bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of KRAS and BRAFV600E mutations stratified by tumor site in resected stage III colon cancer patients treated with adjuvant mFOLFOX6 with or without cetuximab: NCCTG N0147 (Alliance).
Authors: Sinicrope Frank A. , Mahoney Michelle R. , Smyrk Thomas C. , Thibodeau Stephen N. , Goldberg Richard M. , Nelson Garth D. , Sargent Daniel J. , Alberts Steven R. ,   North Central Cancer Treatment Group (Alliance)
Published: March 2020

3523 Background: The association of KRAS or BRAFV600E mutations with prognosis in colon cancers has been inconsistent. Since primary tumor site may influence outcome, we analyzed KRAS and BRAFV600E stratified by tumor site in resected stage III colon cancers from a randomized adjuvant trial of mFOLFOX6 + cetuximab chemotherapy (N= 2,686) where no survival difference by treatment was found. Methods: 2,580 tumors were analyzed for mutations in BRAFV600E (exon 15) or KRAS (codons 12, 13), and for deficient DNA mismatch repair (dMMR). Cox models were used, adjusting for mutation status, age, sex, treatment, T-stage, histologic grade, nodal status, tumor site, and MMR. After study initiation, eligibility was restricted to patients (pts) with KRAS wild-type (WT) tumors. At a median follow-up 4.1 yrs, 83% of pts are alive. Results: KRAS and BRAFV600E mutations were detected in 716 (28%) and 346 (14%) tumors, respectively; dMMR was found in 314 (12%). Proximal (to splenic flexure) tumors (50%) were associated with older age and were more likely to be high grade (33 vs 18%), T-stage3,4 (88 vs 82%), mutated for KRAS (33 vs 23%) or BRAFV600E (23 vs 4%), and dMMR (21 vs 3%)[all p <0.02]. Pts with distal vs proximal tumors showed improved disease-free survival (DFS)[ HR 0.7, 95% CI (0.6-0.9); p<0.01 unadjusted for KRAS or BRAF;]. Mutant KRAS [HR=1.5 (1.2-1.7); p<.0001] or mutant BRAF [HR=1.4 (1.1-1.7); p=0.02] were each independently associated with worse DFS. The KRAS and tumor site interaction was significant (unadjusted pinteraction=0.02; adjusted pinteraction=0.07), with poorer DFS among distal tumors having mutant KRAS [HR 1.7 (1.3-2.2); p<.0001]. No interaction was observed for BRAFV600E and tumor site, despite worse DFS for mutant BRAFV600E among proximal tumors [HR 1.3 (1-1.8); p=0.04]. Conclusions: The adverse prognostic impact of KRAS, but not BRAFV600E, mutations was confined to the distal colon. This finding underscores the importance of tumor site in the interpretation of the prognostic impact of KRAS status, and motivates similar analyses in pts with advanced disease.
Proximal and distal colon tumors as distinct biologic entities with different prognoses.
Authors: Missiaglia Edoardo , Jacobs Bart , Di Narzo Antonio Fabio , Soneson Charlotte , Roth Arnaud , Bosman Fred , d'Ario Giovanni , Klingbiel Dirk , Yan Pu , Delorenzi Mauro , Tejpar Sabine 
Published: March 2020

3526 Background: It has been shown that tumors arising in the proximal and distal colon, defined by the embryological midgut and hindgut, have distinctive clinical and molecular features, but very little is known concerning the differences in the mechanism of tumorigenesis and the effect that this could have on therapy. Methods: The distribution of clinico-pathological and molecular features was evaluated between proximal (N = 1110, Caecum to hepatic flexure) and distal colon (N = 1728, splenic flexure down to sigmoid) in patients included in the PETACC3 trial. Gene expression profile was also available from 783 tumors and 32 normal colon. A further set of 473 metastatic patients treated with cetuximab combined with chemotherapy (De Roock Lancet Oncol. 2010) was used to test tumor location with response. Results: Pathological features, such as tumor differentiation, and mucinous histology as well as molecular characteristics, such as MSI status, BRAF, PIK3Ca mutations and LOH18q loss show higher frequency in proximal compared to distal colon (N = 1214; Fisher test, P<0.001). Proximal tumors showed a significantly worse overall survival (N= 2838; HR=1.4 [1.18 - 1.64] P<0.001) and survival after relapse (N = 861; HR=1.97 [1.65 - 2.35] P <0.001) only if they were stage III at diagnosis, while no difference was observed for relapse free survival. Microarray profiling identified 997 genes differentially expressed between the two anatomical sites, after adjustment for age, gender, mucinous histology, BRAF, KRAS and MSI status. Only 20 of those were present in normal colon site comparison indicating tumor specificity. Data mining analysis of the differentially expressed genes showed that the distal colon is characterized by an enrichment for MAPK activated pathways as well as for the cetuximab response gene signature (Khambata-Ford JCO 2007). In fact, cetuximab treated KRAS/BRAF wild-type tumors in distal colon had prolonged PFS and a 2-fold higher response rate then proximal. Conclusions: Proximal and distal colon tumors have distinctive patterns of clinical-pathological and molecular features. These biological differences likely have significant prognostic and therapeutic implications.
MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.
Authors: Raghav Kanwal Pratap Singh , Amin Hesham M. , Wang Wenting , Manyam Ganiraju C. , Broom Bradley , Eng Cathy , Overman Michael J. , Kopetz Scott 
Published: March 2020

