bluuebunny/crossref_metadata_2025 huggingface dataset:
Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142.
Authors: Andre Thierry , Lonardi Sara , Wong Mark , Lenz Heinz-Josef , Gelsomino Fabio , Aglietta Massimo , Morse Michael , Van Cutsem Eric , McDermott Raymond S. , Hill Andrew G , Sawyer Michael B. , Hendlisz Alain , Neyns Bart , Svrcek Magali , Moss Rebecca Anne , Ledeine Jean-Marie , Cao Z. Alexander , Kamble Shital , Kopetz Scott , Overman Michael J.
Published: January 2019

553

Background: Nivolumab (NIVO) provided durable responses (investigator-assessed [INV] ORR, 31%) and disease control (DCR, 69%) in pretreated pts with dMMR/MSI-H mCRC in CheckMate-142 (NCT02060188; Overman et al Lancet Oncol 2017). An interim analysis of the NIVO + ipilimumab (IPI) combination cohort of CheckMate-142 reported a preliminary ORR of 55% and manageable safety profile in a subset of pts (n = 84) with dMMR/MSI-H mCRC and ≥ 6 mo of follow-up (André et al ASCO 2017). Here we report for the first time efficacy and safety from the complete population (N = 119) of the NIVO + IPI cohort of CheckMate-142, which is the largest single-study report of an immunotherapy regimen in pts with dMMR/MSI-H mCRC. Methods: Pts with dMMR/MSI-H mCRC received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W. Primary endpoint was ORR (INV; RECIST 1.1). Other endpoints were DOR, PFS, OS, and safety/tolerability. Results: Of 119 treated pts, 76% had ≥ 2 prior lines of therapy. Median follow-up was 13.4 mo. The ORR was 55% and DCR was 80% (Table). Notably, ORR in pts with a BRAF mutation was 55%. Among all responders, median DOR was not reached (NR), with 94% of responses ongoing at data cutoff. Tumor burden was reduced from baseline in 77% of pts. The 9-mo PFS and OS rates were 76% and 87%, respectively. Gr 3–4 TRAEs occurred in 32% of pts; 13% (any gr) and 10% (gr 3–4) of pts had TRAEs that led to discontinuation. No treatment-related deaths were reported. Results including a similar follow-up of the NIVO arm will also be presented. Conclusions: In the largest cohort of dMMR/MSI-H pts treated with an immunotherapy regimen, NIVO + IPI built on the efficacy reported with NIVO monotherapy, demonstrating enhanced clinical benefit and manageable safety, and may represent a new standard of care in pts with dMMR/MSI-H mCRC. Clinical trial information: NCT02060188. [Table: see text]
Cost-effectiveness of immune checkpoint inhibition in metastatic gastric and esophageal tumors.
Authors: Ostvar Sassan , Choi Jin G. , Chu Jacqueline N. , Dougan Michael Lawrence , Gainor Justin F. , Reynolds Kerry Lynn , Nipp Ryan David , Kong Chung Yin , Hur Chin
Published: January 2019

56

Background: Immune checkpoint inhibition has shown early promising results in patients with chemotherapy-refractory metastatic or advanced tumors of the esophagus, gastroesophageal junction, and stomach. We explore the cost-effectiveness of checkpoint inhibitors as second-line treatment agents for this group of patients using a decision analytic approach. Methods: A Markov model was developed to simulate the course of a virtual cohort of patients treated by (i) nivolumab 3 mg/kg, (ii) combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg, and (iii) best supportive care (BSC). Patients in the hypothetical cohort were 55-year-olds in an advanced/metastatic stage who had received at least one prior line of chemotherapy. Patients who remained stable in treatment were monitored for adverse events until death. Rates of cancer-specific mortality, disease progression, and drug-related adverse events were estimated using results from the CheckMate 032 clinical trial. The primary endpoints were survival, measured in life-years (LY), quality adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER). Cost-effectiveness of each strategy was evaluated from a US-payer perspective considering costs of drugs, treatment, and management of immune-related adverse events. Cost-effectiveness was defined with a willingness to pay threshold of $100,000/QALY. Results: Combination therapy with nivolumab and ipilimumab yielded the highest effectiveness (QALYs = 0.47, LYs = 1.09) in our base case modeling results, compared with nivolumab (QALYs = 0.43, LYs = 1.03), and BSC (QALYs = 0.19, LYs = 0.42). Nivolumab had an incremental cost of $84,555/QALY compared with BSC, while nivolumab with ipilimumab resulted in an incremental cost of $1.1M/QALY compared with nivolumab alone. The cost gap between the two was associated with the higher price of ipilimumab, and costs of managing increased toxicity. Conclusions: Our modeling analysis finds that combination therapy of ipilimumab and nivolumab is the most effective, but from a cost-effectiveness perspective, it is expensive, making nivolumab monotherapy the cost-effective option. Additional clinical data are needed to confirm our modeling results.
The prognostic role of microsatellite status, tumor mutational burden, and protein expression in CRC.
Authors: Schwartz Sarit , Tian Yuan , Cecchi Fabiola , Nguyen Andrew , Kim Yeoun Jin , Goh Brian , Chew Min Hoe , Tang Choon Leong , Toh Ee-Lin , Skanderup Anders , Koo Si-Lin , Chua Clarinda Wei Ling , Leow Wei Qiang , Tan Iain Beehuat , Vaske Charles Joseph , Sanborn Zack , Benz Stephen Charles , Lim Kiat Hon Tony , Hembrough Todd A.
Published: January 2019

