bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variants in RNA binding protein (RBP) to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE, and MAVERICC trials.
Authors: Arai Hiroyuki , Cao Shu , Loupakis Fotios , Stintzing Sebastian , Tokunaga Ryuma , Battaglin Francesca , Lo Jae Ho , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J , Liang Gangning , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef 
Published: May 2019

3545 Background: RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by stabilizing or destabilizing target messenger RNA. Although alteration of RBPs affects many steps of cancer development, its clinical implication in mCRC remains unclear. Methods: We analyzed data from mCRC patients (pts) enrolled in three first-line randomized trials (FIRE-3, TRIBE, and MAVERICC). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 30 SNPs in 10 RBP genes (MSI1, MSI2, ELAVL1, RBM3, LIN28A, LIN28B, IGF2BP1, IGF2BP2, IGF2BP3, ZFP36) were tested on association with progression-free survival (PFS) and overall survival (OS). To evaluate prognostic effects and heterogeneities across treatment arms, meta-analysis approach using the METASOFT software was conducted. We also tested interaction between each SNP and treatment within each trial, i.e. FIRE-3 cohort (FOLFIRI+cetuximab (Cet) vs FOLFIRI+bevacizumab (Bev)) and MAVERICC cohort (FOLFIRI+Bev vs FOLFOX6+Bev). For multiple testing, p values were adjusted by the false discovery rate (FDR) method. Results: A total of 884 pts’ SNPs data were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 324). Meta-analysis combining three trials showed RBM3 rs926152 (adjusted p = 0.045) and RBM3 rs2249585 (adjusted p = 0.016) were significantly prognostic for PFS. Whereas, in terms of OS, only LIN28B rs314277 (adjusted p = 0.045) was significant, and RBM3 rs926152 (adjusted p = 0.057) and RBM3 rs2249585 (adjusted p = 0.059) had a trend. Interaction test showed several SNPs were potentially predictive (raw p < 0.05), although without any significance after FDR adjustment: in FIRE-3 cohort, MSI2 rs1822381, RBM3 rs926152, LIN28B rs221635, IGF2BP1 rs2969 for OS; in MAVERICC cohort, MSI1 rs1179442 and MSI2 rs3826301 for OS, ELAVL1 rs4804244 for PFS. Conclusions: Our results indicate prognostic potential of SNPs in RBP genes, such as RBM3 and LIN28B, in mCRC. However, we find no distinct evidence that these SNPs can predict differential effect between Cet and Bev, or between oxaliplatin- and irinotecan-based chemotherapy.
Modulation of autophagy: A phase II study of vorinostat (VOR) plus hydroxychloroquine (HCQ) vs regorafenib (RGF) in chemo-refractory metastatic colorectal cancer (mCRC).
Authors: Arora Sukeshi Patel , Tenner Laura LaNiel , Sarantopoulos John , Morris Jay Larry , Longoria Lisa , Liu Qianqian , Michalek Joel , Mahalingam Devalingam 
Published: May 2019

3551 Background: Agents targeting the angiogenic pathway have been a cornerstone therapy in mCRC. In chemo-refractory mCRC, RGF, an oral multikinase inhibitor with considerable angiogenic inhibition, has shown modest effects on survival. We reported that autophagy modulation using the autophagy inhibitor, HCQ, enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR, via ubiquitinated protein accumulation in CRC. A phase 1b study confirmed VOR/HCQ is active and tolerated in refractory mCRC. We conducted a prospective randomized study to evaluate efficacy of VOR/HCQ vs RGF in mCRC patients (NCT02316340) and report a planned interim analysis. Methods: Randomized, controlled trial of VOR 400 mg and HCQ 600 mg PO daily vs RGF 160 mg PO daily (3 weeks on, 1 week off), Q4weeks, in advanced CRC patients. Crossover was optional after first progression. A total of 76 patients are planned. Primary endpoint: mPFS. Secondary endpoints: mOS; adverse events (NCI-CTCAEv3.0); PD analysis: 27-plex Human Cytokine Array, NGS analysis (Guardant Health) on cell-free, ctDNA. Results: At interim analysis, n = 42 patients enrolled from 2/2015-10/2017: n = 20 VOR/HCQ (5 crossed to RGF), n = 22 RGF (13 crossed to VOR/HCQ). 38 patients evaluable (at least C1 completed). Median age 58.4, 40% NH vs 60% H. mPFS on first arm: 1.90 mo VOR/HCQ vs 4.35 mo RGF [p = 0.032, HR: 2.277]. mOS: 6.77 mo VOR/HCQ vs 7.23 mo RGF [p = 0.90, HR: 1.05]. Grade 3/4 AEs (see table). In both arms, there was trend towards decreased IL-1b, IL-2, IL-6, IL-10, TNFα, IFNγ but an increase in GM-CSF after treatment. Responders (4+ cycles) had lower baseline MaxMAF versus nonresponders for both arms. In responders, there was trend toward a decrease in MaxMAF at C2 and then increase at progression. Conclusions: VOR/HCQ did not improve survival when compared to RGF. VOR/HCQ has a favorable safety profile, but further planned subgroup analysis is pending to identify biomarkers of efficacy in responders. Clinical trial information: NCT02316340. [Table: see text]
Aggressiveness of care and overall survival in young metastatic colorectal cancer patients.
Authors: Fish Madeleine , Kanter Katie , Mauri Gianluca , Horick Nora , Allen Jill N , Blaszkowsky Lawrence Scott , Clark Jeffrey William , Ryan David P. , Nipp Ryan David , Giantonio Bruce J. , Goyal Lipika , Murphy Janet E. , Roeland Eric , Weekes Colin D. , Wo Jennifer Yon-Li , Hong Theodore S. , Zhu Andrew X. , Van Seventer Emily E. , Corcoran Ryan Bruce , Parikh Aparna Raj 
Published: May 2019