3529 Background: Epithelial-mesenchymal transition (EMT) has been identified as a dominant molecular subtype of colorectal cancer (CRC). This EMT phenotype as recognized by complex gene signatures is prognostic and associated with chemoresistance, but a biomarker for EMT suitable for clinical utilization has not yet been validated. The purpose of this study was to compare MET protein expression with protein/gene expression of EMT markers and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 139 untreated primary CRC samples using data from The Cancer Genome Atlas. Protein and gene expressions were measured using reverse-phase protein array (RPPA) and RNA-sequencing, respectively. MET high/overexpressed group was defined by protein level in the highest quartile. Mann-Whitney U-test and Spearman rank correlation was used to determine association between MET protein expression and protein/gene expression of EMT markers and EMT gene signature scores. Regression tree method and Kaplan-Meier estimates were used to assess overall survival (OS). Results: The MET protein distribution is right skewed, demonstrating a unique population of MET high expressing tumors (P < 0.01). Colon tumors had higher MET protein levels compared to rectal tumors (P < 0.01). MET overexpression was associated with decreased OS (HR 2.92; 95% CI: 1.45 - 5.92). MET protein expression correlated strongly with protein expressions of SLUG (transcription factor for EMT) (r = 0.6) and ERCC1 (a marker for oxaliplatin chemo-resistance) (r = 0.6) (P < 0.01). Higher MET protein levels were associated with higher gene expression of 28 EMT markers including AXL, VIM, ZEB1, ZEB2, FGF1, TGFB1I1 and MMP11 (P < 0.05). Higher MET protein levels were also associated with higher gene scores derived from three published EMT gene signatures (P < 0.05). MET protein expression did not correlate with MET gene expression (r = 0.16). Conclusions: Increased MET protein expression strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be used as a surrogate biomarker to represent and select for this unique molecular subset of CRC driven by EMT biology.
Randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC): A meta-analysis from the Cancer Care Ontario program in evidence-based care.
Authors: Berry Scott R. , Cosby Roxanne , Asmis Timothy R. , Chan Kelvin K. , Hammad Nazik , Krzyzanowska Monika K. 
Published: March 2020

3534 Background: Given the varying impact on efficacy demonstrated in individual RCTs of CS vs IS of delivering systemic Tx for mCRC, a meta-analysis of the available RCTs was performed. Methods: RCTs that compared a CS versus IS of delivering systemic Tx were identified by a systematic search (MEDLINE, EMBASE and ASCO and ESMO proceedings) and review. The results of identified trials were clinically homogeneous (Table) so the data was pooled using Review Manager software (RevMan 5.2). Overall survival (OS) hazard ratios were extracted directly from the most recently reported trial results. A random effects model was used for all pooling. Results: 10 RCTs were identified (n= 4,296). After an induction period, the maintenance Tx patients received during the IS was: none (5 trials, n=2,562), fluoropyrimidine (F) (2 trials, n=759), biologic (B) (2 trials, n=852), F+B (1 trial, n=123). Results of the meta-analysis are summarized in the Table (HR>1 favors CS). Sensitivity analyses performed demonstrate results are robust independent of the induction or maintenance Tx used. QOL (data from 2 trials) was either the same in both arms (single Tx induction trial with no maintenance Tx, n=354) or improved in the IS arm (combination tx induction trial with no maintenance Tx, n=1,630). Conclusions: IS of delivering systemic Tx for mCRC do not result in a statistically significant reduction in OS compared to a CS of delivery whether or not maintenance therapy is included. QOL is the same or better with an IS. [Table: see text]
Genetic variations in miRNA binding site of TPST1 and ZG16B associated with prognosis for patients with colorectal cancer.
Authors: Kang Byung Woog , Lee Soo Jung , Lee Yoo Jin , Kim Jong Gwang , Chae Yee Soo , Sohn Sang Kyun , Moon Joon Ho 
Published: March 2020