572

Background: Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death. Microsatellite instability (MSI) is prognostic in CRC and is used to select patients for immunotherapy. High tumor mutational burden (TMB) is associated with genomic instability and is prognostic in melanoma. Expression of p16 protein is prognostic in many tumor types. We used proteomic and genomic profiling to measure MSI, TMB and p16 in CRC tumors and to assess associations with patient survival. Methods: In archived clinical samples of CRC, 76 proteins were quantitated with mass spectrometry-based proteomics. MSI was measured by WGS and RNA-seq; unstable loci were quantified in tumor and normal samples. Cutoffs were derived via ROC analysis: high TMB was defined as > 4.5 somatic mutations per megabase; p16 as > 108 amol/ug. Patients were grouped by microsatellite status (MSI vs. microsatellite stable [MSS]), TMB (high vs. low), and p16 protein expression level. Survival curves were compared with the Mantel-Cox log-rank test. Results: Of 145 samples, 39 (27%) had high TMB and 29 (20%) had MSI. Patients with MSI tumors had longer OS than patients with MSS tumors (HR: 0.096; p = 0.003). Similarly, patients with high TMB had longer OS than those with low TMB (HR: 0.076; p < 0.001). High p16 expression was prognostic of poor survival (HR: 2.874; p = 0.019). Among patients with MSS tumors or low TMB, those with low p16 levels had longer OS than patients with high p16 (HR: 0.257; p = 0.002 and HR: 0.249; p = 0.002, for MSS and low TMB, respectively). A combination of MSS, low TMB, and low p16 also differentiated between long and short survivors (HR: 0.249; p = 0.002). These associations remained after adjustment for tumor sidedness. Further analyses of clinical correlates will be presented. Conclusions: A combination of MSS, low TMB and low p16 expression characterized a subset of patients with longer survival. This is important because patients with MSS tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression. Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.
Single nucleotide polymorphisms of mir-608, LCS-6, and overall survival in the MAGIC trial.
Authors: Smyth Elizabeth Catherine , Kouvelakis Kyriakos , Cunningham David , Peckitt Clare , Nankivell Matthew Guy , Allum William H. , Wotherspoon Andrew , Hahne Jens , Lampis Andrea , Langley Ruth E. , Valeri Nicola
Published: January 2019

58

Background: Single nucleotide polymorphisms (SNPs) in mir-608 (rs4919510) are prognostic in colorectal cancer (CRC) and hepatocellular cancer. SNPs of the let-7 complementary site 6 (LCS-6) 3'-untranslated region of KRAS (rs61764370) are associated with prognosis in CRC and platinum sensitivity in head and neck cancer. We investigated the prognostic effects of these SNPs in patients treated with surgery and with perioperative epirubicin, cisplatin and 5-fluorouracil chemotherapy plus surgery in the MRC MAGIC trial. Methods: DNA was extracted from tumour tissue using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Samples were genotyped using the Taqman assay (Life Technologies, Carlsbad, CA) for rs4919510 in mir-608 and rs61764370 in LCS-6. SNP status was assessed for association with patient characteristics and survival. Results: 305 patients (of 456 operated) had mir-608 and/or LCS-6 results available. SNPs mir-608 and LCS-6 were in Hardy-Weinberg equilibrium. Pathological tumour regression grading was not different for any SNP genotype. No genotype was statistically significantly associated with overall survival in either surgery arm or chemotherapy plus surgery arm of the trial (Table). Conclusions: Germline polymorphisms in mir-608 and LCS-6 showed no evidence of a prognostic effect in patients with gastric and gastroesophageal cancer treated with surgery or chemotherapy plus surgery in the MAGIC trial. However, the small number of patients with selected genotypes means that these analyses may be underpowered to detect survival differences. [Table: see text]
Contribution of Lynch syndrome to early onset malignancy in Ireland.
Authors: Talbot Alice , Gallagher David James
Published: January 2019

586

Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]
LINE-1 hypomethylation in colon cancer.
Authors: Vodolazhsky Dmitriy I. , Timoshkina Natalya N. , Panina Svetlana B.
Published: January 2019