3563 Background: Colorectal cancer (CRC) incidence in patients younger than 50 years of age is steadily rising by 2% annually. Early-onset CRC usually presents with more aggressive features; however, data on prognosis are widely conflicting. Clinicians may hold an age-related bias in treating younger patients, but this proclivity and its effects have not been quantified. Methods: Patients with a history of metastatic CRC who consented to a departmental chart review protocol were collected between 2014 and 2018 at Massachusetts General Hospital. The cohort was divided into two groups based on age at initial diagnosis: < 50 and ≥50. Data were gathered on treatments and clinicopathological features. A log-rank test compared survival from the diagnosis of metastatic disease between age groups. The distributions of clinicopathological features were compared using Wilcoxon rank sum tests. Results: 464 metastatic CRC patients were identified. 155 patients (33%) were < 50 (median age 43, 49% female) and 309 patients (67%) were ≥50 (median age 61, 45% female). Sex did not significantly differ between the two groups (p = 0.45). Patients < 50 received more lines of therapy after metastatic diagnosis than patients ≥50 (mean 2.7 v. 2.2; p = 0.002). Younger patients also received more resections of distant metastases (mean 0.62 v. 0.48; p = 0.01). A higher rate of enrollment in clinical trials for patients < 50 approached significance (p = 0.06). Even so, patients < 50 did not see a significant survival benefit over older patients (2/5-year survival from metastatic diagnosis 77%/47% v. 73%/38%, p = 0.23). Patients < 50 had a lower proportion of right-sided tumors (p = 0.0002) and BRAF mutations (p = 0.0009). There was no difference in MSI status (p = 0.28), RAS mutational status (p = 0.40), mucinous features (p = 0.53), or signet ring features (p = 0.26). Conclusions: Overall survival in patients < 50 is similar to patients ≥50, despite patients < 50 receiving more aggressive therapy. Further study is warranted to better understand these differences. Potential areas of interest include performance status, age-related treatment bias, and biological factors.
Anti-epidermal growth factor receptor therapy in combination with chemoradiotherapy for the treatment of locally advanced anal canal carcinoma: Results of a phase II study with panitumumab (FFCD 0904).
Authors: Aparicio Thomas , Ronchin Philippe , Bazire Louis , Le Malicot Karine , Lemanski Claire , Mirabel Xavier , Etienne Pierre-Luc , Lièvre Astrid , Cacheux Wulfran , Darut-Jouve Ariane , De La Fouchardiere Christelle , Breysacher Gilles , Argo Leignel Delphine , Tessier Alexandre , Magne Nicolas , Ben Abdelghani Meher , Lepage Come , Vendrely Veronique 
Published: May 2019

