bluuebunny/crossref_metadata_2025 huggingface dataset:
Micro- and macroarteriolar blockade of hepatocellular carcinoma (HCC): Ramping up the dose of sorafenib over two weeks before hepatic arterial chemoembolization (HACE) for liver cancer.
Authors: de la Torre Andrew N , Castaneda Ismael , Contractor Sohail
Published: February 2017

472

Background: Multiple sessions of hepatic artery chemo-embolization (HACE) are usually necessary to achieve partial or complete ablation of a hepatoma (HCC). Blocking the pro-angiogeneic environment and re-establishment of tumor microvasculature with the tyrosine kinase inhibitor sorafenib administered prior to HACE may enhance tumor necrosis and possibly patient survival. Methods: Twenty patients with inoperable HCC were subject to 2 weeks of sorafenib, followed by HACE using Adriamycin and mitomycin C. The first 10 patients were treated with a sorafenib 400 mg twice a day. The second 10 patients had their dose of sorafenib ramped up from 200 mg twice a day to 400 mg twice a day over 1-2 weeks according to tolerability. Patients were continued on sorafenib during as many HACE procedures needed to achieve no evidence of enhancement on multi-phase imaging. Results: The mean length of treatment for the ramped up group was significantly longer that the non-ramped up group as shown in table 2. (3.90 vs 3.05, N < 0.05). There was no significant difference in survival, nor adverse events between groups. Three patients (5, 12, 13) ultimately went on to receive a liver transplant. Conclusions: Use of sorafenib prior to HACE is feasible and safe. Ramping up the dose over 2 weeks allows more patient to stay on treatment longer. Further studies are needed to determine how best to combine sorafenib with HACE in order to increase survival and eligibility of patients to be listed for liver transplant. Clinical trial information: NCT00949182.
Effect of preoperative hepatic and regional arterial chemotherapy on metachronous liver metastasis after curative colorectal cancer resection: A prospective, multicenter, randomized controlled trial.
Authors: Xu Jianmin , Xia Jianguo , Gu Yan , Lin Jianjiang , Ding Kefeng , Wei Ye , Qin Chunzhi , Zhu Dexiang , Ren Li , Qin Xinyu
Published: February 2017

511

Background: To evaluate the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis for stage II and III colorectal cancer in a multicenter setting. Methods: Patients with clinical stage II or stage III colorectal cancer (CRC) were randomly assigned to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary end point was disease free survival (DFS). Second end points were incidence of metachronous liver metastasis, overall survival (OS) and safety. Results: A total of 688 patients from 5 centers of China were randomly assigned to each arm. Five-year DFS were 75% for PHRAC arm and 61% for control arm (HR 0.60; 95% CI, 0.45 to 0.80; p<0.001). Five-year liver-metastasis rate was 8% and 18% in PHRAC arm and control arm, respectively (HR 0.39; 95% CI, 0.24 to 0.64; p<0.001). Five-year OS was 81% in PHRAC arm and 72% in control arm (HR 0.59; 95% CI, 0.42 to 0.84; p=0.003). There were no significant differences in morbidity or mortality between two arms. The results of eligible patients were barely changed. Subgroup analysis shows differences of DFS, liver-metastasis rate and OS were significant in stage III patients, but not in stage II patients. Conclusions: Additional PHRAC could reduce the incidence of metachronous liver metastasis and improve DFS and OS in patients with stage III CRC, without compromising patient safety. Clinical trial information: NCT00643877.
Racial disparities in survival after young-onset colorectal cancer.
Authors: Stoffel Elena Martinez , Ruterbusch Julie , Rozek Laura S. , Cote Michele L.
Published: February 2017

524

Background: Despite overall reductions in morbidity and mortality from colorectal cancer (CRC), racial disparities persist. In addition, incidence among individuals age <50 is rising. Our aim was to compare survival of young onset CRC cases diagnosed in black and white individuals. Methods: Using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program we identified individuals with CRC between the ages of 20 to 49, diagnosed in 2000-2008. Kaplan-Meier and Cox proportional hazards models were used to compare stage-specific 5 year survival between black and white individuals with young onset CRC. Results: A total of 26,236 incident young onset CRC cases (22,121 white, 4,115 black) were identified during the 9 year study period. Overall survival at 5 years following CRC diagnosis was 54.8% among blacks and 67.4% among whites (p<0.001), with blacks having a significantly higher hazard of death after adjusting for age, sex, stage, tumor site, and treatment history (HR 1.34, 95% CI 1.26-1.43). Stratifying by stage at CRC diagnosis, blacks had worse survival at every disease stage compared with whites, with the greatest racial disparities observed among stage II cancers of colon (HR 1.68 95% CI 1.38-2.04) and stage II and III cancers of the rectum (HR 1.78, 95% CI 1.51-2.09, and HR 1.86, 95% CI 1.54-2.24, respectively). Conclusions: Survival after diagnosis of CRC at young age is significantly worse among blacks compared to whites, even among individuals with early stage disease. These findings suggest that differences in tumor biology may play a role in racial disparities in CRC outcomes, which may have implications for adjuvant treatment.
Routine screening for mismatch repair proteins: The impact on genetic testing.
Authors: O'Kane Grainne , Flannery Delia , O'Connor Katrina , Nolan Carmel , Farrell Michael P. , Green Andrew J. , Meighan Brian , McCormick Paul , Kennedy M. John , Muldoon C. , Gallagher David James
Published: February 2017