588

Background: Global hypomethylation of the genome is one of the causes of chromosomal instability and aneuploidy and is associated with an increased risk of colorectal cancer (CRC). The long interspersed nucleotide element-1 (LINE-1) is the main part of the mobile repeated elements of the genome, and the level of its methylation is concordant with genome-wide methylation. The aim of the study was to assess the methylation of LINE-1, as well as methylation of the promoter of six cancer-associated genes adjusting for the clinical and pathological characteristics in colorectal cancer (CRC). Methods: Using pyrosequencing (PyroMark Q24 analysis system, Qiagen, Germany) DNA methylation levels of LINE-1 and 6 genes ( APC, CDH13, MLH1, MGMT, P16 and RASSF1A) were measured in tumoral and normal tissues of 50 patients with CRC. Results: The level of LINE-1 methylation was 66.8 ± 0.89% in tumors, 72.5 ± 0.45% in normal tissues ( p = 0.0013). The differences in LINE-1 methylation level were not associated with age, differentiation grade, tumor localization, and the presence of activating mutation within the KRAS gene. At the same time, the MGMT methylation was positively associated with age ( p = 0.04), and the hypermethylation of the CDH13 gene was more common in tumors of the proximal colon ( p = 0.004). Methylation of the CDH13 promoter negatively correlated with methylation level of LINE1 ( r = -0.427, p < 0.05). Hypomethylation of LINE-1 was associated with progression of TNM-stages of the tumors ( r = +0.606, p < 0.001). The cancer-associated genes were hypermethylated in 70% of CRC cases when compared with normal epithelium, and hypomethylation of LINE-1 was observed in 90% of CRC cases. Conclusions: The present study demonstrated the association of LINE-1 methylation with the TNM tumor stage, which may be used as a biomarker for early diagnosis and prognosis of sporadic CRC, together with assessment of hypermethylation of tumor suppressors.
Evaluation of the sensitivity of RAS mutation detection of the Idylla platform in comparison to the OncoBEAM RAS CRC assay.
Authors: Vivancos Anna , Aranda Enrique , Benavides Manuel , Elez Elena , Gomez A. , Toledano Marta , Alvarez Martina , Parrado M Rosario Chica , García-Barberán Vanesa , Diaz-Rubio Eduardo
Published: January 2019

592

Background: Accurate detection of RAS mutations in metastatic colorectal cancer (mCRC) patients is of high clinical importance for therapy selection as RAS detection methods lacking sensitivity may lead to poor patient outcomes. Liquid biopsy has emerged as a viable alternative to individualize the management and treatment of mCRC patients. However, there is a current need to cross-compare the performance of liquid biopsy platforms. The OncoBEAM RAS dPCR assay offers highly sensitive RAS mutation detection in clinical practice, achieving > 90% concordance when compared to results obtained by tumor mutation testing. The Idylla platform offers a highly-automated qPCR platform for RAS mutation testing of tissue samples, and has shown potential for liquid biopsy. The objective of this study was to provide a head-to-head comparison of the sensitivity of OncoBEAM and Idylla for KRAS mutation detection in plasma from mCRC patients. Methods: Plasma samples from 92 mCRC patients determined to be KRAS-positive using OncoBEAM were re-tested using Idylla. Samples with mutant allelic fractions (MAF) below 5% were selected for analysis. The positive percent agreement (PPA) of KRAS mutation results was compared for replicate samples analyzed by OncoBEAM and Idylla. Results: So far, Idylla detected KRAS mutations in 63 out of 92 (68.4%) OncoBEAM KRAS-positive plasma samples. Categorization of results based on MAF% revealed distinct differences in sensitivity between the two technologies. Conclusions: OncoBEAM demonstrated significantly greater sensitivity for plasma detection of RAS mutations than Idylla. Moreover, these data identify a “gray zone” below 1% MAF where Idylla fails to identify RAS-positivity in patient plasma samples. These findings serve as a reminder that liquid biopsy assays with diminished sensitivity may lack the dynamic range to provide accurate and timely RAS mutational status information to properly guide highly individualized anti-EGFR therapy and chemotherapy treatment decisions that may benefit patient outcomes. [Table: see text]
Molecular characterization of intestinal (IS) and diffuse subtypes (DS) of gastric adenocarcinomas.
Authors: Salem Mohamed E. , Xiu Joanne , Puccini Alberto , Philip Philip Agop , Goldberg Richard M. , Hwang Jimmy J. , Kc Birendra , Korn Wolfgang Michael , Shields Anthony Frank , Lenz Heinz-Josef , Marshall John
Published: January 2019

60

Background: Gastric adenocarcinomas are histologically categorized into IS and DS. TCGA categorization suggests that IS is more common in tumors arising via the chromosomal instability pathway and DS is more common in genomically stable tumors. However, molecular differences between these subtypes are not well understood. Methods: Gastric adenocarcinomas were examined using NextGen sequencing (MiSeq platform on 47 genes or NextSeq on 592 genes), protein expression, and gene amplification techniques. For tumors sequenced with NextSeq, tumor mutational load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated on known MSI loci in target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 268 gastric adenocarcinomas with annotated histology (DS [n = 144]; IS [n = 124]) were analyzed. Patients with DS were younger than those with IS (mean age: 27y [DS] vs. 65y [IS], p < 0.0001). The majority of patients with DS were female (56% [DS] vs. 35% [IS], p = 0.0004). Most frequently mutated genes in DS were TP53 (44%), ARID1A (37%) , CDH1 (14%), BAP1 (8%), and PIK3CA (5%); whereas the most frequent mutations in IS were ARID1A (57%), TP53 (51%), CDKN2A (13%), MUTYH (13%), and PIK3CA (12%). IS had a higher rate of APC mutations (10% vs. 2%, p = 0.04), whereas DS had a higher rate of CDH1 (14% vs. 2%, p = 0.01). There was no difference in PD-L1 tumor expression (DS: 4%; IS: 8%). IS, when compared to DS, exhibited higher overexpression of TOP2A (90% vs 50%, p < 0.0001), TS (58% vs 28%, p < 0.0001), RRM1 (47% vs 22%, p = 0.0006), and Her2/neu (14% vs 1%, p < 0.0001), and greater Her2 amplification (19% vs 2%, p < 0.0001). Microsatellite instability was not detected in DS, and there was a trend toward a higher frequency of MSI-high in IS (6% [IS] vs. 0% [DS], p = 0.06), as well as a higher mean TML (10.3 vs. 6.6 mutation/megabase, p = 0.01). Conclusions: Significant molecular differences between IS and DS gastric adenocarcinomas were observed, a finding that indicates different carcinogenic pathways and biology, as well as potential differences in response to therapy. Low frequency mutations in several druggable genes may provide therapeutic options.
Impact of age on clinical and pathological features as well as outcome in Egyptian patients with colorectal cancer (CRC).
Authors: Rashad Noha , Heeke Arielle Lutterman , Khaled Hussein Mustafa , Ali El din Nelly , Abd El Motaal Gamal , Wang Hongkun , Salem Mohamed E.
Published: January 2019

600

Background: The incidence of early onset CRC is rising. Little is known about the clinicopathological differences between younger and older Egyptian (EGY) adults with CRC. Herein we explore these differences. Methods: A retrospective review of younger EGY adult (YA; ≤ 46 years) and older EGY adult (OA; > 65 years) patients (pts) with CRC was performed. T and Fisher’s exact tests were used for comparative analyses. Kaplan-Meier methodology estimated survival. Results: In total, 997 EGY pts with CRC were studied, including 443 YA (median age 35 years; range 15-46) and 153 OA pts (median 70 years range 65-84).There were no statistically significant differences with respect to gender, degree of tumor differentiation, extracolonic extension, stage at presentation, or patterns of metastasis between the two groups. YA pts had more rectal primaries compared with OA pts (49% vs. 31%, p < 0.001), whereas older pts had more colon primaries (69% vs. 51%, p < 0.001). Additionally YA pts had more left-sided tumors (78% vs. 62%, p < 0.001) compared with OA pts, whereas older pts had more right-sided tumors (32% vs. 17%, p < 0.001). YA pts were more likely to have mucin-producing tumors (40% vs. 23%, p = 0.003). Although there were no differences in the proportion of pts presenting with metastatic disease (28% [YA] vs. 32% [OA], p = 0.615), or the pattern of metastasis to the liver, lung, or peritoneum (40% vs. 50%, p = 0.288; 5% vs. 6%, p = 1.00, 16% vs. 17%, p = 1.00), YA were more likely to have CRC-related lymph node (LN) involvement (mean: 3.2 vs. 1.6, p = 0.006). There were no differences in PFS (Median: 12 months for YA vs. 13 months for OA) or OS (median: 76 months for YA vs. not reached for OA) between the two groups. However male YA pts had a better OS that female pts (median OS not reached in males, 72 months in females). Conclusions: Significant differences were evident between YA and OA pts with CRC, notably locations of primary tumors. Male had improved outcome compared to female YA patients. Additional evaluation of the molecular features of CRC in young and older patients in Egypt is warranted.
Racial/ethnic variation in incidence rates for anal cancer in New Mexico.
Authors: Osman Diaa , Fahy Bridget N. , Belmonte Jessica , Meisner Angela W. , Wiggins Charles
Published: January 2019

