bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE).
Authors: Hong Yong Sang , Nam Byung-Ho , Jung Kyung Hae , Lee Jae-Lyun , Kim Kyu-Pyo , Park Young Suk , Park Joon Oh , Kim Sun Young , Kim Tae-You , Kim Jee Hyun , Ahn Joong Bae , Kim Tae Won
Published: March 2020

3570

Background: Preoperative chemoradiotherapy (Pre-CRT) with fluoropyrimidines (Fp) followed by surgery is one of the standard treatments for patients (pts) with locally advanced rectal cancer (LARC); however, the role of adjuvant chemotherapy is still controversial. The aim of this study is to investigate the efficacy of adjuvant FOLFOX for LARC pts who underwent Fp-based Pre-CRT and complete total mesorectal excision (TME). Methods: This randomised phase II study accrued LARC pts whose ypStage was II (ypT3-4/ypN0) or III (any ypT/ypN1-2) after Fp-based Pre-CRT followed by TME. Pts were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-FU 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-FU bolus 400 mg/m2 on D1, 5-FU infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles). The primary endpoint was disease-free survival (DFS). Results: A total of 320 pts were randomly assigned (161 FL and 159 FOLFOX) between November 2008 and June 2012, the arms were balanced. By intent-to-treat analysis, estimated 2-year DFS rate was 82.0% in FOLFOX arm and 69.4% in FL arm (HR 0.46 [95% CI, 0.28-0.76], p=0.002) after the median follow-up duration of 22.5 months. The statistical improvements of DFS were maintained regardless of ypStage: 2-year DFS rate was 89.7% (FOLFOX) vs 76.4% (FL) in pts (n=122) with ypStage II (HR 0.32 [0.10-0.98], p=0.035), and 78.1% (FOLFOX) vs 64.4% (FL) in pts (n=198) with ypStage III (HR 0.49, [0.27-0.86], p=0.011). All grade leucopenia (32% vs 22%), neutropenia (70% vs 46%), thrombocytopenia (26% vs 2%) and sensory neuropathy (71% vs5%) were more frequently observed in FOLFOX arm; however, grade 3/4 adverse events (AE) were not different between arms. Conclusions: Adjuvant FOLFOX improved 2-year DFS relative to FL for LARC pts whose ypStage II or III after Fp-based Pre-CRT followed by TME. Significant AEs were not different between arms. The DFS results will be updated in the presentation. Clinical trial information: NCT00807911.
Survival benefit and complications of primary tumor resection (PTR) in patients with stage IV colorectal cancer (CRC) in the era of modern chemotherapy: A systematic review and meta-analysis.
Authors: Ahmed Shahid , Shahid Rabia K , Pahwa Punam , Kanthan Selliah , Reeder Bruce , Yadav Sunil , Sami Amer , Haider Kamal , Leis Anne
Published: March 2020

3580

Background: Although there is evidences that PTR in advanced CRC may improve outcome, most studies were conducted during the period of monotherapy with 5-fluorouracil. Limited data is available regarding potential benefits and risk of PTR in patients with stage IV CRC treated with modern chemotherapy (MC). A recent phase II study suggested that outcomes are not compromised by leaving the primary colon tumor intact in such patients (JCO.2012;30:3223). Purpose:To compare survival of patients with advanced CRC who underwent PTR with patients without resection in the era of MC. The review also aims to determine post-operative mortality and non-fatal complications rates, primary tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR) and quality of life (QOL). Methods: A literature search was conducted by using CENTRAL (2012), Medline (1946-2012), and EMBASE (1947-2012). Studies involving patients with stage IV CRC who underwent PTR were selected with restriction to publication dates from 2000, English language and human studies. Screening, evaluation of relevant articles and data abstraction was done in duplication and agreement was assessed. Articles that met the inclusion criteria were assessed for quality by using Ottawa-Newcastle score. Data was collected and synthesized as per protocol. Results: Of total of 3,379 reports, 10 retrospective studies were selected with patients population of 2,655. Among 2,655 patients, 1616 (61%) underwent PTR with a median overall survival of 18.7 months (range: 11-30.7) compared with 12.9 months (range: 5.8-22) in the control. The HR for survival was in 0.68 (95% CI: 0.56-0.83) favoring the PTR. Mean 30 days post-operative mortality rate in the PTR group was 3.9% (95% CI: 0-11). Mean PTCR and NSPR in the control group were 27.4% (95% CI: 16.4-38.5) and 27% (95% CI: 12.5-41.6) respectively. No study provided QOL. Conclusions: The retrospective data favors PTR in advanced CRC in the era of modern chemotherapy. Future prospective randomized trials are warranted to confirm the findings.
The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC).
Authors: Hochster Howard S. , Messersmith Wells A. , O'Neil Bert H. , Groshen Susan G. , Lenz Heinz-Josef , Cohen Deirdre Jill , Denlinger Crystal Shereen , Gold Philip Jordan , Eckhardt S. Gail , Locker Gershon Y. , Ames Patricia , McKinley Marti , Leichman Lawrence P. ,   Academic GI Cancer Consortium (AGICC)
Published: March 2020

