bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results of the UGT1A1-based dose modification of irinotecan and its impact on rates of severe neutropenia and hospitalization.
Authors: Tan Benjamin R. , Wu Ningying , Wang-Gillam Andrea , Suresh Rama , Picus Joel , Baranda Joaquina Celebre , Lockhart Albert C. , McLeod Howard L.
Published: February 2017

461

Background: UGT1A1 7/7 genotype has been associated with a 3-fold increase in severe neutropenia for patients treated with irinotecan (IRI) (Mcleod 2010, Liu 2013). UGT1A1 determination may tailor IRI therapy and reduce toxicities. However, the impact of the FDA-recommended IRI dose modification on outcomes is unclear. Methods: UGT1A1 genotyping was done for patients with various cancers wherein IRI therapy was planned and who consented to 1 of 3 IRB-approved registries. For patients with UGT1A1 7/7, a reduction in IRI doses was recommended per FDA and toxicities monitored during the first 2 doses. Results: 323/341 patients registered had UGT1A1 determined, of which 13% (42/323) had the 7/7 or 7/8 genotypes. Notably, a significantly higher proportion of African-Americans (AA) harbor these genotypes compared to Caucasians (C) (26.32% vs 10.08%, p=0.001). Among the 251 evaluable for toxicities, the incidence of grade 3-5 ANC for patients with 7/7 was not significantly different than those with 6/6 or 6/7 (Kendall's Tau-b coefficient p=0.494) (see Table). Among the 7/7 patients, 23/33 were treated at IRI doses of 150 mg/m2 or higher. 30% of patients treated at the higher dosages still developed grade 3-5 neutropenia compared to 17-21% for those with other genotypes. 38 of 251 patients were hospitalized during their first 2 cycles of therapy. The proportion of hospitalized patients with 7/7 genotype was not significantly different than those with 6/6 or 6/7 (15% vs 17% vs 12.6%). Conclusions: UGT1A1 can be used to tailor IRI therapy and reduce toxicities. The incidence of severe neutropenia and rate of hospitalization is comparable among patients with all UGT1A1 genotypes when IRI dose is adjusted for those with UGT1A1 7/7. There is a higher incidence of UGT1A1 7/7 genotype among African-Americans comnpared to Caucasians, which warrants further evaluation. [Table: see text]
Results of the MARS study on the management of antiangiogenics’ renovascular safety in colorectal cancer.
Authors: Ray-Coquard Isabelle , Janus Nicolas , Spano Jean-Philippe , Thery Jean Christophe , Goldwasser Francois , Mir Olivier , Beuzeboc Philippe , Daniel Catherine , Morere Jean Francois , Rey Jean-Baptiste , Jouannaud Christelle , Oudard Stephane , Scotte Florian , Azizi Michel , Dorent Richard , Deray Gilbert , Launay-Vacher Vincent
Published: February 2017

466

Background: MARS is a prospective multicentric study conducted to assess the renovascular tolerance of anti-VEGF drugs (AVD) in the clinical setting in France, in a number of different tumor types. Methods: Patients (pts) from 8 centers were included when they were 1) naive of any AVD and 2) about to start treatment with an AVD, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit during f/u. This subgroup analysis presents the results for colorectal cancer (CRC) pts receiving bevacizumab (BVZ). Results: 1,124 pts were included. 200 had CRC and all but 5 received BVZ. Median age: 63.2 years. Visceral, bone, and cerebral metastasis frequencies were 91.3, 10.8, and 0.5%, respectively. All pts presented metastasis. At inclusion, HTN prevalence was 26.2%. Baseline renal assessment retrieved: Pu 30.6%, Hu 10.1%, mean aMDRD 91.1 ml/min/1.73m2. The incidence of de novo Pu and HTN during f/u was 78.2 and 16.1% (Table). 75.6% of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 60.8% afterward improved/normalized. No grade 4 Pu has been reported (at inclusion or during f/u). Renal function decreased with a mean aMDRD of 90.3 at the end of f/u. 5.9% had grade 2 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of BVZ in CC patients showed that 1) TMA is rare, 2) Pu develops in 78.2% of the pts (no grade 4), 3) 16.1% developed HTN. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Overall and abdominal adiposity in a prospective colorectal cancer patient cohort: The COPE study.
Authors: Siegel Erin M. , Maddox Kristen , Riggs Bridget , Townsend Ione G. , Calzada Jazmin , Coppola Domenico , Shibata David
Published: February 2017

467

Background: Obesity is an important risk factor for colorectal cancer (CRC); however, the exact role of adiposity on CRC remains unknown. Our overarching hypothesis is that abdominal fat, specifically visceral fat, through alterations in pro-inflammatory and tumor-promoting factors (e.g., IGF-1 or insulin) promotes aggressive tumor behavior and proliferation. To address this hypothesis, we have established an ongoing cohort of CRC patients [Colorectal Outcomes, Prognosis and Epidemiology (COPE) Study] with repeated adiposity and blood measures during the first year post-diagnosis. The objective of this study is to begin examining differences in diagnostic overall and abdominal adiposity by clinicopathological factors. Methods: Newly diagnosed patients with invasive adenocarcinoma of the colon or rectum were enrolled from 2010 to 2013 (N=213). Baseline overall adiposity by body mass index (BMI) and abdominal adiposity by waist circumference (WC) were collected. In a pilot study in 30 cases, baseline levels of IGF, IGFBP3, insulin and glucose to examine if serum markers were associated with obesity among CRC patients. The differences were evaluated by gender and clinical factors using ANOVA. Results: This study included 126 male and 87 female CRC patients with a median age of 64 years (range: 29-93). A majority of the patients were Caucasian (94%), married (68%), and never smokers (59%). The mean BMI and WC were 27.6±5.2 kg/m2and 96.5±15.8 cm, respectively. WC, but not BMI, was significantly higher among men (p=0.02), among patients with colon cancer (p=0.01), with higher stage (stage I/II vs. III/IV; p=0.02) and in high grade tumors (p=0.03). Serum IGFBP3 was significantly elevated in patients with abdominal adiposity (p=0.004) and colon cancer (p=0.004). Conclusions: Excess abdominal adiposity (WC) was related to advanced stage and high grade, whereas overall adiposity (BMI) was not. This study highlights the prevalence of abdominal adiposity and its potential biological importance among CRC patients. The development of more refined techniques (e.g. CT-based) of further defining the visceral and subcutaneous components of abdominal adiposity in cancer patients may prove to be informative.
Transcriptomic profiles to differentiate colon and rectal adenocarcinomas.
Authors: Hogan John , Dejulius Kathryn , Li Xiaoxia , Coffey John Calvin , Kalady Matthew
Published: February 2017