3570 Background: Standard treatment of anal squamous cell carcinoma is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study studied the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU based CRT. Methods: Patients with locally advanced tumor without metastases (Stage T2, T3 or T4, whatever N stage; Stage N1-N3 whatever T stage) were treated with two RT periods (45Gy in 5 weeks and a boost of 20Gy in 2 weeks) with concomitant CT sessions of 5FU/MMC at RT weeks 1 and 5. Pmab was administered on RT weeks 1, 3, 5 and 7 according to the doses defined by a previous phase 1.study (MMC: 10 mg/m² at J1 and J29; 5FU: 400 mg/m² from J1 to J4 and from J29 to J32, Pmab: 3mg/kg). The expected rate of CR at 8 weeks to continue in phase III was 80%. Results: Forty-five patients (male: 9 (20%), female: 36 (80%); median age: 60.1 [41.5-81]) were enrolled in 15 French centers. All patients but one completed the CRT. Median duration of CRT was 52 days [30-76].Fourteen patients had a RT interruption because of toxicity. Most common related grade 3-4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (28.8%) and asthenia (11.1%). On patient died because of mesenteric ischemia during the CRT (total dose: 36 Gy). In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4-78.2]. Median follow-up was 16.2 months [14.1-18.2]. Overall survival, recurrence-free and colostomy-free survival at one year were 94.6% [95%CI: 75.8-98.7], 72.2% [95%CI: 55.0-83.7] and 78.2% [95%CI: 60.6 – 88.6] respectively. Six (13%) patients had a colostomy with abdomino-perineal amputation due to a tumour recurrence. Conclusions: Despite an acceptable tolerance, panitumumab in combination with CRT for locally advanced anal cancer failed to meet the expected CR rate to justify further clinical trials. Clinical trial information: NCT01581840.
Association of TGF-β expression with intratumoral infiltration of cytotoxic T lymphocytes in patients with microsatellite-stable colorectal cancer.
Authors: Mehrvarz Sarshekeh Amir , Katkhuda Riham , Verma Anuj , Advani Shailesh M , Overman Michael J. , Maru Dipen M. , Kopetz Scott 
Published: May 2019

3577 Background: Transforming growth factor- β pathway (TGF-β) has an established role in promoting growth, invasion, metastasis as well as epithelial to mesenchymal (EMT) transition. Among 4 different described molecular subtypes of colorectal cancer (CRC), consensus molecular subtype 4 (CMS4) comprises up to 25% of CRC pts, distinguished by activation of this pathway, and is associated with higher relapse rate and poor prognosis. Recently, it has also been proposed that TGF-β activation drives immune evasion in murine models, but these findings have not been clinically validated. Methods: Using multi-gene RNA expression profiling, fresh-frozen paraffin-embedded samples of 35 patients with CRC were analyzed to determine TGF-β and EMT expression levels. Multiplexed IHC staining was performed on FFPE tumor blocks by using the Opal 7-Color fIHC Kit and the stained slides were scanned by a Vectra multispectral microscope (PerkinElmer) to measure infiltration of immune cells (i.e., T lymphocytes, cytotoxic T lymphocytes (CTL), T cell antigen-experienced, macrophages, etc.) in the tumor, stroma, and both components. TGF-β and EMT expression levels – as continuous variables - were compared with the infiltration of various immune cells using Spearman’s rank correlation analysis. Results: Among 35 pts, 28 pts had non-CMS1/MSS CRC. TGF-β RNA expression in the tumor microenvironment of these samples was inversely associated with the infiltration of CTL into the tumor (r=-0.43, p= 0.022). In contrast, there was no association of TGF-β with non-cytotoxic T-cells or macrophage infiltration. The tumor and stromal CTL infiltration differed substantially by CMS ( p=0.04, p=0.02, respectively) with tumor infiltration lowest in CMS4 (n=7). Consistent with this, EMT gene signature, which includes TGF-β expression, showed a similar inverse correlation with CTL infiltration (r=-0.48, p=0.009). Conclusions: TGF-β and EMT gene signatures have important roles in the exclusion of CTL in the tumor microenvironment of CRC pts. Inhibiting TGF-β pathway can potentially increase the intratumoral infiltration of CTL, which is a necessary (but not sufficient) step for immunotherapy response in MSS CRC. Clinical trials evaluating this hypothesis are currently ongoing (NCT03436563).
Performance comparison of the methylated BCAT1/IKZF1 ctDNA test (COLVERA) with the CEA assay for detection of recurrent colorectal cancer.
Authors: Symonds Erin L. , Pedersen Susanne Kartin , Murray David , Byrne Susan E , Hollington Paul , Rabbitt Philippa , Jones Frederick S. , Segelov Eva , Lazarus Tadd Scott , Lapointe Lawrence Charles , Young Graeme P. 
Published: May 2019