3587

Background: There are few therapies for second-line KRASm CRC. Inhibiting downstream signal transduction may offer therapeutic options. Use of selumetinib (MEK 1/2 inhibitor; AstraZeneca) is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI + SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin + bevacizumab regimen; PS 0-1; acceptable organ function. Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3+3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PI-determined response rate (RR) by RECIST. A Simon 2-stage design allowed expansion to 45 pts if ≥1 responses in 20 pts was seen; ≥4/45 responses would be encouraging, when compared to historical RR of 4% (and median PFS 2.5 mo) [EPIC, Sobrero 2008], with approximately 90% power to detect an ORR of 15% at the 10% alpha level (one-sided). Results: N =32 pts entered; 31 treated. Median age was 54 (27-75) yrs; 18 male and 24 Caucasian. The first 3 pts tolerated SEL 50 mg bid without DLT and the remaining 28 were treated at 75 bid. Median number of cycles on study was 3.5 and median PFS was 3.4 mo. Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash. There was one Grade 4 neutropenia. The best PI-reported response included 3 (10%) confirmed PR and 16 (52%) SD [including 1 unconfirmed PR]. 6 patients were on study for more than 6 (up to 22) months. The study was terminated early due to non-protocol considerations. Conclusions: In this small study, the RR of 10% and med PFS of 3.4 mo in pts with KRASm CRC treated with IRI + SEL in 2nd line are promising compared with prior studies in non-selected patients. MEK inhibition in KRASm CRC should be explored further. Supported in part by AstraZeneca.
Prognostic stratification of k-RAS wild type colorectal cancer patients receiving irinotecan-cetuximab treatment: Preliminary results of a prospective study.
Authors: Scartozzi Mario , Giampieri Riccardo , Mandolesi Alessandra , Abouelkhair Khaled Mahmoud , Loretelli Cristian , Del Prete Michela , Faloppi Luca , Bittoni Alessandro , Bianconi Maristella , Cecchini Luca , Ibrahim Ezzeldin M. , Bearzi Italo , Cascinu Stefano
Published: March 2020

3591

Background: Translational research identified numerous putative markers for a “beyond-k-RAS” selection of colorectal cancer patients receiving cetuximab, but none of these entered clinical practice mainly because prospective validation is lacking. The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed may be able to predict patients’ clinical outcome more accurately than k-RAS status alone. Methods: Metastatic, K-RAS wild type colorectal cancer patients, candidate to receive second/third-line cetuximab with chemotherapy have been prospectively allocated, after informed consent, into 2 groups on the basis of their genetic profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) and unfavourable (any of the previous markers altered or mutated). All patients received cetuximab treatment as planned by treating physician who was unaware of biomarkers results. To detect a difference in terms of response rate (RR) among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 46 patients. Results: 31 patients have been enrolled, most patients (27, 86%) received cetuximab as third-line. Eleven patients (35%) were allocated to the favourable profile and 20 patients (75%) to the unfavourable profile. Patients with the unfavourable profile showed 1 BRAF mutation, 2 PIK3CA exon 20 mutations, 12 cases of EGFR GCN < 2.6, 13 cases of HER-3 and 11 cases of IGF-1 overexpression respectively. RR in the favourable and unfavourable group was 7/11 (64%) and 1/20 (5%) (p= 0.008) respectively. The favourable group also showed an improved median TTP (8 months vs. 2.6 months, p = 0.0007) and OS (16 months vs. 6 months, p = 0.0002). Conclusions: Our results suggest that prospective selection of candidates for cetuximab may be able to improve clinical outcome in patients with a favourable profile. This approach, if confirmed, may also allow an early switch to alternative treatment in patients with an unfavourable profile.
Bevacizumab plus chemotherapy continued beyond first disease progression in patients with metastatic colorectal cancer previously treated with bevacizumab-based therapy: Patterns of disease progression and outcomes based on extent of disease in the ML18147 study.
Authors: Greil Richard , Von Moos Roger , Bennouna Jaafar , Osterlund Pia J. , André Thierry , Van Cutsem Eric , Kubicka Stefan , Arnold Dirk , Vieitez de Prado Jose Maria , Bouche Olivier , Alonso Vicente , Borg Christophe , Schlichting Christoph , Steffens Claus-Christoph , Osborne Stuart , Waterkamp Daniel , Makrutzki Martina , Sastre Javier
Published: March 2020