468

Background: Dissimilarity exists between colon and rectal cancer at a genetic, clinical, and molecular level. This is likely to reflect variation at a transcriptomic level. Transcriptional studies of colorectal cancer have previously combined colonic and rectal adenocarcinoma in a single group. Consequently few studies accurately describe the transcriptional profile of colon and/or rectal cancer. This study aims to develop classifiers based on transcriptomic differences between colon and rectal cancer and utilize these classifiers to predict tumor origin (colon vs. rectum). Methods: Comparisons were made between cDNA microarrays derived from colon (87) and rectal (125) adenocarcinomas. Gene expression data was filtered according to standard deviation to retain only highly dysregulated genes. Genes differentially expressed between colon and rectal adenocarcinoma were identified on two groups t test (p<0.05, Bonferroni p value adjustment) and further analysed. Genes were rank ordered in terms of descending fold change. Comparisons included a) colon adenocarcinoma vs. rectal adenocarcinoma (stages I - III), b) stage II colon adenocarcinoma vs. stage II rectal adenocarcinoma and c) stage III colon adenocarcinoma vs. stage III rectal adenocarcinoma. For each comparison, those five genes with the greatest positive fold change were grouped in a classifier. Five separate tests were applied to evaluate the discriminatory capacity of each classifier and summary receiver operating characteristic curves generated for each classifier. Results: Genetic classifiers dervied from a comparison of stage II colon and stage II rectal adenocarcinoma were the most accurate in distinguishing tumor type (mean sensitivity 82.5%, mean specificity 81.7%). Classifiers derived from a pooled analysis comparing colon and rectal cancers (stages I - III) (mean sensitivity 79.8%, mean specificity 71.1%) and those derived from a comparison of stage III colon and stage III rectal cancers (mean sensitivity 57.1%, mean specificity 98.6%) were also accurate in determining tumor type (colon vs. rectum). Conclusions: Colon and rectal adenocarcinoma differs at a transcriptomic level. These findings provide insight into underlying biologic differences.
Molecular epidemiology of RAS/RAF-mutant colorectal cancer metastases.
Authors: Atreya Chloe Evelyn , Watters James , Rowley Steve , Lee Joon Sang , Iartchouk Oleg , Light Madelyn , Warren Robert S. , Venook Alan Paul
Published: February 2017

470

Background: A comprehensive molecular characterization of primary colorectal cancers (CRC) was recently reported. Less is known about mutation patterns in CRC metastases and association with survival. Our sequencing analysis focused on CRC liver metastases with RAS/RAF mutations, representing a patient population with limited therapeutic options. Methods: DNA was extracted from formalin-fixed paraffin-embedded CRC liver metastases. Fifty tumors found by Sequenom MassARRAY to harbor KRAS, NRAS or BRAF mutations underwent next generation sequencing on the Ion AmpliSeq Comprehensive Cancer Panel of 409 genes. Co-investigators were blinded to Sequenom mutations identified at UCSF. Variants called by Strelka and VarScan were extensively filtered to control the False Positive Rate and find mutations occurring with > 5-10% variant allele frequency compared to normals. The dataset was evaluated for significant co-mutations, biclustering, and population probabilities of mutations. Results: Following sequencing, 37,744 variants were called in 409 genes with a median coverage depth of 1053x. After filtering to minimize false positives, 2335 variants in 315 genes remained. ARID1A and PIK3R1 were the most significantly associated co-mutation pair, P < 3.5e-5. Biclustering showed no stratification of patients; genes stratified only by mutation frequency. Further filtering yielded 1,186 variants present at < 1% allele frequency within 1,000 Genomes, of which 131 variants in 24 genes are referenced in the Catalog of Somatic Mutations in Cancer. In addition to anticipated mutations in mismatch repair genes and the RTK/RAS/PI3K, Wnt, TP53, and TGF beta pathways, infrequent mutations were found in Akt1, mTOR, MET and PPP2R1a. After APC, TP53 was the most commonly mutated gene, in 44% of the tumors (95% cl: 31.1% - 57.8%). Survival was similar with mutation of RAS/RAF plus either TP53 or PIK3CA. Conclusions: Next generation sequencing was used to characterize co-variants in RAS/RAF mutated CRC liver metastases. The complexity of our results is consistent with the clinical observation that targeting RAS/RAF mutated metastatic CRC is a formidable challenge. These analyses may nonetheless inform the design of future clinical trials.
Cancer stem cells profile and clinical outcome in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.
Authors: Giampieri Riccardo , Scartozzi Mario , Loretelli Cristian , Del Prete Michela , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano
Published: February 2017