525

Background: Lynch Syndrome (LS) accounts for approximately 3% of all colorectal cancers (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Increasing literature supports routine screening for LS using immunohistochemistry (IHC) to detect loss of MMR protein expression on tumour samples. We evaluated genetic clinic referrals and consequent LS diagnoses at our institution pre and post the adoption of universal screening. Methods: Reflex immunohistochemistry (rIHC) on all colorectal adenocarcinomas was implemented in November 2008. Prior to this IHC was performed at the pathologist’s discretion or upon request. Tumour specimens reviewed from November 2004 to October 2008 (pre rIHC) and from November 2008 to October 2012 (post rIHC) were evaluated and patients with evidence of MMR deficiency (MMR-D) were identified. The number of genetic referrals and number of patients with confirmed LS were determined. Results: During an 8-year period, 1,131 pathology specimens were reviewed in 1,103 patients (Table). Completion of IHC increased from 19% to 75% post implementation of rIHC. Ninety-two percent of incomplete samples in the post rIHC period (133/145) had insufficient tumour material for analysis. In patients with available IHC, 18/96 (20%) in the pre rIHC era were MMR-D of which 44% were referred to genetics, resulting in the diagnosis of LS in 4 patients. In the post rIHC era 30/429 (7%) of patients had evidence of MMR-D of which 20% were referred for genetic testing resulting in the detection of 3 LS patients. Conclusions: Universal testing for MMR protein expression is difficult to achieve, and does not necessarily result in increased genetic testing or Lynch Syndrome diagnosis. Systematic work-up of test results is essential once mismatch repair evaluation is initiated. [Table: see text]
Clinicopathologic characteristics of early onset colon-rectal cancer: A single center experience.
Authors: Perez-Florez Narjust , Gandhi Arpita , Gromko Larysa Jessica , Fernandez Enoc , Jennis Andrew , Bamboat Zubin M. , McCain Donald A. , Gutierrez Martin
Published: February 2017

538

Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. Early recognition of CRC in young patients (pts) is a challenge, and clinicopathologic features at the time of presentation are not well described. The aim of this study was to compare clinico-pathological characteristics and survival between early onset CRC (Age <50) and late onset CRC (Age ≥50). Methods: We reviewed the records of all patients diagnosed with CRC at our institution from 1999 to 2013. Total of 3,066 pts were studied. Demographics, tumor characteristics, and survival rate were analyzed. Patients with polyposis syndromes or genetic predisposition for CRC were excluded. Kaplan-Meier and Cox regression were used for the statistical analysis. Results: Of 3,066 pts, 425 pts (14%) under the age of 50 were identified (28-49). Hispanics (13% vs 8%, p<0.01) and African Americans (7% vs. 4%, p<0.009) were more prevalent in the early onset subgroup (EO) when compared to the late onset subgroup (LO). Pts were more likely to have sigmoidal and rectal tumors in the EO 187 (44%) than in the LO 799 (30%), (p<0.0001). Mucinous and signet cell tumors were more frequent histological subtypes in EO pts (12% vs. 7%, p<0.0003; 5% vs. 3%, p<0.04, respectively). At diagnosis, EO pts were more likely to have well-differentiated tumors and advanced disease than LO pts (59% vs. 34%, p<0.0001; 61% vs. 44%, p<0.0001, respectively). Median survival was 133 months in EO (95% CI: 113-160) and 87 months in LO (95% CI: 77-89) (p<0.01). African American descent (OR: 1.6 p<0.009), Hispanic ethnicity (OR: 1.9 p<0.001) right-colon tumors (OR: 1.65 p<0.003) and positive margins (OR: 1.98 p<0.001) were independent and significant predictors of survival by multivariate analysis in the EO subgroup. Colon cancer was the primary cause of death in 24% of EO vs. 11% LO (p<0.0001). Conclusions: In our cohort, EO subgroup was more likely to have advanced disease with predominance of well-differentiated and left-colon tumors. EO subgroup has better overall survival and that could be explained by the lack of comorbidities in this group. Further research should aim to elucidate the basis of these differences, as this could potentially impact screening and management.
Risk factors for lymph node metastasis in submucosally invasive colorectal cancer.
Authors: Huang Liyong , Li Xinxiang , Cai Sanjun
Published: February 2017