3604

Background: ML18147 demonstrated that bevacizumab (BEV) + chemotherapy (CT) continued beyond first disease progression (PD) significantly prolongs overall survival (OS) and progression-free survival (PFS) as second-line treatment for metastatic colorectal cancer (mCRC) [Bennouna et al. Lancet Oncol 2012]. Here we report exploratory analyses of patterns of PD and outcomes based on extent of disease. Methods: In ML18147, patients (pts) with unresectable, histologically confirmed mCRC who progressed ≤3 months after discontinuation of first-line BEV were randomised to second-line CT±BEV. This exploratory analysis evaluated PD patterns, time from discontinuation of study medications to PD, and survival outcome (OS, PFS) based on liver-limited vs extensive disease. Results: Details on patterns of PD and outcome by extent of disease are shown in the table. Conclusions: These exploratory analyses suggest that pts with liver-limited or extensive disease seem to benefit equally from BEV+CT continued beyond PD. Our findings indicate that the pattern of PD does not appear to differ between the two treatment arms following cessation of BEV treatment in this setting. Clinical trial information: NCT00700102. [Table: see text]
Association of KRAS mutation with worse recurrence-free survival and site of metastatic progression after resection of hepatic colorectal metastases.
Authors: Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Gewirtz Alexandra N. , Cercek Andrea , Kingham T. Peter , Jarnagin William R. , Fong Yuman , DeMatteo Ronald P. , Allen Peter J. , Shia Jinru , Ang Celina , Vakiani Efsevia , D'Angelica Michael Ian
Published: March 2020

3609

Background: There are conflicting results regarding the influence of KRAS mutation status and outcome in patients (pts) with colorectal cancer. A recent report suggested worse outcome in KRAS mutated (MUT) pts who underwent resection of hepatic metastases (Karagkounis et al, ASCO 2012). Methods: Recurrence patterns and survival were evaluated in 169 patients who had undergone resection of liver metastases, then received adjuvant hepatic arterial infusion and systemic chemotherapy, and for whom KRAS data were available. Kaplan-Meier methods were used to estimate recurrence free survival (RFS) and overall survival (OS). Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adjuvant therapy to bone, brain, lung and liver metastases separately. Mutations in KRAS (codons 12, 13) were detected using the iPLEX assay (Sequenom, Inc). Results: Median follow-up for the entire cohort was 38.8 months. 118 were KRAS wildtype (WT), and 51 were KRAS MUT (45 G12, 5 G13, 1 K117N). The 3 year RFS was 48% [95%CI: 37-58%] for KRAS WT pts and 30% [15-44%] for MUT pts (p<0.01). OS at 3 years was 96% [88-98%] for KRAS WT and 80% [61-90%] for MUT pts (p=0.08). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in Table 1. The cumulative incidence of metastases to bone at 2 years was 0% and 13.7% in KRAS WT versus MUT pts (p<0.01), to brain 0% versus 4.6% for KRAS WT versus MUT (p=0.05), and to lung 27% versus 47.5% in KRAS WT versus MUT pts (p<0.01). Conclusions: In pts who have had liver resection followed by adjuvant therapy, those with KRAS MUT have a worse RFS and seemingly worse OS than those who are KRAS WT. Also, patients with KRAS MUT appear more likely to develop bone, brain, and lung metastases. Further investigation of a larger number of patients is warranted. [Table: see text]
Analysis of NRAS mutation as poor prognostic indicator and predictor of resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Morvillo Manfredi , Bergamo Francesca , Zoratto Federica , Salvatore Lisa , Antoniotti Carlotta , Marmorino Federica , Sensi Elisa , Lupi Cristiana , Fontanini Gabriella , De Gregorio Veronica , Giannini Riccardo , Basolo Fulvio , Masi Gianluca , Falcone Alfredo
Published: March 2020