474

Background: Although an oxaliplatin-based adjuvant treatment is a widely accepted option for radically resected stage III colorectal cancer patients, it is not uncommon to observe an heterogeneous clinical outcome independently from stage. Cancer stem cells (CSC) profile has been suggested to regulate key steps leading to progression, relapse and metastasis and therefore may be responsible for this otherwise unpredictable heterogeneity. ALCAM, CD133, CD24, LRG5, SOX2, ALDH1A1 have been reported as potential markers for CSC, particularly in digestive system cancer. Aim of our study was to assess the role of these markers in determining clinical outcome for stage III colon cancer patients receiving adjuvant chemotherapy. Methods: Patients undergoing radical surgical resection for stage III colon cancer and receiving adjuvant oxaliplatin in combination with either 5FU or capecitabine were eligible for our analysis. CSC profile (ALCAM, CD133, CD24, LGR5, SOX2, ALDH1A1) was analysed by RT-PCR in primary tumour samples. The multivariate analysis also included adjustments for other variables such as T and N stage, sex, age and tumour location. Results: Seventy-eight patients were eligible for analysis. Only high ALCAM expression was associated with clinical outcome. In particular in colon tumours overexpressing ALCAM we observed a significant interaction for a higher risk of relapse (p = 0.04) and a reduced time to relapse (not reached vs. 33.24 months, HR:0.46, 95%CI:0.23-0.89, p = 0.02). There were no significant differences according to main stratification factors between the high ALCAM group vs. low ALCAM group. In our series N stage (N1 vs. N2-3) resulted also relevant for clinical outcome. Conclusions: Our analysis supports the hypothesis that ALCAM expression may represent a crucial marker for a better risk stratification in stage III colon cancer patients receiving adjuvant chemotherapy. According to our data we also suggest that other potential markers of CSC are probably ineffective for patients stratification. Patients expressing high ALCAM levels may be optimal candidates for therapy intensification and possibly different treatment options.
Correlation of peripheral blood lymphocyte counts with outcome and histopathologic features of lymphocytic inflammation in patients with stage II colorectal carcinoma.
Authors: Li-Chang Hector Hugo , Assarzadegan Naziheh , Messenger David , Grin Andrea , Howlett Christopher , Kirsch Richard
Published: February 2017

475

Background: The prognostic importance of the local antitumor immune response in colorectal carcinoma (CRC) is well established. Recent studies suggest that systemic antitumor immunity may also impact on survival. This study aimed to determine the relationship between peripheral blood lymphocyte counts (PBLCs), reactive features in regional lymph nodes, local tumoral/peri-tumoral lymphocytic inflammation and survival in stage II CRC. Methods: Resection specimens from 185 patients with stage II CRC were assessed for peri-tumoral lymphocytic inflammation, tumor-infiltrating lymphocytes, lymph node yield, lymph node size, and reactive changes in individual lymph nodes. Reactive changes were scored semi-quantitatively and given a reactivity [R] score of 1-4 based on the presence and size of germinal centers. Pre-operative PBLCs and neutrophil counts were recorded. Results: Lower peripheral lymphocyte counts were associated with advanced age (p = 0.016), T4 disease (p = 0.006), venous invasion (p = 0.006), lymph node yields <12 (p = 0.024), smaller mean nodal diameters (p = 0.021), absence of tumor-infiltrating lymphocytes (p = 0.002) and fewer highly-reactive lymph nodes (R score 4) per case (p = 0.032). Cox regression analysis revealed that advanced age (Hazard Ratio, 1.03 per year [95% confidence interval, 1.01-1.05]; p = 0.015) and higher peripheral lymphocyte counts (HR, 0.52 per 1x109cells/L [95% CI, 0.31-0.86]; p = 0.011) were independently predictive of disease-free survival. Neutrophil counts were not associated with outcome. A higher neutrophil to lymphocyte ratio was associated with worse survival on univariate, but not multivariable analysis. Conclusions: The PBLC is an independent predictor of survival in stage II CRC, and is significantly associated with the immune status of regional lymph nodes and the local lymphocytic immune response.
Potential regulators of HER2 activity in HER2-overexpressing gastric and gastroesophageal tumors: Analysis of HER3 and heregulin expression.
Authors: Kudla Arthur J. , Paragas Violette , Geretti Elena , Onsum Matthew D. , McDonagh Charlotte Fenton
Published: February 2017