542

Background: The aim of this study was to identify risk factors for lymph node metastasis (LNM) in submucosally invasive colorectal cancer (SICC) that might be used in selecting patients for local excision. Methods: Records were reviewed from consecutive patients who had undergone curative resection of SICC at the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China, between 2006 and 2013. Clinical features such as age, gender, tumor size, and location were reviewed. Histopathologic examinations including tumor growth type, growth pattern at the invasive front, histopathological type, depth of tumor invasion, tumor budding, lymphovascular invasion, and neural invasion were performed. The expression of E-cadherin, p53, and Ki-67 were examined by immunohistochemistry. The association between the clinicopathologic factors and LNM was evaluated. Results: A total of 265 patients (140 men and 125 women) treated for SICC were included. The overall LNM rate was 12.8%. The incidence of LNM was significantly associated with growth pattern at the invasive front (p=0.028), tumor budding (p=0.006), histopathological type (p<0.001), and lymphovascular invasion (p<0.001). Other clinicopathologic and immunohistochemical factors were irrelevant to LNM. In multiple variable logistic analysis, histopathological type, and lymphovascular invasion were the two independent risk factors of LNM (p=0.015 and p=0.007, respectively). Conclusions: Histopathological type and lymphovascular invasion are significant independent risk factors for LNM in SICC. Careful selection for local excision in SICC should be considered.
Preoperative Chitinase 3-like-1, Galectin-3, and Activin Aplasma levels: A novel diagnostic panel for colorectal cancer.
Authors: Shantha Kumara Hmc , Miyagaki Hiromichi , Herath Sajith A , Gaita David , Yan Xiaohong , Njoh Linda , Cekic Vesna , Gandhi Nipa Dilip , Whelan Richard L
Published: February 2017

546

Background: Colorectal cancers (CRC) expressChitinase 3-Like-1(Chi3L1), Galectin-3 (Gal-3) and Activin A (Act-A). Chi3L1, indirectly, via IL8 and MCP-1, promotes tumor angiogenesis and progression. Gal-3 promotes tumor cell invasion and angiogenesis while Act-A supports cancer cell migration. This study’s goal was to assess the diagnostic value of plasma levels of Chi3L1, Gal-3 and Act-A, alone or together, for CRC. Methods: PreOp plasma samples were obtained from consenting CRC and benign pathology (BP) patients (pts) undergoing elective resection (IRB approved tissue bank). Plasma levels of Chi3L1, Gal-3 (ng/ml), and Act-A (pg/ml) were determined via ELISA and reported as median + 95% CI. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the CRC diagnostic value of single and multiple plasma protein levels. The Mann-Whitney test was used for statistical analysis (significance p<0.05). Results: A total of 118 CRC (81% colon, 19% rectal) and 42 BP pts (adenoma 31%, diverticulitis 53%, other 16%) were studied. The CRC median plasma protein levels were significantly higher vs. the BP group results [Chi3L1: 120.1, CI: 95.0, 146.6 vs. 36.8, CI; 29.3, 44.4; Gal-3: 12.0, CI: 10.5, 13.3 vs. 7.7, CI: 7.2, 9.9; Act-A: 368.0 CI: 341.0, 421.6 vs. 272.1, CI: 196.0, 327.3 [p<0.001 for all]). The AUC value for the ROC curve for Chi3L1, Gal-3 and Act-A were 0.850, 0.724 and 0.734 respectively with 76%, 52% and 38% specificity. The AUC for the combination of these 3 proteins was 0.890 with 88% specificity. Conclusions: Themedian Chi3L1, Gal-3 and Act-1 values in CRC pts were significantly higher (226%, 55% and 35%) then BP levels. The 3 protein combination had improved AUC and specificity vs single protein results and may have value as a diagnostic panel. A larger study is needed.
Nightly dosing of regorafenib.
Authors: DeSimone Philip A. , Overley Colleen , Long Katie E
Published: February 2017

549

Background: Fatigue and anorexia are major side effects in the use of regorafenib. These effects are compounded in patients with metastatic colon cancer to the liver. Finding a good fit for this agent has been difficult in patients when used in third and fourth line treatments. Our clinic has treated 21 patients with this agent. Methods: After the first four patients’s experienced extreme fatigue and anorexia at the recommended starting dose of 160mg daily, it was decided to start at a 21 day dose of 120mg. Even at this starting dose, it was necessary to dose deescalate. Ten patients were treated at the 120 mg daily dose and escalated 160 mg daily if tolerated. The agent was given at night to take advantage of the sleep period and the diurnal variation in adrenal gland function. No patient was treated with oral corticosteroids. Results: Two patients previously treated and responders were retreated after they decided they would give the agent a second opportunity. One of these patients, on day two of receiving the agent, developed a severe rash and the treatment was stopped. One patient received the agent for one week before he decided to stop, but was experiencing no side effects. Eight patients were eligible for evaluation. All patients had metastatic disease to the liver. Six were treated for at least two months and two were treated only for one month. All therapy was discontinued because of progression of disease. Fatigue and anorexia were evaluated by a change in their ECOG performance status, fatigue criteria and weight change. ECOG performance status of the patients was, ECOG 1, one patient, ECOG 2, six patients, ECOG 3, one patient. The evaluation was done before, during and after each monthly treatment. No patient had a greater than 5% weight loss. Four patients had Grade 1 fatigue, (fatigue relieved by resting). Six of the eight patients were escalated to 160mg daily after two weeks. Conclusions: Although this is a small sample study, it appears that night time dosing may be effective in helping a patient to achieve maximum benefit of regorafenib therapy. This study did not address the changes in absorption caused by a light fat free meal taken at night, and does not take into consideration the possible change in half-life of the agent when taken at night.
Therapeutic dual inhibition of HER2 pathway for metastatic colorectal cancer (mCRC): The HERACLES trial.
Authors: Siena Salvatore , Sartore-Bianchi Andrea , Trusolino Livio , Martino Cosimo , Bencardino Katia , Lonardi Sara , Leone Francesco , Zagonel Vittorina , Bertotti Andrea , Valtorta Emanuele , Siravegna Giulia , Amatu Alessio , Vanzulli Angelo , Regge Daniele , Ghezzi Silvia , Ciardiello Fortunato , Veronese Silvio , Comoglio Paolo Maria , Bardelli Alberto , Marsoni Silvia
Published: February 2017