3613

Background: NRAS belongs to RAS family. NRAS mutations are mutually exclusive with KRAS and BRAF mutations and contribute to the activation of Ras/Raf/MAPK pathway. Previous experiences evaluated the prognostic/predictive role of NRAS mutations suggesting a poorer prognosis and resistance to anti-EGFRs for NRASmutant (mut) mCRC pts. The aim of the present study was to confirm such preliminary findings in a large cohort of mCRC pts. Methods: Data on KRAS (codons 12, 13 and 61) and BRAF-V600E mutational status of mCRC pts referred to our pathology from '09 to '12 were collected. NRAS mutational status (codons 12, 13 and 61) was evaluated in KRAS and BRAF wt pts. OS was calculated from date of diagnosis of metastatic disease. Data on response and PFS according to RECIST were collected for NRASmut irinotecan-refractory pts treated with anti-EGFRs +/- irinotecan. Results: 774 mCRC pts were included. KRAS/BRAF mutations were found in 384 (50%)/69 (9%) cases. NRAS was mut in 47 (15%) out of 318 KRAS and BRAF wt pts. NRAS mut pts had significantly shorter OS in comparison to KRAS-BRAF-NRAS wt pts (HR=0.60 [0.29-0.99] p=0.045). BRAF mut pts had significantly worse OS in comparison to NRAS mut pts (HR=1.75 [1.073-2.87] p=0.03). No difference was observed between NRAS mut and KRAS mut pts (HR=0.86 [0.51-1.43] p=0.61). 18 pts out of 47 NRAS mut pts received anti-EGFRs in advanced lines. 8 pts (7 cetuximab-based, 1 panitumumab monotherapy) were evaluable according to RECIST criteria and therefore eligible for the present analysis. None of them responded and only 1 SD was observed. Pooling our results with available data on anti-EGFRs’ activity in NRASmut pts in advanced lines of treatment (De Roock, 2010; Peeters, 2013; Andrè, 2012), only 1 response is described out of 35 treated pts (2,9%). Conclusions: Our data demonstrate that NRAS mutations have a relevant incidence in KRAS and BRAF wt mCRC pts. Present results are consistent with previous experiences and confirm that NRAS mutations affect prognosis of mCRC patients and predict lack of response to anti-EGFRs. Further insights into NRAS mut mCRC biology and prospective validation are warranted.
Primary prophylactic granulocyte colony-stimulating factor (GCSF) in Gilbert’s disease patients treated with FOLFIRI first line for metastatic colorectal cancer (mCRC): Final results of the FFCD 0604 study.
Authors: Lecomte Thierry , Bouche Olivier , oden-Gangloff Alice , Le Malicot Karine , Aparicio Thomas , Mitry Emmanuel , Bedenne Laurent , Deplanque Gael , Volet Julien , Tougeron David , Bonnetain Franck , Moreau Marie , Dorval Etienne , Loriot Marie-Anne , Laurent-Puig Pierre , Lepage Come
Published: March 2020

3614

Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (>30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI + bevacizumab 1st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (α=5% and β=90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125.
Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer.
Authors: Senzer Neil N. , LoRusso Patricia , Martin Lainie P. , Schilder Russell J. , Amaravadi Ravi K. , Papadopoulos Kyriakos P. , Segota Zdenka E , Weng David Edward , Graham Martin , Adjei Alex A.
Published: March 2020