48

Background: HER2 is overexpressed in gastric and gastroesophageal junction (GEJ) tumors. Though treatment of these tumors with the HER2-targeted agent trastuzumab offers clinical benefit, patients ultimately progress. Signaling by HER2/HER3 heterodimers following activation by HER3’s ligand heregulin has been shown to be a resistance mechanism to trastuzumab. The objective of this study was to quantitate HER2, HER3 and heregulin in gastric and GEJ tumor samples to determine whether these tumors express components for signaling through this complex and thus have potential for developing trastuzumab resistance. Methods: A novel immunofluorescent assay was used to quantitate HER2 and cytokeratin in 236 gastric and GEJ tumors. Using image analysis, each cell within a section was classified as tumor or non-tumor based on cytokeratin level. HER2 fluorescence was also quantitated in each cell and converted to number of HER2 receptors per cell using a standard curve from an array of cell lines with defined HER2. The assay’s single cell output enables an assessment of HER2 heterogeneity in any tissue. In those tumors overexpressing HER2, HER3 and heregulin were quantitated using immunofluorescence as for HER2 and by RT-PCR. Results: In concordance with published data, HER2 was overexpressed in ~10% of gastric and ~20% of GEJ tumors. HER2-overexpressing tumors could be divided into two groups with levels of HER2 consistent with IHC scores of 2+ and 3+ as assessed by clinical assays. All HER2-overexpressing samples also expressed HER3 and heregulin. Heregulin expression was detected in both tumor cells and/or in adjacent stroma. Conclusions: HER3 and heregulin are present in HER2-overexpressing gastric and GEJ tumors. To evaluate the importance of HER3 and heregulin in these patients, a randomized open label second line Phase 2 trial has been initiated with MM-111, a HER2/HER3 bispecific antibody that inhibits HER3 activity in HER2-overexpressing cells by blocking heregulin binding. HER2, HER3 and heregulin expression will be retrospectively analyzed in tumor samples from patients in this trial, providing further insight into the role of this complex in gastric and GEJ cancer.
SDF-1 and VEGF-C as potential circulating angiogenic biomarkers for bevacizumab in patients with metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Matsusaka Satoshi , Shinozaki Eiji , Ogura Mariko , Ozaka Masato , Nakayama Izuma , Wakatsuki Takeru , Chin Keisho , Mizunuma Nobuyuki , Yamaguchi Toshiharu
Published: February 2017

480

Background: Bevacizumab (BV) plus chemotherapy (chemo) has been shown to improve survival for metastatic colorectal cancer (mCRC). Stromal cell-derived factor-1 (SDF-1) is known as a ligand for CXCR-4. We previously reported that proportion of CXCR4-positive circulating endothelial cells at baseline was correlated with the prognosis of BV plus chemo (Matsusaka, et al. Cancer. 2011). The aim of this study was to investigate changes during treatment in serum candidate cytokines including SDF-1 as potential markers of treatment response to BV. Methods: Patients receiving first-line BV plus chemo with mCRC were enrolled in this prospective study. Serum samples were analyzed before initiation of treatment and during treatment (on days 14 and 56) and at the time of progressive disease. Correlation between tumor response and changes in serum levels of the cytokines (such as VEGF, SDF-1, Ang-1 and -2, etc.) were investigated. Differences in the means of continuous measurements were tested by the Student’s t test. A two-way repeated-measures analysis of variance was used to evaluate differences between sequential continuous variables. Results: 24 were enrolled at the first interim analysis. 14 patients were assessable; some who got conversion surgery or discontinued treatment due to toxicity in early were excluded. Tumor response was achieved in 57% of the patients. SDF-1 levels at baseline (p=0.045) and on days 14 (p=0.049) were significantly lower in tumor responder, while a trend toward higher on days 56 compared to non-responder. The results of a two-way repeated-measures analysis of variance to evaluate differences between sequential continuous variables showed significant differences in VEGF-C (p=0.043) and SDF-1 (p=0.02), influenced by tumor response. Serum levels of SDF-1 trended toward increase on days 14 and decrease on days 56, whilst VEGF-C trended toward decrease on days 14 and 56. Conclusions: Changes Serum levels of SDF-1 and VEGF-C showed correlation with tumor response to BV plus chemo, suggesting that these surrogate markers may represent anti-angiogenic condition for BV treatment. This study is currently ongoing, and further analysis will be performed in more population.
The role of the organic anion transporting polypeptide OATP4A1 in immunactivation in colorectal cancer and inflammatory colon disease.
Authors: Ausch Christoph Alexander , Zotter Simone , Scheikh Maidah , Bauer Heike , Mollik Marina , Bajna Erika , Sebesta Christian , Reiner Angelika , Thalhammer Theresia , Buxhofer-Ausch Veronika
Published: February 2017

481

Background: OATP-transporter proteins, such as OATP4A1, present influence cancer progression by providing compounds (hormones, prostaglandins, cyclic nucleotides, second messenger proteins, drugs) which either inhibit or stimulate tumor cells growth. Therefore, OATP expression in cancer cells and in the stroma, i.e., the microenvironment surrounding the epithelial cells can become a critical parameter. Methods: OATP4A1 was investigated in paraffin-embedded specimens from 148 patients with colorectal cancer and 20 with diverticulitis by immunohistochemistry (IHC) on an automatic quantitative microscopic image analysis system (TissuesFaxs). With the Histoquest program, the immunoreactive score (IRS), was calculated from the degree of the staining intensity and the number of OATP4A1-positive cells. To identify OATP4A1+-cells, double-immunofluorescence staining (IF) was done with antibodies against appropriate cellular markers. Results: OATP4A1 was located in the membrane and cytosol of colon cancer cells and immune cells, while membranous OATP4A1staining was seen in normal mucosa. OATP4A1 levels were higher in cancer cells in patients without tumor recurrence for up to 5 years (NR) than in patients with an early relapse (R) having IRS of 4391±231 and 3026±373 (Mean±SEM), respectively. Highest OATP4A1 levels were observed in immune cells in the tumors of Rs (IRS, 5712 ±254, while in NRs they were lower (IRS: 3549±358; p=0.05). In both groups, OATP4A1 levels in stroma cells were low (288±54 vs. 611±82). OATP4A1 expressing immune cell subtypes in cancer and diverticulitis sections were identified as CD45+ leukocytes, CD3+ T- and CD20+ B-cells, CD68+ macrophages, CD34+precursor cells. OATP4A1 was not detectable in Conclusions: High levels of OATP4A1 in immune cells in malignant and non-malignant colon disease suggest a role of the transporter in the activation of the immune system in malignant and non-malignant colon disease. Whether OATP4A1 might be a therapeutical target has to be established.
A novel and robust technique for determining lymph node status in colorectal cancer.
Authors: Hogan John , O Callaghan Michael , Judge Conor , O Connor Cormac , Aziz A , Burke John , Dunne Cormac , Kalady Matthew , Walsh Stewart , Coffey Calven
Published: February 2017