601

Background: Anal cancer comprises only 2.5% of all digestive system malignancies in the United States; only 8200 new cases are diagnosed annually, nevertheless, an increasing incidence rate has been noted. The goal of this study is to describe the incidence rates of anal cancer in New Mexico. New Mexico is a unique, mainly rural state, with unique demographics consisting of a large mix of patients being primarily Non-Hispanic White, Hispanics or Native Americans. Methods: All incident cases of anal cancer diagnosed among New Mexico residents during the twenty-year period 1995-2014 were identified from the population-based New Mexico Tumor Registry. Average annual age-adjusted incidence rates (US 2000 standard) were calculated by the direct method for non-Hispanic whites, Hispanics and American Indians. Incidence rates for non-Hispanic whites in nine core areas of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program served as the comparison. Results: A total of 556 anal cancers were diagnosed among New Mexico residents during the study period, an average of approximate 28 cancers annually. Anal cancer incidence rates per 100,000 were highest for non-Hispanic whites (1.80, 95% Confidence Interval (CI) 1.62-1.98) in New Mexico, which were similar to rates for non-Hispanic whites (1.70, 95% CI 1.66-1.74) in nine core areas of the SEER Program. Statistically significant lower rates were observed in New Mexico Hispanics (0.92, 95% CI 0.76-1.11) and American Indians (0.75, 95% CI 0.45-1.16). Females had higher rates than males in each of these three racial/ethnic groups. Incidence rates increased from 1995-2004 to 2005-2014 for all race/ethnic groups, with the largest increase observed in Hispanic females. Conclusions: Anal cancer incidence rates vary by race/ethnicity and sex in New Mexico. Further research is needed to characterize time trends in incidence and to identify factors that may account for observed differences in incidence rates by race/ethnicity and sex in New Mexico.
Peritoneal carcinomatosis of colorectal origin: Impact of ovarian metastases.
Authors: Ghouti Laurent , Pinto Amandine , Kirzin Sylvain
Published: January 2019

604

Background: To compare survival and morbidity in women treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for colorectal peritoneal carcinomatosis with or without ovarian metastases (OM). Methods: A prospectively maintained database was analyzed to identify women treated by CRS- HIPEC between 2009 and 2015. Results: Among 62 included women, 39 had ovarian metastasis (63%) with comparable PCI (10 vs. 7 p=0.15). OM patients experienced more frequent grade III/IV postoperative morbidity (56.4% vs. 30% p=0.04), and postoperative haemoperitoneum (23.1% vs 4.3% p=0.07) leading to more frequent reoperation (36 vs. 21.7% p=0.2). Among OM patients, 20 (52 %) had undergone ovariectomy previously to CRS-HIPEC procedure. Haemoperitoneum (30% vs 15% p=0.4) and reoperation (45% vs. 26% p=0.2) were more frequent if previous OM resection had been performed as compared to synchronous. The 36-month survival (94.7 % vs 61.7 %) was significantly impaired by OM (p=0.007) and 36- month survival without recurrence was better when ovariectomy was performed during CRS- HIPEC (24 % vs. 5.5%, p=0.4). Conclusions: Survival and morbidity of patients with CRS-HIPEC for colorectal peritoneal carcinomatosis were impaired by the presence of OM and previous OM resection.
HER2 positivity in brain metastases from gastrointestinal primary malignancies.
Authors: Mitra Devarati , Shih Helen Alice , Oh Kevin , Brastianos Priscilla , Wo Jennifer Y , Curry William , Clark Jeffrey W. , Parikh Aparna , Corcoran Ryan Bruce , Ryan David P. , Lennerz Jochen K , Hong Theodore Sunki
Published: January 2019