565

Background: HER2 amplification in mCRC associates with resistance to anti-EGFR moAbs and, based on studies in patient-derived xenografts (Bertotti et al, Cancer Discov 2011), predicts response to combined therapy with anti-HER2 moAbs and lapatinib (L). Accordingly, we conducted an independent proof-of-concept phase II study of trastuzumab (T) and L in HER2+ mCRC after failure of standard therapies (HERACLES Trial - EudraCT 2012-002128-33). Methods: mCRC patients (pts) progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab were eligible if tumors were HER2+ [IHC 3+ or 2+ and FISH positive (HER2:CEP17 >2) in >50% cells]. L was given po daily and T iv weekly at standard doses. Tumor response was assessed every 8 weeks. The primary end-point was objective response (OR, RECIST v1.1). To consider the study positive 6/27 ORs had to be observed (α=0.05; β=85%; H1=30%). Serial liquid biopsies for ctDNA (ddPCR), and HER2 ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: We screened 646 pts with KRAS exon 2 WT mCRC and found 28 (4.3%) HER2+; 18 (2.8%) were fully eligible and evaluable for response as of September 10, 2014. Pts had a median of 5 (r=3-8) prior therapies, median age 61 (r=41-86), ECOG PS ≤1, 2F/16M. Primary endpoint was met with 6/18 ORs (1 CR, 4 PR, 1 PRunc; ORR=33.3%, 95% CI 0.16-0.56). Stable disease (SD) lasting > 4 mos. was obtained in four further pts. Five of six ORs and the longest SD (10 mos.) were observed in pts with HER2 gene copy number variations (CNVs) ≥20 copies. Treatment was well tolerated with toxicities limited to grade 2 diarrhea, fatigue, and skin toxicities (one grade 3). HER2 CNV in ctDNA decreased in 2/3 ORs and 0/2 non responders. HER2 ECD plasma levels also decreased in 2/2 ORs but not in 6/6 pts with SD or progression. Exome analysis of index cases will be presented. Conclusions: As predicted by HER2+ mCRC xenografts, the combination of T and L was remarkably active in standard therapy refractory mCRCs with HER2 amplification. HERACLES represents the first precision medicine trial with positive results in mCRC. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.
Differences between colon cancer primaries and metastases utilizing a molecular assay for tumor radiosensitivity and implications for potential oligometastatic SBRT patient selection.
Authors: Ahmed Kamran A. , Fulp William J. , Berglund Anders E. , Hoffe Sarah E. , Dilling Thomas J. , Eschrich Steven A. , Shridhar Ravi , Torres-Roca Javier
Published: February 2017

569

Background: We have previously identified a multigene expression model of tumor radiosensitivity with validation in four independent cohorts (breast, rectal, esophageal, and head and neck). This model predicts a radiosensitivity index (RSI) that is directly proportional to tumor radioresistance, (RSI, high index = radioresistance). The purpose of this study was to assess differences in RSI between primary colon cancer and metastases. Methods: Patients were identified from our institutional IRB-approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. Gene expression was obtained from Affymetrix Hu-RSTA-2a520709 microarrays. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 38 lung and liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p<0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=69). In our independent cohort of lung and liver metastases, lung metastases had an improved outcome over patients with liver metastases (2 yr local control, lung vs. liver metastases; 100% vs. 74.0%, p=0.027). Conclusions: Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.
Cetuximab-induced skin rash: A molecular map relating polymorphisms, cell-adhesion, and autoimmunity.
Authors: Schaaf Sebastian , Froelich Matthias , Kirchner Thomas , Heinemann Volker , Jung Andreas , Stintzing Sebastian , Mansmann Ulrich Robert
Published: February 2017