483

Background: Currently, techniques that determine lymph node positivity (prior to resection) have poor sensitivity and specificity. The ability to determine lymph node status, based on preoperative biopsies, would greatly assist in planning treatment in colorectal cancer. This is particularly relevant in polyp-detected cancers. This study aims to harness the potential of public gene expression repositories, to develop gene expression profiles that could accurately determine nodal status in colorectal cancer. Methods: Public gene expression repositories were screened for experiments comparing metastatic and non-metastatic colorectal cancer. A customized graphic user interface was developed to extract genes dysregulated across the majority of identified studies (i.e., consensus profiles or “CP”). The utility of CP was tested by determining if classifiers could be derived that determined nodal positivity or negativity. CP-derived classifiers were tested on separate Affymetrix and Illumina–based experiments and collated outputs compiled in summary-receiver operator curve characteristic format. The association between classification and oncologic outcome was determined using an additional, independent data set. Results: Four consensus profiles were generated from which classifiers were derived that accurately determined node positive and negative status (pooled AUC were 0.79 ± 0.04 and 0.8 ± 0.03 for nodal positivity and negativity respectively). Overall AUC ranged from 0.73 to 0.86 demonstrating high accuracy across consensus profile type, classification technique and array platform used. As CP enabled classification of nodal status, survival outcomes could be compared for those predicted node negative or positive. Patterns of disease-free and overall survival were identical to those observed for standard histopathologic nodal status. Genes contained within consensus profiles were strongly linked to the metastatic process and included FYN, WNT5A, COL8A1 and BMP. Conclusions: Microarray expression data available in public gene expression repositories can be harnessed to generate consensus profiles. The latter are a source of classifiers that have prognostic and predictive properties.
Association between KRAS mutation and lung metastasis in advanced colorectal cancer.
Authors: Pereira Allan Andresson Lima , Rego Juliana Florinda De Mendonga , Morris Van Karlyle , Overman Michael J. , Eng Cathy , Garrett Chris R. , Ferrarotto Renata , Lee Michael Sangmin , Jiang Zhiqin , Hoff Paulo Marcelo , Vauthey Jean-Nicolas , Vilar Sanchez Eduardo , Maru Dipen M. , Kopetz Scott
Published: February 2017

494

Background: The role of KRAS status in the time-dependent pattern of metastasis in colorectal cancer (CRC) patients has been reported but not validated in independent series of unresectable metastatic CRC. We aimed to determine its potential value as a predictive factor for development of lung metastasis. Methods: We retrospectively evaluated data from MD Anderson Cancer Center from 494 patients diagnosed with metastatic CRC with KRAS mutation testing (codons 12, 13, 61) by Sanger sequencing or mass spectroscopy genotyping in 2008 through 2010. Medical records and image reports were assessed to determine date of lung metastasis diagnosis, pattern of lung involvement and presence of thoracic lymph nodal metastasis. Time-to-lung metastasis (TTLM), lung-metastasis-free survival (LMFS) and overall survival (OS) were calculated from the time of diagnosis of first metastasis in any site according to the Kaplan-Meier method and were compared by log-rank test. Results: We included 494 patients (41% female) with a median age of 55 years. 292 tumors were KRAS wild type (WT, 59%) and 202 (41%) were KRAS mutants. OS was not different between the groups (45.5 months for KRAS mutants vs. 50.6 months for KRAS wild type; p=0.6). At the time of diagnosis of metastatic disease, 36% of patient had lung metastases, with 1.6-fold higher odds of lung metastases with a KRAS mutation (p=0.013, 95% CI 1.1 – 2.4). Compared to KRAS WT, KRAS mutations were associated with a shorter TTLM (15.2 vs. 22.4 months; p=0.002) and LMFS (12.9 vs. 16.7 months; p= 0.019). There was no difference in thoracic lymph node involvement (p= 0.18), number of lung metastasis (p=0.71), lung lobes involved (p=0.19) or disease in bilateral lung (p=0.27) according to KRAS status. There were no differences in lung metastasis frequency or pattern between codons 12, 13, and 61 mutations. Conclusions: In this retrospective analysis, lung metastases were more common at diagnosis of mCRC in KRAS mutant patients and more likely to develop during the disease course. This data suggests a potential role for KRAS mutations in determining a metastatic tropism of CRC to the lung and can be used to risk stratify patients.
Changes in circulating lymphocyte counts and tumor-infiltrating lymphocyte subpopulations among patients receiving endorectal brachytherapy for rectal adenocarcinoma.
Authors: Ellsworth Susannah G. , Sopha Sabrina C. , Drake Charles G. , Campian Jian Li , Gearhart Susan , Azad Nilofer Saba , Hacker-Prietz Amy , Grossman Stuart A. , Herman Joseph M.
Published: February 2017