3621

Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs and has potent preclinical anti-tumor synergy combined with TNFa-inducing chemotherapies [i.e irinotecan (I)]. B and I combination is well-tolerated and has encouraging activity in a phase 1 study. This study tested B+I with an ascending dose strategy (ADS) of B to mitigate Bell’s palsy (BP) risk, an unusual and reversible side effect of SMAC mimetics. Methods: I at 350mg/m2 IV q3weeks was administered with B weekly (2 of 3 weeks). The dose of B was titrated incrementally during Cycle 1: C1D1 at 5.6mg/m2 and C1D8 at 11mg/m2 for ADS. For Cycle 2 (C2) and ongoing treatment, the B dose was 22mg/m2 or 35mg/m2, which were the MTD and DLT (BP) dose levels when combined with I from the Ph 1 study. Safety and clinical activity for KRAS mutant (KRAS-MT) and wild-type (KRAS-WT) were assessed in 3 cohorts: (1) at 22mg/m2 for CRC KRAS MT; (2) 22mg/m2 for CRC KRAS WT; (3) 35mg/m2 for CRC KRAS MT. Results: 51 patients (pts) with CRC had a median number of 4 prior regimens with 47 refractory/relapsed to irinotecan (92%). Tolerability was comparable to I alone. There were 2 PRs (4%), 27 SD (>2 cycles; 53%, median 4.7 mo), 17 PD (33%), and 5 non- evaluable pts (9%) for an overall clinical benefit (CR+PR+SD) rate of 57%. Median progression-free survival (PFS) was 2.1 months, and 6 mo PFS was 20%. KRAS MT CRC with prior I had a median PFS of 2.9 mo and 6 mo PFS of 25% (n=20). KRAS WT CRC with prior I had a median PFS of 1.4 mo and 6 mo PFS of 17% (n=18). The ADS seemed to reduce BP risk. No BP events occurred among 40 pts (22mg/m2 with ADS), compared to 1 of 7 pts (22mg/m2 without ADS). In the 35mg/m2 cohort, 1 BP event occurred among 12 pts (with ADS), compared to 3 of 6 (35mg/m2 without ADS). Conclusions: B + I demonstrated clinical benefit in pts refractory/relapsed to irinotecan, with greatest benefit in KRAS MT CRC. The ADS may provide a mitigation strategy for BP risk. Prior studies with I retreatment have showed no benefit in KRAS MT CRC. Comparable CRC pts with best supportive care have 6 mo PFS of 2%. Clinical activity supports the hypothesis for therapeutic synergy of B + I, with I as a TNFa-inducing agent. Further study of this combination is warranted. Clinical trial information: NCT01188499.
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors.
Authors: Tabernero Josep , Powderly John D. , Hamid Omid , Gordon Michael S. , Fisher George A. , Braiteh Fadi S. , Garbo Lawrence E. , Fine Gregg Daniel , Kowanetz Marcin , McCall Bruce , Shen Xiaodong , Chen Daniel S. , Kohrt Holbrook Edwin
Published: March 2020

3622

Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A. Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.
Prognostic biomarkers in a series of stage II colon cancer.
Authors: Santos Cristina , Terricabras Marta , Lopez-Doriga Adriana , Gonzalez Sara , Fernandez Anna , Martinez Iniesta Maria , Sanjuan Xavier , Garcia-Molleva David , Villanueva Alberto , Moreno Victor , Biondo Sebastiano , Kreisler Esther , Capella Gabriel , Salazar Ramon
Published: March 2020

3629

Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component (EMT+ subtypes) has also been associated with poor outcome. The aim of the study is to analyze the prognostic value of MSI, BRAF and tumor-stroma ratio in a prospective series of stage II CC patients. Methods: FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge (1996 - 2006) were included in the study. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined in 350 patients. 48 (14%) had MSI high (MSI-H) tumor. BRAF status could be assessed in 380 cases. 58 (15%) cases were BRAF mutated. Tumor-stroma ratio was analyzed in 407 tumor samples. 176 (43%) tumors had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in right colon (X2 p-value = 1.03e-5), were poorly differentiated (X2 p-value = 0.003) and had more than 12 lymph nodes resected (X2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value = 0.02) and stroma-low (X2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, microsatellite stable (MSS)/stroma-low and MSS/stroma-high patients (HR = 3.15; 95 CI, 0.76 – 13.1, p-value = 0.0602). Conclusions: MSI-H tumors have BRAF mutation as well as low intra-tumor stroma. Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors.