MDSC (myeloid-derived suppressor cells), one of major immunosuppressing cells, was measured by flow cytometry (CD11b+CD14-CD33+). Neutrophil to lymphocyte ratio (NLR) and C-reactive protein (CRP) were used as inflammatory markers. Production of IL-12 and SI (stimulation index) of blastogenic response of lymphocytes were used as markers of cell-mediated immune response. Results: The concentrations of VEGF were positively correlated with levels of MDSC, production of IL-17, NLR and CRP, and were inversely correlated with IL-12 production, SI and nutritional markers including prealbumin and retinol binding protein. The patients were both divided into two groups with a serum level of VEGF (330 pg/ml) and OS (overall survival) of patients with stages III and IV gastric or colorectal cancer were both significantly worse in patients with high levels of VEGF than in those with low VEGF although the differences were not significant in patients with stagesⅠand II. Conclusions: The results of the present study suggested that VEGF may have an impact on advancement and progression involving inflammation and serve as useful markers of the immune suppression involving MDSC, malnutrition and poor prognosis in patients with gastric and colorectal cancer.
Identifying the barriers to cancer care at safety-net hospitals: A novel comparison of a safety-net hospital to a neighboring quaternary referral academic institution in the same health care system.
Authors: Zaidi Mohammad , Rappaport Jesse , Ethun Cecilia Grace , Gillespie Theresa Wicklin , Hawk Natalyn Nicole , Chawla Saurabh , Cardona Kenneth , Maithel Shishir , Russell Maria C.
Published: January 2019

59

Background: The three-delays model for vulnerable and minority populations to receive care include delays in seeking, reaching, and receiving care. The dominant delay for vulnerable patients with gastric adenocarcinoma (GAC) is not known. Our aim was to define those patients with GAC who reached care at our regional safety-net hospital compared to academic centers from the National Cancer Database (NCDB). We also aimed to compare survival outcomes of patients who received curative-intent resection at our safety-net hospital to those in a nearby quaternary referral hospital. Methods: Grady-Memorial-Hospital (GMH), a safety-net hospital and Emory-University-Hospital (EUH), a quaternary referral hospital, are within the same healthcare-system. Clinicopathologic data of patients at presentation from NCDB-participating academic centers were compared with GMH from 2004-2014. Patients undergoing curative-intent resection of GAC at GMH were compared to those at EUH during a similar time period. Primary outcome for the latter was overall survival (OS). Results: At presentation, compared to NCDB-participating academic centers (n = 69,662), GMH patients (n = 154) were more likely to be black (85.1 vs 17.2%; p < 0.001), uninsured (30.5 vs 4.7%; p < 0.001), have stage IV disease (43.5 vs 30.1%; p = 0.017), and receive no treatment (40.3 vs 18.4%; p < 0.001). When only comparing those who underwent curative-intent resection at GMH (n = 23) to EUH (n = 137), median OS was similar between both groups (GMH: median not reached; EUH: 59.8mos; p = 0.785). Conclusions: Patients with gastric cancer who reached care at our safety-net hospital are more likely to be uninsured, have stage IV disease, and receive no treatment compared to academic centers. When they receive curative-intent resection, however, overall survival is similar. Efforts must be made to identify and overcome the barriers in seeking and reaching care for this vulnerable patient population, as it appears that outcomes are acceptable in those who receive care.