570

Background: Colorectal cancer (CRC) treatment with the EGFR-inhibitory antibody Cetuximab (CTX) is known to cause skin rashes (SR) of varying degree in most patients. Severity of SR is positively associated with tumor response. The underlying molecular mechanism linking both effects is still unknown. Detangling its genetic background would allow a simultaneous understanding of SR and response. Stratification of patients based on the related polymorphisms (PMs) is of clinical relevance. Methods: A systematic literature review was performed to develop a molecular map which incorporates specific pathways related to cancer, CTX specific mechanisms of action, skin rash, and autoimmunity. Exome data was generated from blood samples of 23 KRAS wild type patients taken prior to CTX treatment. Under CTX, eleven of the 23 patients showed SR of grades 3-4, twelve reacted with a grade 1 SR. Differential somatic PMs were analyzed between both groups. A gene set enrichment analysis for the imbalanced PMs was performed against gene sets of our molecular map. Imbalance was stated if at least seven patients more in the one group compared to the other carried this specific PM. Results: A total of 591 genes containing imbalanced PMs were found. Bioinformatic validation focused on the following findings of potential clinical interest: (1) PMs in genes specifically related to cell adhesion (CDH1, LAMC1, FBN2, NCAM1) or its regulation (WNT9B), (2) to autoimmunity (CXCL16, ADAM12, OS9, DOCK2), (3) in the central regulator TP53, (4) in genes playing a role in immunity and cell adhesion (DOCK2 and THBS2). PMs in the mentioned genes enabled to discriminate patients with and without severe skin rash. Validation of these findings is needed based on new independent CTX treated patients. Conclusions: Our findings suggest that genomic predisposition may exist which interact with CTX treatment by inducing alteration of cell adhesion. Altering adhesion between tumor cells makes them more accessible to the EGFR-inhibitory effect of CTX. Altering cell adhesion between epithelial cells introduces the acne like phenotypes of skin rash, presumably via the mechanism of epithelial activation. This will be the starting point for further research.
Multiple independent methods fail to confirm MET amplification rate reported in literature for metastatic colorectal cancer (mCRC).
Authors: Raghav Kanwal Pratap Singh , Tang Chad , Morelli M. Pia , Amin Hesham M. , Chen Ken , Manyam Ganiraju C. , Broom Bradley McIntosh , Talasaz AmirAli , Overman Michael J. , Shaw Kenna Rael , Meric-Bernstam Funda , Maru Dipen M. , Eng Cathy , Hong David S. , Kopetz Scott
Published: February 2017

572

Background: MET inhibition is emerging as a potent therapeutic strategy and MET gene amplification has shown predictive significance. MET amplification rate in mCRC, as previously reported in literature, varies from 9% in primary to 18% in metastases but intermixes increased copy number from chromosomal level aberrations with focal gene amplification. Validation of MET amplification rate in mCRC is needed. Methods: We performed analyses of MET amplification in mCRC patients (pts) (n = 636) across multiple cohorts. Cohort 1 (n = 103) included tissue microarray from liver metastases analysed using fluorescence in situ hybridization (FISH) [cMET and CEP7 probes, MET/CEP7 ratio > 2]. Cohort 2 (n = 205) included pts referred for phase I trials who had MET amplification testing using FISH. Cohort 3 (n = 279) included cases sequenced with HiSeq (Illumina) with full exome coverage for 202 genes including MET (average depth 800) with focal gene amplification (≥ 4 copies) identified by an in-house algorithm. Cohort 4 (n = 49) included pts refractory to EGFR monoclonal antibodies enrolled in the ATTACC (a prospective molecular screening) program for mCRC, in whom plasma circulating-free DNA (cfDNA) was analyzed by Guardant sequencing technology. Results: In tissue based analyses, focal MET amplification rate was 1.7% and was higher in primary tumors compared to metastases [3.1% (9/291) vs. 0.4% (1/288), p = 0.02] [Table]. In cohorts 2 & 3 MET amplification was found in 4 [MET/CEP7: 2.1 – 7.7; primary (4/130), metastases (0/75)] and 6 [copy number: 4.0 – 6.7; primary (5/161), metastases (1/110)] cases, respectively. MET amplification rate in pts who had progressed on anti-EGFR therapy was 14.3% (Table). Conclusions: Contrary to prior reports, in this large cohort, MET amplification was a rare event in mCRC pts and the rate was not higher in metastatic sites. However, MET amplification occurred in a sizable subset of pts refractory to anti-EGFR therapy as identified by cfDNA analysis. MET amplification appears to play a minor role in de novo colorectal carcinogenesis but may play an important role in acquired resistance to anti-EGFR therapy. [Table: see text]
Efficacy of Goshajinkigan for prophylaxis against oxaliplatin-induced peripheral neuropathy.
Authors: Kono Toru , Suzuki Yasuyuki , Mizuno Keita , Miyagi Chika , Omiya Yuji , Sekine Hitomi , Mizuhara Yasuharu , Miyano Kanako , Kase Yoshio , Uezono Yasuhito
Published: February 2017