3589 Background: Early detection of recurrent colorectal cancer (CRC) will improve treatment options, but the current standard blood test of carcinoembryonic-antigen (CEA) has suboptimal sensitivity for recurrence. This study compared performance of a quantitative circulating tumor DNA (ctDNA) assay for methylated BCAT1 and IKZF1 (COLVERA) with that of CEA. Methods: 301 patients were monitored for recurrence after clearance of primary CRC. Blood was collected at scheduled intervals and concentrations of CEA and ctDNA were measured using the LIAISON CEA test (Diasorin) and the COLVERA ctDNA test (Clinical Genomics). Surveillance for recurrent disease was examined using regular CT scans. Sensitivity of each blood test for recurrence was assessed in the sample collected closest to the time of imaging confirming recurrence status. Absence of recurrence was defined as at least two consecutive clear CT scans. Receiver operator characteristic (ROC) analyses were used to determine optimal positivity threshold for Colvera. Results: 131 patients underwent satisfactory assessment for recurrence and had blood testing performed within 12 months of determining recurrence status (61.8% male, mean age 62.6 ±.12.2(SD)y). Of the 47 recurrence cases, 37 (74%) were distant. The areas under the ROC curves were 0.7761 and 0.8188 for CEA and COLVERA, respectively (each p < 0.001). An optimal cut-off of 12.8pg/sample was determined for COLVERA and the standard 5ng/mL cut-off was selected for CEA. COLVERA had a significantly higher sensitivity for detecting recurrence as compared to CEA (68.1% vs 31.9%, p < 0.001) with a similar specificity (97.6% Vs 96.4%, p = 0.6547). A multivariate analysis determined COLVERA to be a predictor of recurrence independent of CEA with positive COLVERA samples being 66.4 times (95%CI 14.0-315.8) more likely to have recurrence confirmed within the study timeframe, whereas CEA was not a significant predictor of recurrence (p = 0.228). Conclusions: These findings indicate that COLVERA, reporting in quantitative mode, is a more sensitive test than CEA. It provides a viable alternative for sensitive and early detection of recurrent CRC. Clinical trial information: 12611000318987.
Gene expression and genetic variants in Parkinson's disease (PD) genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3 phase III trial.
Authors: Battaglin Francesca , Cao Shu , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Arai Hiroyuki , Berger Martin D. , Ning Tricia , Soni Shivani , Lo Jae Ho , Barzi Afsaneh , Millstein Joshua , Zhang Wu , Heinemann Volker , Stintzing Sebastian , Lenz Heinz-Josef 
Published: May 2019

3595 Background: PD is one of the most common age-related neurodegenerative disorders. Large epidemiological studies have consistently reported a reduced risk of CRC in PD patients (pts), but the biology behind this evidence is unclear. The methylation status of SNCA, one of the causal PD genes, has been identified as a tool for CRC screening and early diagnosis when detected in stool samples, and alterations in core PD genes are prevalent across human malignancies including CRC. Methods: The impact on outcome of 13 SNPs within 6 core PD genes ( SNCA, PRKN, UCHL1, PINK1, DJ-1, LRRK2) was analyzed in pts enrolled in the randomized FIRE-3 trial. Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the cet cohort, pts carrying the G/G variants of SNCA rs356165 and rs2736990 had significantly shorter mOS (30 vs 41.1 mo) compared to any A genotype in both uni- and multivariable analysis (adjusted P[ Padj] = .047 and .042, respectively). LRKK2 rs3761863 T/T allele carriers showed shorter mPFS (9.5 vs 13.3 mo, Padj = .01), while rs11564148 any A carriers had longer mPFS (14.2 vs 10.2 mo, Padj = .01) compared to reference genotypes. LRKK2 rs11564148 any A carriers also showed longer mOS in multivariable analysis (43.7 vs 33.2 mo, Padj = .044). Any C allele carriers of PINK1 rs1043424 showed longer mPFS in uni- and multivariable analysis ( Padj < .001). No significant interaction was found with gender, tumor location and RAS status. These associations were not observed in bev arm. High SNCA expression was associated with worse mPFS (log2 > 7.89, 5.9 vs 11.2 mo) and mOS (log2 > 7.68, 17.9 vs 31.1 mo) in FIRE-3 cet arm ( P < .05). Conclusions: We provide the first evidence that gene expression and genetic variants in PD genes may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment. Our findings open new perspectives on the role of PD genes in CRC biology warranting further investigation.
The 55 STAR study: Prognostic and predictive value of the 55-gene classifier (55GC) in stage III colon cancer.
Authors: Ishikawa Toshiaki , Oki Eiji , Shinto Eiji , Shimokawa Mototsugu , Yamaguchi Shigeki , Ishiguro Megumi , Hasegawa Seiji , Takii Yasumasa , Ishida Hideyuki , Kusumoto Tetsuya , Morita Masaru , Tomita Naohiro , Shiozawa Manabu , Tanaka Masafumi , Ozawa Heita , Hashiguchi Yojiro , Ohnuma Shinobu , Tada Sachiyo , Matsushima Tomoko , Hase Kazuo 
Published: May 2019