3553 Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expressions of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) located in the 3’-UTR of miRNA target genes might affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in the putative miRNA-binding sites of the 3’-UTR of various genes and their impact on the prognosis for patients with colorectal cancer by altering miRNA binding efficiency. Methods: Eight hundred and thirty-one consecutive patients (discovery cohort, n=309; validation cohort, n=522) with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue. One hundred fifty-seven SNPs were selected in Silico analysis for the current study, which was based on several miRNA database and HapMap database. The SNP genotyping was performed using the Sequenom MassARRAY. Results: The median age of all patients was 65 years, and 468 (56.3%) patients had colon cancer, while 363 (45.1%) patients had rectal cancer. The pathologic stages after the surgical resection were as follows: stage I (n=150, 18.1%), stage II (n=332, 40.0%), stage III (n=333, 40.1%), and stage IV (n=16, 1.9%). In the discovery cohort, 19 SNPs were identified as possible prognostic biomarkers in a multivariate survival analysis [disease-free survival (DFS) and/or overall survival (OS)] adjusted for age, preoperative CEA level, and pathologic stage. In the validation cohort, the TPST1 rs3757417T>G and ZG16B rs12373A>C were significantly associated with prognosis as same direction in the discovery cohort (discovery + validation cohort; TPST1 rs3757417T>G, DFS, p value=0.0007, OS, p value=0.0091 in recessive model; ZG16B rs12373A>C, DFS, p value=<0.0001, OS, p value=0.0009 in dominant model). Conclusions: The current study provides evidence that the rs3757417T>G and rs12373A>C polymorphism in the 3’-UTR of TPST1 and ZG16B, respectively, are possible prognostic biomarker for patients with colorectal cancer.
Neoadjuvant chemoradiotherapy (NCRT) using concurrent S-1 and irinotecan in rectal cancer: Impact on long-term clinical outcomes and prognostic factors.
Authors: Tsutsui Atsuko , Nakamura Takatoshi , Yamashita Keishi , Sato Takeo , Watanabe Masahiko 
Published: March 2020

3556 Background: To assess long-term clinical outcomes of neoadjuvant chemoradiotherapy (NCRT) of rectal cancer using concurrent irinotecan and S-1. Methods: One hundred and fifteen patients without distant metastases entered this phase II trial in cT3/T4 rectal cancer (n=104/11). Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral S-1 at 80 mg/m2 and intravenous irinotecan at 80 mg/m2 once weekly. Median follow-up term was 60 months (ranged from 20 to 96 months). Results: Adverse effect of Grade 3 was recognized in 7 patients (6%), and completion rate of this NCRT regimen was 87 %. All 115 patients (100%) could undergo R0 surgical resection. Twenty-eight patients (24%) demonstrated a pathologic complete response (ypCR). Local recurrence-free survival was 93%, disease-free survival (DFS) was 79%, and overall survival (OS) was 80%. By the multivariate proportional hazard model for DFS and OS, ypN2 was only remnant independent prognostic factor (P=0.0019 and P=0.0064, respectively). ypN2 was recognized in 9 patients (8%), and prognosis was extremely dismal (8 patients were recurred within 2 years). We again performed the multivariate analysis for 106 cases restricted to ypN0/1, which exhibited 85% of DFS, and both ypT and tumor portion were independent predictors (P=0.0065 and P=0.003, respectively). Combination of them could greatly enrich high risk patients for recurrence (P<0.0001), and dominant recurrences were uniquely found in lung. Conclusions: Novel NCRT regimen using S1/irinotecan demonstrated high response rates and excellent long-term survival, with acceptable adverse effects. ypN2 is a definitive indicator of dismal prognosis, and combination of ypT and tumor portion can identify high risk patients among the ypN0/1 patients.
Genes involved in EGFR-degradation to predict for efficacy in metastatic colorectal cancer patients treated with cetuximab.
Authors: Stintzing Sebastian , Zhang Wu , Wakatsuki Takeru , Ning Yan , Volz Nico Benjamin , Li Joseph Ethan , Labonte Melissa Janae , Wilson Peter M. D. , Kardosh Adel , Loupakis Fotios , Salvatore Lisa , Schirripa Marta , Lenz Heinz-Josef 
Published: March 2020