576

Background: Oxaliplatin-induced peripheral neuropathy (OPN) is often observed and is the most frequent dose-limiting toxicity. However, there is no effective therapeutic option for preventing OPN. Goshajinkigan (GJG), a traditional Japanese herbal medicine, has widely been used for disease-assessed neuropathy in Japan. Recently, the preventive effect of GJG against OPN in a placebo-controlled double-blind randomized phase II study was reported (Kono T et al., Cancer Chemother Pharmacol. 2013, 72,1283-90). However, the precise mechanisms underlying preventive effect of GJG are unknown. Methods: To be established the OPN rat model, oxaliplatin (4 mg/kg) was injected intraperitoneally twice weekly for 8 weeks in rats. Animals were treated with oral administration of GJG (0.3, 1.0 g/kg) five times a week for 8 weeks. We performed behavioral tests (acetone test and hot plate test) and pathological examination of neuronal tissue using the OPN rat model. We carried out pharmacokinetic study of GJG and searched for active ingredients in GJG in order to explore the mechanism of GJG. Results: The rats injected with oxaliplatin for a long-term showed both cold hypersensitivity and heat hyposensitivity. Co-administration of GJG ameliorated OPN in the rat. In light and electron microscopic study, scattered axonal damages in sciatic nerve of oxaliplatin groups were observed, which were substantially suppressed by GJG. Pharmacokinetic study revealed that considerable neuroprotective and analgesic ingredients were detected after oral administration of GJG in rat plasma. Some ingredients in GJG significantly suppressed oxidative stress caused by oxaliplatin in the experiment using neuronal cells. Conclusions: Oxaliplatin-induced chronic neuropathy symptoms are similar to human symptoms caused by long-term oxaliplatin administration. Oral administration of GJG in rat substantially diminished OPN, and promises to provide an effective and convenient treatment at risk of developing peripheral neuropathy in oxaliplatin-treated patients.
Molecularly-guided therapeutic options beyond tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST).
Authors: Feldman Rebecca , Gatalica Zoran , Reddy Sandeep K. , Chawla Sant P. , Sankhala Kamalesh Kumar
Published: February 2017

58

Background: GISTs are characterized by KIT/PDGFRA mutations. A range of multi-targeted tyrosine kinase inhibitors (TKIs) are available for treatment, however, resistance mechanisms inevitably emerge. Recent data (Boichuk, et al 2014) suggests the potential efficacy of various cytotoxic therapies that were identified as being able to effectively kill TKI-responsive and -resistant GIST cells. We sought to investigate the theranostic markers associated with non-TKI therapy options for their potential role in treatment of GIST. Methods: 147 GIST cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). Results: Multidrug resistance phenotype was found in 52-68% (PGP, MRP1). Tubulin-binding agents (taxanes, vinca alkaloids) may be of potential use due to the high frequency of low TUBB3 expression (72% or 39/54). Anthracyclines and topoisomerase inhibitors may be of potential benefit in 1/3 of patients based on expression of TOPO2A (32% or 32/99) and TOPO1 (34% or 37/110). Cytotoxic agents used in non-GIST solid tumors, may also be considered, based on high frequency of low expressin of MGMT (47% or 57/122), TS (70% or 76/109) and RRM1 (79% or 88/111). PTEN was intact (positive expression) in the majority of GIST (87%). Nine patients were examined for PD1/PDL1: 56% exhibited positive tumor infiltrating lymphocytes and 33% exhibited PDL1 tumor expression. Only one amplification event was observed: cMET (0/53), HER2 (0/69), EGFR (0/16), PIK3CA (0/1) and TOP2A (1/11). Mutational screening using a hot spot cancer panel (and Sanger sequencing for some genes) resulted in the detection of variants in only 10 genes, excluding KIT (97/132) and PDGFRA (5/55). Variants were detected in the following genes, in decreasing order of frequency: RB1, APC and JAK3 (2/55; 2/55; 2/57), PIK3CA (2/69) and ABL1, cMET, EGFR, KDR, VHL and BRAF (1/55, 1/57, 1/57, 1/57, 1/52, 1/78). Conclusions: A multi-platform approach of theranostic biomarkers identified therapies beyond TKIs for GIST. Various cytotoxics and non-KIT/PDGFRA targeted therapies were identified based on protein expression or gene variations.
Association of EGFR CA simple sequence repeat 1 (CA-SSR1) variant with cetuximab (cet)-induced skin toxicity (ST) in Japanese metastatic colorectal cancer (mCRC) patients (pts) with overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) (JACCRO CC-05/06 AR).
Authors: Ichikawa Wataru , Sunakawa Yu , Tsuji Akihito , Takahashi Takehiro , Denda Tadamichi , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Segawa Yoshihiko , Tanioka Hiroaki , Negoro Yuji , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Masuishi Toshiki , Takeuchi Masahiro , Lenz Heinz-Josef , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