500

Background: Radiation-induced lymphopenia (RIL) is common in patients with rectal cancer and is associated with worse outcomes in rectal cancer and other solid tumors. We investigated whether endorectal brachytherapy (EB) is associated with milder RIL than external radiation treatment (XRT) in patients with rectal cancer and whether EB is associated with altered tumor-infiltrating lymphocyte (TIL) subpopulations. Methods: Records from 11 patients enrolled in a prospective study of EB for T2-3, N0-1 rectal cancer were reviewed; total lymphocyte counts (TLC) at baseline and 2 months after treatment were recorded. EB was given to tumor alone (6.5Gy x 4). XRT was given to the whole pelvis (median dose 50.4Gy). All patients underwent proctectomy after EB/XRT. TLCs from EB patients were compared to 62 rectal cancer patients receiving pelvic XRT + capecitabine. Proctectomy specimens were immunostained for TIL (CD3, CD4, CD8, FoxP3, and CD25) subtypes. Results: Median baseline TLC in EB patients was 1930 vs 1570 cells/uL in XRT patients (p>0.05). Two months after treatment, median TLC was 1550 in EB patients vs 520 in XRT patients (p<0.01). EB patients had higher absolute numbers of CD3, CD4, CD8, and FoxP3+ TILs (Table). Conclusions: EB spares circulating lymphocytes and is associated with increased TIL expression after therapy. Further investigation is needed to determine if there is a causal association between these phenomena and if the increased TIL expression in EB patients is associated with better outcomes in these patients. [Table: see text]
Generation and application of a colorectal cancer microarray library to identify a novel prognostic biomarker, adipose differentiation related protein (adipophilin).
Authors: Hogan John , O Byrne Laura , O Callaghan Michael , Kalady Matthew F. , Coffey John C.
Published: February 2017

508

Background: Substantial volumes of genetic expression data are archived within public gene expression repositories (PGER). Although the data contained is reported according to particular standards, it is not feasible to search the data using clinically relevant search terms (i.e., oncologic outcome). This study aimed to generate an archive of microarray expression data that could be searched using oncologically-relevant terminology, and then to test this facility. Methods: A UL Colorectal Cancer Archive was established based on data derived from the Gene Expression Omnibus (GEO). A software (Rover) was developed to permit clinically relevant searches using terminology such as stage and disease-free survival. As a first test, experiments were identified that compared early and late stage colorectal cancer. From these, consensus profiles were developed and adipocyte differentiation related protein identified as the top-most frequently dysregulated gene. As a second test, the cancer archive was again challenged to identify data sets annotated with outcome data. The association between ADFP and outcome was assessed using a regression-tree (CRT) based approach and Kaplan-Meier estimates. Results: The UL Colorectal cancer archive was constructed so as to permit the novice-user to search for gene expression data associated with particular clinical parameters. Rover was a graphic user interface that permitted these searches. ADFP was identified as dysregulated across the majority of experiments comparing early and late stage colorectal cancer. CRT-analyses identified levels of ADFP above which adverse outcomes were identified. In general, increasing ADFP was independently associated with adverse disease-free outcomes in stage II and III cancer. Conclusions: A novel archive of gene expression data was generated that (a) related to colorectal cancer and (b) could be searched using clinically-relevant terms. Using this archive ADFP was identified as dysregulated between early and late stage colorectal cancer. Increasing ADFP expression levels were associated with adverse disease-free survival in stages II and III colorectal cancer.
c.35 G > A KRAS-mutant genotype and clinical outcome of patients with metastatic colorectal cancer.
Authors: Bruera Gemma , Cannita Katia , Alesse Edoardo , Ficorella Corrado , Ricevuto Enrico
Published: February 2017

512

Background: KRAS genotype does not significantly affect prognosis of MCRC patients treated with bevacizumab-containing chemotherapy. Codon 12 mutations increase aggressiveness by differently modifying mutated KRAS and downstream signalling, thus conferring worse clinical behavior. Prognostic relevance of the prevalent c.35 G > A KRAS mutation in MCRC patients fit and unfit for first-line bevacizumab added to triplet chemotherapy (FIr-B/FOx) was evaluated. Methods: KRAS codon 12/13 mutations were screened. Efficacy was evaluated and compared by log-rank. Results: Fifty-nine fit patients were treated with firstline FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). Wild-type compared to mutant status did not significantly affect PFS (14 and 11 months) and OS (38 and 20 months). c.35 G > A mutant showed: no significantly different PFS compared to wild-type; significantly worse OS (14 months) compared to wild-type and to other mutant (39 months). After progression, wild-type compared with mutant did not show significantly different PFS (10 months equivalently) nor OS (17 and 12 months); c.35 G > A compared to wild-type and/or other mutant showed significantly worse PFS and OS. Among 39 unfit patients, treated with conventional regimens, wild-type compared to mutant significantly affected PFS (8 and 6 months), and not OS (13 and 8 months); c.35 G > A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutant. Conclusions: KRAS genotype does not significantly affect clinical outcome of MCRC patients treated with first line FIr-B/FOx, while mutant status may significantly affect worse PFS in patients unfit for intensive treatments. c.35 G > A mutant status, compared to wild type and other mutant, may significantly affect worse clinical outcome in MCRC patients treated with first line intensive FIr-B/FOx and after progression, as well as in patients unfit for FIr-B/FOx, due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with FIr-B/FOx, probably due to effectiveness of triplet chemotherapy plus VEGF inhibitor.
Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first disease progression (PD) in patients with metastatic colorectal cancer (mCRC) previously treated with BEV-based therapy: Outcomes according to KRAS status and first-line CT backbone in the ML18147 study.
Authors: Kubicka Stefan , Greil Richard , André Thierry , Bennouna Jaafar , Sastre Javier , Van Cutsem Eric , Von Moos Roger , Osterlund Pia J. , Hegde Priti , Sersch Martina A. , Osborne Stuart , Hermann Frank , Arnold Dirk ,   on behalf of the ML18147 Study Investigators
Published: February 2017