3597 Background: Patient prognosis can be predicted based on cancer subtypes classified according to DNA microarray results. The most robust classification system involves the consensus molecular subtypes, which uses over 600 genes for classification. To simplify this classification, we recently constructed a 55-gene classifier (55GC) to classify colon cancer (CC) into three subtypes with different recurrence rates: “microsatellite instability (MSI)-like,” “chromosomal instability (CIN)-like,” and “stromal” colon cancers. The 55GC has been reported to be a useful and reproducible grading system for stage II CC recurrence risk stratification. This study aimed to explore the usefulness of 55GC for classifying stage III CC patients. Methods: We retrospectively identified stage III CC patients aged 20-79 years who underwent curative surgery and received adjuvant chemotherapy with or without oxaliplatin (OX) between 2009 and 2012 from 15 institutions. Propensity score matching was used to adjust for the number of lymph node metastases, tumor location, sex, and age. Results: Among 938 eligible patients, 203 and 201 cases involving adjuvant chemotherapy with and without OX were selected, respectively, using propensity score matching. Ninety-five cases each from groups were analyzed after exclusion of cases involving low-quality specimens and those involving chemotherapy for < 3 months. The 5-year relapse-free survival (RFS) in patients receiving adjuvant chemotherapy with and without OX were 77.1% and 73.7%, respectively. Classification of the stage III CC according to 55GC and related 5-year RFS rates were as follows: stromal (N = 60), 66.6%; CIN-like (N = 78), 80.5%; and MSI-like (N = 52), 78.4%. The HRs for 5-year RFS for adjuvant chemotherapy with and without OX in each subtype were as follows: stromal, HR = 0.791 (95% CI = 0.329-1.901); CIN-like, HR = 1.241 (95% CI = 0.465-3.308); and MSI-like, HR = 0.495 (95% CI = 0.145-1.692). Conclusions: The stromal subtype showed poor prognosis in stage III as well as stage II patients. Oxaliplatin had a good additive effect in adjuvant chemotherapy for MSI-like subtype. The 55GC is useful for predicting the efficacy of adjuvant chemotherapy for CC.
Gender differences in prognostic value of immune-related biomarkers in colon cancer patients randomized to surgery or surgery and adjuvant chemotherapy treatment.
Authors: Villabona Lisa , Masucci Giuseppe V. , Ragnhammar Peter 
Published: May 2019

3603 Background: HLA-A*02, a common allele in the Scandinavian population, is a negative prognostic factor in epithelial ovarian cancer. It is a strong predictor of patient outcome, only inferior to clinical staging. This prognostic trait in epithelial ovarian cancer is stronger by the presence of the gene compared with the expression of its protein, MHC class I. Microsatellite instability (MSI) is used as a biomarker for prognosis and is suggested an increased tumor mutational burden which can make the tumor more susceptible for T cell mediated immunotherapy. Our aim was to analyze the prognostic markers HLA-A*02 genotype, MHC class I on tumor cells, the CD8+ lymphocyte infiltration and MSI status in colon cancer patients with randomized treatment. Methods: Clinical information and primary tumors were collected from 520 colon cancer patients and followed for overall survival for 120 months. Patients hade stage II and III colon cancer and were randomized to surgery alone or surgery and adjuvant chemotherapy. HLA-A*02 genotype was determined by conventional PCR. MHC class I, MSI status and CD8+ lymphocyte infiltration were determined by immunohistochemistry. Results: Female patients with a stage III tumor and HLA-A*02 genotype had a better outcome if they had received adjuvant chemotherapy instead of just surgery (p = 0.03), whereas this was not the case for patients with other HLA-A genotypes or in the male patients where HLA-type did not correlate to outcome. MHC class I expression did not act as a prognostic factor, however the presence of CD8+ lymphocytes in the invasive margin and inside the tumor was a positive prognostic factor for overall survival (p = 0.01), although only statistically significant in the male patients (p = 0.03). 21% patients had a tumor with MSI (23% of the female and 19% of the male patients respectively). MSI tumors had a slightly better outcome and this was irrespective of gender and HLA-type. Conclusions: The prognostic traits of HLA-A*02 appear in this colon cancer cohort to act differently in male and female patients. Also CD8+ infiltration is different between genders. These findings suggest that men and women may have two different immune responses to malignancy.