61

Background: HER2 amplification in gastrointestinal (GI) cancers, beyond gastric cancer, is uncommon and as a result infrequently tested. In breast cancer, HER2 amplification has been associated with brain metastases (BM) with associated prognostic value and therapeutic opportunity. The purpose of this project was to determine if HER2 amplification is more frequent in GI cancer patients with brain metastases. Methods: Retrospective review of our institution’s medical record system identified all patients with GI primary malignancies who had resection of BM between 1999-2015 with tissue available. Fluorescence in-situ hybridization for HER2 amplification and immunohistochemistry for HER2 expression was performed on each sample and quantified by a board-certified pathologist. Results: Twenty-five GI cancer patients with BM were identified: 40% esophageal adenocarcinoma (AC), 12% esophageal squamous cell carcinoma (SCC), 44% colorectal AC and 4% pancreatic AC. At diagnosis 36% had metastatic disease. A BM was the isolated first site of metastasis in: 11/13 esophageal cancers, 1/11 colorectal cancers and 1/1 pancreatic cancer. Two esophageal cancer patients and one colon cancer patient had BM at diagnosis but otherwise median time to BM was 30 months (range 4-127 months). There was a median of 1 BM with a maximum of 4 lesions per patient. The most common intracranial site was the cerebellum (40%) with a median metastasis size of 27 mm (range 5-55 mm). Overall, HER2 was amplified in 24% (n=6) with 4 of these patients having paired primary tumor tissue available. None of the primary tumor tissue was HER2 amplified. No colorectal cancer patients had HER2 amplification but 67% of esophageal SCC, 30% of esophageal AC and the only pancreatic AC patient had Her2 amplified and overexpressed brain metastases. Conclusions: HER2 amplification was enriched in esophageal SCC and AC patients who developed resectable BM despite none of these patients having HER2 amplification in their primary tissue. HER2 amplification testing in esophageal cancer patients with BM (regardless of histology) may lead to additional therapeutic options, even if primary tissue was negative for HER2 amplification.
Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)â€“An ACCRU Network study.
Authors: Bekaii-Saab Tanios S. , Ou Fang-Shu , Anderson Daniel M. , Ahn Daniel H. , Boland Patrick McKay , Ciombor Kristen Keon , Jacobs Nisha Lassi , Desnoyers Rodwige J. , Cleary James M. , Meyers Jeffrey P. , Chiorean E. Gabriela , Pedersen Katrina , Barzi Afsaneh , Sloan Jeffrey , McCune Jeannine S. , Lacouture Mario E. , Lenz Heinz Josef , Grothey Axel
Published: January 2019

611

Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.
The 12-gene Oncotype DX Colon Recurrence Score (RS) test: Experience with > 20,000 stage 2 patients (pts).
Authors: Bailey Helen , Turner Michelle , Stoppler Melissa C , Chao Calvin
Published: January 2019

618

Background: Genomic assays can provide information beyond the traditional methods used to assess risk of recurrence. The 12-gene Oncotype DX Colon RS test is clinically validated to predict recurrence risk after surgical resection in pts with stage 2 colon cancer (CC). The test measures expression of 12 genes (7 cancer-related; 5 reference) to give an RS result (scale 0-100) that estimates the risk of recurrence based on individual tumor biology in MMR-proficient tumors. Here, we report the Genomic Health Clinical Laboratory experience with stage 2 CC since its commercially availability. Methods: Over 20,000 samples from stage 2 CC pts submitted from 4/2010 to 8/2017 were analyzed. Descriptive statistics for the clinical characteristics of pts and RS results were calculated. Standard low (RS < 30), intermediate (RS 30-40), and high (RS ≥41) RS subgroups were used. Results: In 20,406 samples, 92.4% were adenocarcinoma and 7.6% were mucinous carcinoma. Median age was 64 y; 51% were men. Samples were received from 42 countries. The median RS result was 24 (range 0-77); 72% had low, 20% had intermediate, and 8% had high RS results. Mucinous carcinoma had a significantly higher median RS result than adenocarcinoma (34 vs. 23; p < 0.001). Of adenocarcinoma pts, 74% had low, 20% intermediate, and 6% had high RS results. Of mucinous carcinoma pts, 35% had low, 35% had intermediate, and 30% had high RS results. Conclusions: More than 20,000 samples from stage 2 CC pts were submitted over a 7-year period for Colon RS testing. Compared with adenocarcinoma, mucinous carcinoma had a higher median RS result and more high RS results. Overall, there was a wide range of RS results (0-77), indicating that risk of recurrence is continuous and not simply dichotomous. Traditional methods for assessing risk do not reveal the full picture. Because the 12-gene Colon RS result provides a quantitative and more individualized risk assessment for stage 2 CC pts beyond T-stage and MMR status, the test greatly improves the ability of clinicians to personalize care and treatment decisions for these pts.
Effect of matched therapy in metastatic colorectal cancer on progression free survival in the phase I setting.
Authors: Lam Michael , Pereira Allan Andresson Lima , Loree Jonathan M. , Advani Shailesh M , Overman Michael J. , Bailey Ann , Johnson Amber , Holla Vijaykumar , Sanchez Nora Sylvia , Khotskaya Yekaterina , Meric-Bernstam Funda , Kopetz Scott , Pant Shubham
Published: January 2019

619

Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.
The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.
Authors: Shepshelovich Daniel , Townsend Amanda Rose , Espin-Garcia Osvaldo , Latifovic Lidija , O'Callaghan Christopher J. , Jonker Derek J. , Tu Dongsheng , Chen Eric , Morgen Eric , Price Timothy Jay , Shapiro Jeremy David , Siu Lillian L. , Owzar Kouros , Ratain Mark J. , Kubo Michiaki , Dobrovic Alexander , Xu Wei , Mushiroda Taisei , Liu Geoffrey
Published: January 2019