582

Background: Associations of EGFR gene copy number (GCN) and EGFR CA-SSR1 polymorphism with clinical outcome still remain controversial in mCRC pts treated with cet. Interethnic differences in the repeat number of EGFRCA-SSR1 have been reported between Caucasian and Asians, however, there have been few reports about the associations with clinical outcome in Japanese pts. The aim of this study was to evaluate the predictive value of two biomarkers in Japanese mCRC pts treated with cet. Methods: This study enrolled 77 pts with tumor available from two prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in mCRC pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Genomic DNA isolated by macro-dissection from tissue was screened for the EGFR GCN determined by FISH on FFPE tumor specimens with the cut-off value of 2.9, adopted as previously reported (Cappuzzo F, et al., 2008), and the EGFR CA-SSR1 short (S; ≤19) / long (L; ≥20) determined by PCR amplification and fragment length analysis using capillary electrophoresis. Associations of the biomarkers with efficacy, including response, progression-free survival, and overall survival, were evaluated. Additional analysis was addressed at a possible association between the EGFRCA-SSR1 and ST. Results: The frequency of the L alleles of the EGFR CA-SSR1 was 64%. There was no significant association between two biomarkers and efficacy. However, the EGFR CA-SSR1 variant significantly correlated with ST evaluated on 8 weeks after initial administration. The rate of ST with grade 2 or 3 was 33% (10/30), 19% (5/26), and 64% (7/11) in LL, SL, and SS genotype, respectively (fisher's exact test p=0.03). Conclusions: Our study provides first evidence that the EGFR CA-SSR1 variant was associated with cet-induced ST in Japanese mCRC pts. No predictive value for cet treatment could be identified in our screened biomarkers, however, extended RAS mutations analysis is warranted (UMIN000010635).
Impact of standard chemotherapy on peripheral blood immune cell subsets in metastatic colorectal cancer.
Authors: Heery Christopher Ryan , Jochems Caroline , O'Sullivan Coyne Geraldine Helen , Madan Ravi Amrit , Singh Harpreet , Gulley James L. , Schlom Jeffrey , Marshall John
Published: February 2017

597

Background: To date, there has been minimal impact with immunotherapy in patients with metastatic colorectal cancer. We have hypothesized that the lack of effect seen may be due to the refractory nature of the disease after multiple lines of standard chemotherapy. We hope to evaluate immunotherapeutic agents in combination with standard chemotherapy agents for evidence of additional clinical benefit. To our knowledge, there has never been an effort to evaluate the effects of standard chemotherapy agents for metastatic colorectal cancer on the immune system and its ability to respond to immunotherapeutic agents. Methods: We enrolled 8 patients with previously untreated metastatic colorectal cancer starting 5-FU based therapy and collected peripheral blood mononuclear cell (PBMC) samples prior to treatment, on day 8, and on day 15. PBMC were analyzed by a flow-cytometry based analysis using a panel of 26 markers to identify 40+ predefined immune cell subsets. Comparisons from baseline, day 8, and day 15 were made using the Friedman test and Dunn’s Multiple Comparison test to evaluate whether standard chemotherapy significantly altered the frequency of immune cells in any subset. Results: No significant differences were observed post treatment with this regimen in the frequency of any immune subset analyzed. Conclusions: Our preliminary findings indicate that 5-FU- based chemotherapy does not significantly affect the frequency of any of 40 analyzed peripheral blood immune cell subsets in patients with previously untreated metastatic colorectal cancer. Based on findings from other groups indicating potential tumor microenvironmental benefits of active chemotherapy on the immune response, we conclude that there should be no concern of detrimental effects of standard chemotherapy for use in combination with immunotherapy in the first line metastatic disease setting for colorectal cancer. We plan to enroll more patients for further analysis, which will be presented at the time of the meeting.
Routine multiplexed mutational analysis of colorectal cancers (CRCs): A single-institution experience.
Authors: Chan Emily , Goff Laura Williams , Cardin Dana Backlund , Berlin Jordan , Levy Mia Alyce , Vnencak-Jones Cindy L , Pao William
Published: February 2017

599

Background: Colorectal tumors harbor mutations in genes that play key roles in CRC carcinogenesis and that may enable prioritization of appropriate anti-cancer therapy. KRAS testing is part of standard of care testing prior to initiation of anti-epidermal growth factor receptor antibodies. Other mutations are emerging as significant drivers, but they are not yet part of routine screening. Methods: As part of Vanderbilt-Ingram Cancer Center’s Personalized Cancer Medicine Initiative, we developed a clinical algorithm to genotype patient’s colorectal tumors using a SNaPshot-based assay (multiplexed PCR, primer extension, and capillary electrophoresis) designed to detect 65 somatic mutations in 7 genes (KRAS, BRAF, AKT1, PIK3CA, SMAD4, PTEN, and NRAS) important in CRC carcinogenesis. Adult patients with metastatic CRC were consented for genotyping of tumor tissue. Mutational profiling was performed in Vanderbilt’s CLIA-certified Molecular Diagnostics Laboratory. Results were reported in the electronic medical record for clinical use. Results: Study enrolled from May 2012 to February 2014. SNaPshot results were available from 126 patients. 49 tumors (38.9%) were wildtype for all mutations tested. 58 (46.0%) tumors had a KRAS mutation, including one with two KRAS mutations; the most common was G12D (n=23), but two had a Q61H mutation and two had a K117N mutation, which are not included in some commercial KRAS tests. Ten (8.9%) tumors carried the V600E BRAF mutation. Nine (7.1%) tumors harbored a PIK3CA mutation. Three (2.4%) tumors had mutations in SMAD4. Four (3.2%) tumors had a NRAS mutation. One (0.8%) tumor had a PTEN mutation. Nine (7.1%) tumors harbored double mutations, the most common being KRAS and PIK3CA double mutations (N=6). 24 (19%) subjects subsequently were treated on clinical trial therapy, including 6 subjects on therapy based on the SNaPshot results. Not surprisingly, RAS results impacted use of anti-EGFR therapy. Conclusions: 61% of the tumors carried at least one mutation in the seven genes tested, suggesting that trials of tumor genotyping-based treatment assignment are feasible. Study was supported by Vanderbilt University Medical Center.
Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy.
Authors: Bilici Ahmet , Aydin Dincer , Yavuzer Dilek , Odabas Hatice , Ercelep Ozlem , Yuksel Sinemis , Guven Mert Aslihan , Ozcelik Melike , Aliustaoglu Mehmet
Published: February 2017