520

Background: ML18147 is the first randomized phase III study to show that continuing BEV + standard CT as second-line (2L) treatment significantly improves overall survival (OS) and progression-free survival (PFS) in patients with mCRC who progressed after receiving a standard first-line (1L) BEV-containing regimen. Here we report an exploratory analysis of outcomes based on CT backbone and KRAS status. Methods: Patients with unresectable, histologically confirmed mCRC who progressed ≤3 months after discontinuing 1L BEV were randomised to 2L CT (crossed over from oxaliplatin to irinotecan and vice versa) ± BEV. This post-hoc analysis evaluated OS, PFS, overall response rate (ORR) and disease control rate (DCR) according to 1L CT backbone (irinotecan- or oxaliplatin-based) and KRAS status (Scorpion ARMS test for KRAS codons 12 and 13). Results: In total, 616 patients (75% of the ITT population) were included in this analysis; 316 had wild-type (WT) and 300 had mutant-type (MT) KRAS status; 355 received 1L irinotecan and 261 received 1L oxaliplatin. BEV+CT beyond PD prolonged OS and PFS vs CT alone, regardless of whether oxaliplatin- or irinotecan-based CT was used in the 1L and whether patients had WT or MT KRAS (Table). Adverse events were not increased when continuing BEV+CT beyond PD and were consistent with previous findings. Conclusions: This post hoc analysis suggests that continuing BEV + 2L oxaliplatin or irinotecan-based CT (following crossover) leads to prolonged OS and PFS, regardless of KRAS status or if oxaliplatin or irinotecan-based CT was used in the 1L. Clinical trial information: NCT00700102. [Table: see text]
Predictors of early mortality in colorectal cancer patients undergoing chemotherapy: Results from a global prospective cohort study.
Authors: Sohal Davendra , Kuderer Nicole Maria , Shepherd Frances A. , Pabinger Ingrid , Agnelli Giancarlo , Liebman Howard A. , Vicaut Eric , Meyer Guy , Lyman Gary H. , Khorana Alok A.
Published: February 2017

532

Background: Early mortality is a major problem in colorectal cancer and our understanding of risk factors and predictors is incomplete. A venous thromboembolism (VTE) Risk Score, comprising primary site, baseline hemoglobin, leukocyte and platelet counts, and body mass index [Khorana et al, Blood, 2008], has been shown to be associated with early mortality in solid tumors [Kuderer et al, 2008; Ay et al, 2013]. We evaluated the value of this Risk Score and other key prognostic variables in predicting early mortality for colorectal cancer (CRC) patients. Methods: CANTARISK was a prospective, non-interventional, global cohort study in patients with CRC and lung cancer initiating a new chemotherapy regimen. Clinical data were collected at 0, 2, 4, and 6 months. All data were compiled centrally and analyzed after the study closed. Risk score categories were as defined previously [Blood, 2008]. Statistically significant univariable associations and a priori prognostic variables were tested in multivariable models; adjusted odds ratios (OR) are presented. Results: A total of 1,789 CRC patients were enrolled from 2011-12; data on 1,533 evaluable patients are presented. Median age was 62 years; 71% were Caucasian. Geographic distribution was Europe 37%, North America 28%; Asia 23%; South America 12%. One-third (33%) had a rectal primary and 65% had metastatic disease. There were 184 deaths (10.3%) on study. For low, intermediate and high Risk Score, there were 8.1%, 11.2%, and 32.5% deaths, respectively. In multivariate analyses, the Risk Score remained an independent predictor of death (OR for high/intermediate vs. low score = 1.70, p = 0.0027), in addition to age (OR for each incremental year = 1.03, p = 0.0014), presence of metastatic disease (OR = 3.28, p < 0.0001), and ECOG performance status ≥2 (OR = 3.85, p < 0.0001). VTE itself was not associated with death. Conclusions: This prospective global cohort study demonstrates that the Risk Score is prognostic of early mortality in CRC patients, in addition to age, stage, and performance status. Intermediate or high-risk patients, as defined by the Risk Score, may benefit from additional interventions aimed at reducing early mortality.
Colorectal high-grade neuroendocrine carcinoma: A single institution experience.
Authors: Conte Bruno , George Ben , Dasari A. , Overman Michael J. , Estrella Jeannelyn , Jiang Zhiqin , Machado Karime , Mello Celso Lopes , Ferrarotto Renata , Hoff Paulo M. , Yao James C. , Rashid Asif , Kopetz Scott
Published: February 2017

540

Background: Colorectal high-grade neuroendocrine carcinoma (HGNEC) is a rare and aggressive disease that lacks standard management recommendations. Methods: The records of all patients with colorectal HGNEC diagnosed at MD Anderson Cancer Center between 1991 and 2013 were retrospectively reviewed for clinicopathological features and clinical outcomes. Results: One hundred patients with histologically confirmed colorectal HGNEC were identified. Median age at diagnosis was 55 years with 51 males. Family history of cancer was present in 59% (first degree) of patients and a tobacco smoking history in 54%. Most frequent symptoms at diagnosis were: abdominal or rectal pain (52%), rectal bleeding (49%) and change in bowel habit (52%). Small cell carcinoma was the most common histology (89%), with large cell neuroendocrine carcinoma in 8% and mixed histology 2%. The expression of chromogranin, synaptophysin and neuron specific enolase was positive in 58%, 93% and 87%, respectively. In our institution, 40% of HGNECs arise in the rectum, compared to 25% of adenocarcinomas (P<0.001 for comparison). Sixty four patients (64%) presented with metastatic disease at diagnosis. Median overall survival (OS) was 11.8 months, with 19.3 versus 8 months for localized and metastatic disease, respectively (p<0.01). Two and five year OS was 23% and 8%, respectively. Cecal primaries had a higher rates of metastatic disease at presentation (OR=5, P=0.026), but stage-specific outcomes did not differ by tumor location. Treatment with a platinum-based chemotherapy (CT) was used in 63 (81%) patients in first line palliative CT and the objective response rate was 43%. For localized disease, neoadjuvant treatment was used in 36% of patients and adjuvant therapy in 47% and was associated with a trend toward improved survival (median OS 20.4 versus 15.4 months, P=0.08). Conclusions: Colorectal HGNEC has an aggressive biology with rectum being the most common site and cecum the site most associated with distant metastases at diagnosis. For localized disease early diagnosis and multimodality approach are important for better outcomes while systemic CT appears to be the mainstay of treatment for advanced disease.
Randomized controlled trial on the skin toxicity of panitumumab in third-line treatment of KRAS wild-type metastatic colorectal cancer: HGCSG1001 (Japanese Skin Toxicity Evaluation Protocol with Panitumumab; J-STEPP).
Authors: Iwanaga Ichiro , Komatsu Yoshito , Yuki Satoshi , Kobayashi Yoshimitsu , Sakamoto Naoya , Uebayashi Minoru , Okuda Hiroyuki , Kusumi Takaya , Sogabe Susumu , Miyagishima Takuto , Tateyama Miki , Tsuji Yasushi , Hatanaka Kazuteru , Nakamura Michio , Konno Jun , Yamamoto Fumiyasu , Iwai Kazuhiro , Onodera Manabu , Oba Koji , Sakata Yuh
Published: February 2017

541

Background: Panitumumab (Pmab), a fully human monoclonal antibody targeting the EGFR, has been demonstrated the efficacy in patients with KRASwild-type metastatic colorectal cancer (mCRC). Though STEPP study (Lacouture et al, JCO 2010) showed that pre-emptive skin treatment reduced skin toxicities compared with reactive treatment among patients receiving Pmab, the data of Asians has not been reported. We planned a randomized controlled open-label trial to verify the differences between pre-emptive and reactive treatment for skin toxicities in Japanese patients. Methods: Patients receiving Pmab-containing treatments as third line regimen for mCRC were randomly assigned 1:1 to pre-emptive or reactive skin treatment group. In the pre-emptive treatment group, patients received skin moisturizers, sunscreen, topical steroid and minocycline. In the reactive treatment group, patients received only skin moisturizers. The primary endpoint was the cumulative incidence of ≥ grade 2 skin toxicities during the 6-week treatment period. Retrospectively, dermatologist reviewed skin toxicities with photographs in blinded manner. Results: Out of 95 enrolled patients, 47 patients were randomly assigned to pre-emptive group, and 48 to reactive group. The incidence of ≥ grade 2 skin toxicities during the 6-week treatment period (according to investigator’s assessment) was 21.3% and 62.5% (risk ratio [RR] = 0.34, 95% CI 0.19 - 0.62; p<0.001) for the pre-emptive and reactive treatment groups, respectively. A similar trend was observed in central review by dermatologist (18.6% and 50.0%, respectively [RR = 0.37, 95% CI 0.19 - 0.74; p = 0.002]). The concordance rate between them was 75.8%. Median time to first occurrence of ≥ grade 2 skin toxicities was not reached in the pre-emptive group and 3.2 weeks (95% CI 1.9 - 6.1) in reactive group (p < 0.001). Conclusions: The pre-emptive skin treatment could reduce the severity of the skin toxicities during the Pmab treatment. Our data clearly validate that the pre-emptive treatment is also recommended in Japanese patients. Clinical trial information: 000004883.
Semi-automated validation of centralized independent review of radiological data in the OPUS trial.
Authors: Piessevaux Hubert , Zhao Binsheng , Tejpar Sabine , Schwartz Lawrence H.
Published: February 2017

542

Background: There is increasing evidence that evaluation of tumor shrinkage on a continuous scale early on during treatment in metastatic colorectal cancer (mCRC) contains predictive information on long term treatment benefit. These findings were more specifically observed in trials evaluating addition of cetuximab to chemotherapy in first line mCRC (Piessevaux, JCO, 2013). Precise tumor measurements are necessary to implement these findings in clinical trials and practice. Independent central review has been advocated to improve the validity of the radiological measurements in clinical trials. In the phase II mCRC OPUS trial, we compared tumor shrinkage assessments given by an independent review committee (IRC) to results of a semi-automated software algorithm (SOFT). Methods: IRC measurements were performed and reported previously. SOFT requires a seed placement in a metastatic deposit. Once the seed placement is made, the computer automatically generates the boundary of the lesion and calculates the maximal diameter. The original digital radiological data from 217/337 ITT patients was available for review. Early tumor shrinkage, defined as the relative change at week 8 of the sum of the longest diameters was calculated with both measures and compared (ETS-IRC vs. ETS-SOFT). Results: The intra-class coefficient of correlation between ETS-IRC and ETS-SOFT was 0.689 (95%CI 0.604-0.759). When the population was split according to treatment group we observed the following ICC: 0.874 (95%CI: 0.815-0.914) in the chemotherapy with cetuximab arm and 0.486 (0.307-0.632) in the chemotherapy alone arm. Conclusions: Secondary independent review of radiological data from the OPUS trial showed discrepancies between IRC and SOFT. These discrepancies are potentially due to target lesion number and selection. Treatment group seems to differentiate cases more prone to discrepant review. This finding may be related to enhanced reliability when treatment effect is more pronounced. Further comparisons of traditional IRC reviews to semi-automated algorithm-based reviews with regard to outcome evaluation are warranted.