633

Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.
The rate of novel actionable mutations in standard of care NGS panel testing in gastrointestinal malignancies.
Authors: Mehrvarz Sarshekeh Amir , Loree Jonathan , Pereira Allan Andresson Lima , Raghav Kanwal Pratap Singh , Lam Michael , Advani Shailesh M , Davis Jennifer S , Dasari A. , Morris Van Karlyle , Menter David , Eng Cathy , Shaw Kenna Rael , Broaddus Russell , Routbort Mark , Luthra Rajyalakshmi , Maru Dipen M. , Overman Michael J. , Meric-Bernstam Funda , Kopetz Scott
Published: January 2019

640

Background: In advanced gastrointestinal (GI) malignancies, genetic profiling is often performed with the goal of facilitating enrollment of patients into clinical trials. While multigene genetic profiling has become the standard of care in many practices, the data on success rate of identifying actionable genomic alterations remain limited. In this study, we aimed to characterize the rate of actionable mutations using larger ( > 150 genes) and smaller ( < 150 genes) panels across different GI malignancies. Methods: We reviewed all reports of formalin-fixed paraffin-embedded clinical specimens sent for next-generation sequencing (NGS-using assays of at least 45 genes) for patients with advanced GI malignancies between 2012-2017 at MD Anderson Cancer Center. Actionable mutations were defined as those matching or informing the use of targeted therapies available in clinical trials, or FDA-approved. These were determined by a precision oncology support team (pct.mdanderson.org), using available literature and functional genomic screens. Novel actionable mutations were defined as those not used in current testing guidelines for GI malignancies. Results: Out of 11968 detected mutations, 3832(32.0%) were deemed to be actionable mutations and the remainder were either in non-actionable genes, deemed benign, or variants of unknown significance. Therefore, 1987 (65.1%) of assays had actionable mutations. When limited to novel actionable mutations, the rate fell to 21.5% (659/3052). Compared to CRC, other GI malignancies were 1.65 times more likely to have a novel actionable mutation (95% CI 1.35-2.00, p< .001). The use of larger and smaller panels did not differ in detecting novel actionable mutations, but larger panels resulted in a 3.5-fold higher number of mutations not deemed clinically actionable. Conclusions: Despite incorporation of NGS in oncology practice for GI malignancies, the success rate of detecting novel actionable mutations beyond those in the current guidelines remains low. Using assays with larger gene numbers does not seem to improve this detection rate. Future studies are required to evaluate the success rate of clinical interventions when actionable alterations are present.
Association of malignant potential of BRAF mutant colorectal cancer with coexpression of PD-L1.
Authors: Shinozaki Eiji , Konishi Tsuyoshi , Sakata Seiji , Osumi Hiroki , Ueno Masashi , Yamaguchi Kensei , Takeuchi Kengo
Published: January 2019

643

Background: PD-L1 is a member of the B7/CD28 family that regulates immune response, and also well known as targets for immune checkpoint inhibitor. On the other hand BRAF mutation (MT) is recognized as a strongly poor prognostic factor in colorectal cancer (CRC). Recently in addition to the RAS gene, a lot of new knowledge about some molecules playing an important role in the process of carcinogenesis or drug resistance, and emerging molecules as targets for new treatments have been reported. In this research, we aim to address the clinical significance of PD-L1 expression in colorectal carcinoma correlation between emerging molecules and differences through clinical stages in CRC using tissue array. Methods: Consecutive patients who underwent surgery in our hospital from June 2003 to March 2011 were enrolled in this study. Tissue array based profiling of emerging molecules was performed on archival samples using immunohistochemistry for BRAF, MLH1/MSH2/MSH6/PMS2, CDX2, HER2 and PD-L1. We analyzed PD-L1 expression and correlation with molecular profile, survival, clinicopathological findings and location of primary site. Results: A total of 1030 CRC from stage 0 to IV were analyzed. The expression rates of PD-L1 were 3.6% and increased significantly in BRAF MT, dMMR, lack of CDX-2, tumor grade3 (TG3), right sided colon of primary site (25%, 37.8%, 21.6%, 22.1%, 6.9%, respectively; P < 0.001). In the univariate analysis, lack of CDX2, BRAF MT and TG3 were identified as prognostic factors in whole population of this cohort. Furthermore the survival of BRAF MT and lack of CDX2 with co-expression of PD-L1 were extremely poor (median OS in stage IV; 2.6 months in both). In Particular the co-expression rates of PD-L1 in BRAF MT were increasing as the clinical stage progress regardless of dMMR. Conclusions: Our study comprehensively summarized the significance of PD-L1 expression associated with the recent emerging molecules and suggested that malignant potential of BRAF mutant CRC may be explained in part due to escape from immunity by co-expression of PD-L1. Immune checkpoint inhibitor could be a candidate of target of BRAF mutant CRC with PD-L1expression irrespective of MSI status.
Age-related differences in gene expression in colorectal cancer (CRC).
Authors: Byrne Raphael M , Ruhl Rebecca , Lanciault Christian , Anand Sudarshan , Nellore Abhinav , Tsikitis Vassiliki Liana
Published: January 2019

654

Background: Colorectal cancer (CRC) in young patients is increasing in incidence and is associated with worse outcomes than CRC in older patients. While distinct molecular subtypes of CRC have been recently characterized, it is unclear whether there are molecular differences between the tumors of young and old patients. We sought to identify differences in gene expression of CRC between these two groups. Our discovery analysis identified a gene signature of several differentially expressed RNAs, from which we validated PEG10. The PEG10 gene on chromosome 7q21.3 has been implicated in liver, gallbladder, thyroid, and blood cancers, and is thought to play a role in cancer cell survival and regulation of apoptosis. In hepatocellular carcinoma, increased PEG10 expression has been associated with younger patient age. Methods: RNA sequencing data was obtained from The Cancer Genome Atlas (TCGA) and analyzed for differences in gene expression between patients ≤ 45 years old and those ≥ 65 years old. The identified differentially expressed genes were then validated with qPCR using human CRC tissue from patients ≤ 45 years old and those ≥ 65 years old. Results: RNA sequencing data from patients ≤ 45 years old (n = 29) and patients ≥ 65 years old (n = 299) identified seven genes with increased expression in younger patients: ZNF334 (log2 [fold change] = 2.30), DSC3 (1.78), PEG10 (1.67), CACNA1I (1.54), PKIA (1.33), MAP9 (1.27), and EPHX3 (1.17) (p < 0.07). Validation with qPCR for PEG10 was most promising, and was performed on both young (n = 10, mean age = 39) and old patient samples ( n= 8, mean age = 72). Two cancers (20%) in the young group received radiation treatment and five (50%) received chemotherapy. One cancer (12.5%) in the old group received radiation and two (25%) received chemotherapy. PEG10 had increased expression in the young group with log2 [fold change] = 3.16 (p < 0.02). Conclusions: We have identified a potentially unique gene expression signature for CRC in young patients, which includes PEG10. Functional analysis of PEG10 and other genes is underway using in vitro cell culture, archived human tumor tissue, and mouse tumor models.
Eukaryotic initiation factor 4A2 (EIF4A2) expression in colorectal cancer and prediction of prognosis.
Authors: Chen Zhan-Hong , Wu Qinian , Lu Jiahuan , Chen Le-zong , Wu Xiang-yuan , Wang Yun , Ju Huaiqiang , Lu Yun-xin , Chen Ya , Wang Feng , Xu Rui-hua
Published: January 2019

664

Background: Eukaryotic initiation factor 4A2(EIF4A2) is a member of the eukaryotic initiation factor 4A family and it is one of the protein-synthesis initiation factors, which are involved in the binding of messenger RNA to the ribosome. The prognostic roles of EIF4A2 in breast cancer, melanoma and lung cancer have been studied. However, the clinical significance and biologic role of EIF4A2 in colorectal cancer remain unknown. Methods: We used quantitative real-time polymerase chain reaction to compare expression of eIF4A2 mRNA between 72 paired colorectal cancer tissues and non-tumor colorectal tissues. We used immunohistochemistry to study the expression of EIF4A2 in 310 colorectal cancer patients under surgical resection, 247 of them received curative surgery. We also analyzed correlation between EIF4A2 expression and clinicopathological characteristics. The biological function of EIF4A2 on colorectal cancer cells were determined in vitro by knock-downing EIF4A2 in HCT116 and DLD1 cell lines. We performed MTT tests, colony formation assays, transwell and wound healing assays. Results: EIF4A2 mRNA was significantly higher in colorectal cancer tissues compared to the paired non-tumor colorectal tissues(P = 0.0034). Over-expression of EIF4A2 was prognostic of shorter overall survival(P = 0.002) and shorter disease-free survival(P = 0.042). Over-expression of EIF4A2 was significantly correlated with more TNM stage IV(P = 0.012). Multivariate analysis suggested EIF4A2 as an independent predictor of overall survival (hazard ratio 2.041[95% CI 1.385 to 3.008], P < 0.001) and disease-free survival (hazard ratio 1.537[95% CI 1.003 to 2.355], P = 0.049). Functionally, knockdown of EIF4A2 in HCT116 and DLD1 cell lines exerted tumor-suppressive effects by significantly inhibiting cell proliferation, colony formation,migration and invasion(P < 0.05). Conclusions: EIF4A2 is highly expressed in colorectal cancer and predicts poor prognosis. EIF4A2 could be served as a potential prognostic marker for colorectal cancer patients.