3557 Background: As many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (response, PFS and OS) in 108 patients with metastatic colorectal cancer enrolled in clinical trials and treated with cetuximab. Methods: Genomic DNA was isolated from blood from 108 patients treated with cetuximab enrolled in one of two clinical trials. All patients were KRAS and BRAF wildtyp. 20 SNPs were selected based on the involvement in receptor endocytosis (CBL, CIN85, endophilin) ubiquitation/neddylation, recycling and degradation (CBL, EPS15, Ubc12, UbcH7). Minor allele frequency had to by higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. Results: In univariate analysis, rs895374 (HR: 1.69; p= 0.03), which is located in the exome of UbcH7, was able to separate patient cohorts significantly in perspective of progression free survival (CC = 5.7mo, CA= 3.6mo, AA= 3.4mo). Using multivariate analysis, rs895375 stayed to be a significant predictor of progression free survival with a Hazard ratio of 2.08 (95% CI 1.24 – 3.48) and a p value of 0.005. UbcH7 plays a pivotal role in the process of neddylation (adding NEDD8 to the EGFR), which switch the balance between recycling and degradation of the EGFR towards degradation. Conclusions: The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. Anti-EGFR antibody like Sym004 might overcome this resistance mechanism by preventing EGFR recycling.
Hsa-miR-31-3p expression in FFPE tumor samples as a predictor of anti-EGFR response in patients with metastatic colorectal cancer.
Authors: Manceau Gilles , Bachet Jean-Baptiste , Chibaudel Benoist , Liebaert Francois , Thiébaut Raphaële , Demetter Pieter , Van Laethem Jean-Luc , Leroy Karen , Bouche Olivier , Penault-Llorca Frederique , Diebold Marie Danielle , André Thierry , Imbeaud Sandrine , Laurent-Puig Pierre 
Published: March 2020

3562 Background: In metastatic colorectal cancer (mCRC), KRAS mutations are associated with resistance to anti-EGFR antibodies. To identify, in wild-type KRAS mCRC patients, markers that predict response to anti-EGFR antibodies, we focused on miRNAs. Methods: Expression profile of 1145 miRNAs was done on 84 colorectal tumors and 5 normal colon mucosae. Correlations between miRNAs expression level and survival were based on frozen samples of a training set from a retrospective series of 33 patients treated by cetuximab and irinotecan and of two validation set from prospective collections of 38 patients treated by cetuximab or panitumumab based chemotherapy or by panitumumab and irinotecan as third-line, using an adjusted Cox proportional hazards model. Validation on FFPE samples was done on 39 patients treated with panitumumab and irinotecan as third-line. Results: A predictive signature of 11 miRNA linked to the PFS was identified (p<0.01) but only one, hsa-miR-31-3p, exhibited significant different expression level between tumor from bad prognosis and good prognosis from the training set. We tested expression of this miRNA on the training set, and found a HR of 1.9 CI95% [1.1-2.9]. In validation set, the prognostic impact of hsa-miR-31-3p the HR was estimated to 1.9 CI95% [1.1-3.1]. Using multivariate model obtained from the training set to the two validation set, we predict the PFS of the patients (accuracy of prediction: AUC = 0.77). We classified the validation set according to a free PFS score (P=0.005) with a specificity of 62% CI95% [38%-82%] and a sensitivity of 82% CI95% [56%-96%] for the prediction model. A nomogram, established taking into account hsa-miR-31-3p expression level, predicted the progression risk (P<0.0001). Confirmation of the predictive value of hsa-miR-31-3p expression on survival risk progression was done on FFPE sample (p=0.0006). Conclusions: This is the first tool to select individual patients with a wild-type KRAS tumor for anti-EGFR therapy from frozen or FFPE samples.
Use of genetic variants in wnt signaling pathway to predict gender and tumor location dependent survival in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (BEV).
Authors: Ning Yan , Zhang Wu , Yang Dongyun , Loupakis Fotios , Wakatsuki Takeru , Stintzing Sebastian , Volz Nico Benjamin , Li Joseph Ethan , El-Khoueiry Rita Elie , Labonte Melissa Janae , Cremolini Chiara , Marmorino Federica , Barzi Afsaneh , El-Khoueiry Anthony B. , Lenz Heinz-Josef , Kahn Michael 
Published: March 2020