60

Background: Tumor invasion and metastasis are complex processes, involving regulation at the molecular level of adhesive molecules, proteolitic enzymes, and cell growth and angiogenesis factors. A Disintegrin and Metalloproteinase (ADAM)17 has been indicated to be indispensable regulator of celular event from proliferation to migration.Although prognostic importance of ADAM17 expression has been investigated in several tumors, its clinical utility as a useful prognostic molecular marker remains unclearin gastric cancer.In the present study, we evaluated the expression of ADAM17 and its prognostic significance in gastric cancer patients after surgery. Methods: Prognostic significance of ADAM17 expression was analyzed by immunohistochemically in 158 patients with gastric cancer and the relationship between its expression and clinicopathological factors was also evaluated. Results: High expression of ADAM17 was detected in 81 patients(51%),while low expression was found in 77 cases (49%). There was significant correlation between gender, histology, lymph node metastasis, vascular invasion, the presence of recurrence and high ADAM17 expression. Recurrence in patients with high ADAM17 expression was significantly higher than that for patients with low ADAM17 expression(p=0.032). The median disease-free survival (DFS) time for patients with high ADAM17 expressed tumors were worse than those of patients with low ADAM17 expressed tumor (16.6 vs. 44.2 months, p=0.004).In addition, patients with low ADAM17 expression had a higher median overall survival (OS)interval than those of high ADAM17 expressed patients (49.6 vs. 26.9 months, p=0.019). Multivariate analysis indicated that the rate of ADAM17 expression was an independent prognostic factor for DFS, in addition to known important clinicopathological prognostic indicator for DFS. But its' prognostic importance could not be proved by multivariate analysis for OS. Conclusions: The potential value of ADAM17 expression as a useful molecular marker in gastric cancer progression should be evaluated comprehensively,it may predict recurrence and poor prognosis in patients with gastric cancer after curative resection.
Targeting colon cancer metabolism through a long noncoding RNA.
Authors: Hatziapostolou Maria , Koutsioumpa Marina , Kottakis Filippos , Iliopoulos Dimitrios , Polytarchou Christos
Published: February 2017

604

Background: Long non-coding RNAs (lncRNAs) have gained massive attention in recent years as a potentially new and crucial layer of gene regulation. We studied the function of the lncRNA HOTAIR in colorectal cancer, one of the most common causes of cancer mortality worldwide. Methods: Molecular profiling was performed in colonic normal (40) and cancer (160) tissues. Gene expression was evaluated by qRT-PCR and gene expression arrays. LncRNA-protein interactions were investigated by RNA-immunoprecipitation, mass spectrometry and mutational analyses. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq) was employed for the histone acetylome analysis. Subcutaneous xenograft mouse models were used to evaluate tumor growth in vivo. Results: HOTAIR is significantly upregulated (>30 fold) in colon cancer and inversely correlates with patient survival. Molecular profiling revealed a gene signature downstream of HOTAIR that links metabolic pathways to colon cancer cell growth and invasiveness. RNA immunoprecipitation/mass spectrometry analysis revealed the interaction of HOTAIR with the histone acetyltransferase PCAF. Mutational analyses identified the domains of both the lincRNA and acetyltransferase responsible for their interaction and function. Histone acetylome analysis demonstrated that HOTAIR is required for the recruitment and activity of PCAF towards a set of genes involved in the mTOR/insulin receptor/PI3K-Akt pathways. In specific, 44 genes involved in these pathways are regulated by Lysine 27 histone H3 acetylation, catalyzed by PCAF only when recruited by HOTAIR. Genome-wide profiling of colon cancer and normal colonic tissues revealed that the expression of this gene set correlates positively with HOTAIR levels and inversely with patient survival. Knockdown of either HOTAIR or PCAF sensitized colon cancer cells to dietary restriction and inhibited tumor growth in subcutaneous xenograft mouse models. Conclusions: Our results provide the mechanistic link between an lncRNA, a transcription activating chromatin mark and metabolic signaling in colorectal cancer. In conclusion, we identified a novel RNA-protein complex that affects growth factor/metabolic pathways essential for colon oncogenesis.
Next-generation sequencing of advanced, relapsed colorectal adenocarcinoma (CRC) to reveal mutations affecting Wnt, MAPK and PI3K pathway signaling: Emergence of novel combinatorial strategies.
Authors: Subbiah Ishwaria Mohan , Janku Filip , Tsimberidou Apostolia Maria , Naing Aung , Subbiah Vivek , Wheler Jennifer J. , Zinner Ralph , Eng Cathy , Overman Michael J. , Kopetz Scott , Palmer Gary A. , Hong David S.
Published: February 2017

605

Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.