3568 Background: CRC is generally characterized by aberrant Wnt signaling. Wnt signaling pathway genes AXIN2 and TCF7L2 complex control the proliferation and differentiation of intestinal epithelial cells. Previous study showed polymorphisms in TCF7L2 and AXIN2 were associated with increase risk of colon cancer. We tested the hypothesis whether single nucleotide polymorphisms (SNPs) in TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) will predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. Methods: Genomic DNA were extracted from blood of 455 mCRC pts which prospectively enrolled in a pharmacogenetic translational study. Females(n=172) and males(n=252); Median follow up is 24 months, median PFS and OS were 10.5 and 29.9 months, respectively. Candidate SNPs were analyzed by PCR-based direct sequencing. Results: In the overall population analysis, TCF7L2 and AXIN2 polymorphisms were not associated with OS and PFS, but our data showed that 2 polymorphisms may predict clinical outcome when adjusted by pts gender and tumor location: 1) In right-sided tumors, male pts with any T allele of TCF7L2rs7903146 were associated with significantly worse PFS in comparison to those carrying C/C genotype (HR: 2.15; 95% CI: 1.09-4.22; P = 0.027, log-rank test). However, female pts with any T allele reversly showed better PFS compared with those carrying C/C variants (HR: 0.39; 95% CI: 0.17-0.94; P = 0.035, logrank test). 2) In women, pts with AXIN2 rs2240308 any A allele had better PFS and OS in right-sided tumors compared to those with any A allele but located in left side(pinteraction=0.047)(PFS) and (pinteraction=0.025)(OS), respectively. Conclusions: Our data show for the first time Wnt signaling pathway gene polymorphisms TCF7L2 rs7903146 and AXIN2 rs2240308 may predict PFS and OS in mCRC pts treated with first-line FOLFIRI/BEV. More importantly, this predictive value is dependent on gender and tumor location, suggesting a different role of Wnt signaling in female vs male and in right vs left side tumor. Our preliminary data warrants clinical trial validation.
Adjuvant chemotherapy (AC) outcomes in young (YP) and elderly patients (EP) with high-risk stage II colon cancer (CC).
Authors: Kumar Aalok , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Gill Sharlene , Woods Ryan , Speers Caroline , Cheung Winson Y. 
Published: March 2020

3569 Background: High-risk stage II CC is defined as those presenting with T4 stage, obstruction or perforation, <12 lymph nodes retrieved, positive resection margins, and lymphovascular or perineural invasion. Our prior findings suggest that improved outcomes from AC are limited to specific high risk features, such as T4 disease (Kumar et al, ASCO 2012). It is unclear if this benefit is seen across all ages. Our aim was to compare patterns of AC use and outcomes in YP and EP with high risk stage II CC. Methods: All patients diagnosed with high risk stage II CC from 1999 to 2008 and evaluated at any 1 of 5 regional cancer centers in British Columbia were categorized into YP (age <70 years) or EP (age >/=70 years). Kaplan-Meier methods and Cox regression were used to correlate receipt of AC with overall survival (OS), disease specific (DSS) and relapse free survival (RFS), stratified by age group. Results: A total of 1,236 patients were identified: 636 (51%) YP and 600 (49%) EP among whom 363 (57%) and 85 (14%) received AC, respectively. Individuals who received AC in either age group had better performance status than those who did not (ECOG 0/1 47% vs. 34%, p=0.02). After adjusting for known prognostic factors, a significant advantage in OS, but not DSS or RFS, from AC was observed for both YP and EP (Table). The impact of AC on these outcomes was similar across age groups (p interaction of age and treatment = 0.46, 0.64 and 0.69 for OS, DSS and RFS, respectively). In the entire cohort, individuals with T4 lesions had significantly improved OS (HR 0.50, 95%CI 0.33-0.77, p=0.002), DSS (HR 0.59, 95%CI 0.37-0.93, p=0.03), and RFS (HR 0.63, 95%CI 0.42-0.95, p=0.03). The effect of AC in the T4 subgroup was also similar for both YP and EP in terms of OS, DSS and RFS (p interaction of age and treatment = 0.41, 0.71 and 0.77, respectively). Conclusions: In this population-based cohort of high risk stage II CC, improvements in outcomes from AC were seen mainly in those with T4 disease, regardless of age. [Table: see text]