bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of proton pump inhibitors (PPIs) on FOLFOX and XELOX regimens in colorectal cancer (CRC).
Authors: Wong Grace , Ha Vincent , Chu Michael Patvin , Dersch-Mills Deonne , Ghosh Sunita , Chambers Carole , Sawyer Michael B. 
Published: January 2019

621 Title: Effects of Proton Pump Inhibitors (PPIs) on FOLFOX and XELOX Regimens in Colorectal Cancer (CRC) Background: First-line adjuvant chemotherapy options for stage II-III CRC include XELOX (capecitabine (cape), oxaliplatin) and FOLFOX (oxaliplatin, leucovorin, 5FU). Cape is an oral 5FU prodrug, and recent studies suggested that PPIs may detrimentally affect cape efficacy. Conversely, some literature posits that PPIs may negatively impact CRC itself. Our primary objective was to compare 3-year recurrence-free survival (RFS) rates between XELOX-treated PPI-users and non-PPI users, and FOLFOX-treated PPI users and non-PPI users. Our main secondary objective was to compare overall survival (OS). Methods: We conducted a retrospective chart review of 389 stage II-III CRC patients (pts) who received adjuvant XELOX or FOLFOX from a tertiary cancer center in Alberta, Canada between 2004-2013. Information regarding PPI use, cancer treatment, and pt outcomes were gathered and analyzed from pharmacy databases. Results: 23.4% of XELOX-treated pts and 28.0% of FOLFOX -treated pts used PPIs concurrently with treatment. 3-year RFS was significantly lower in XELOX-treated PPI pts than non-PPI pts (69.5 vs. 82.6%, P=0.029). Unadjusted analysis showed that XELOX-treated PPI pts were twice as likely to experience cancer recurrence or death as XELOX-treated non-PPI pts (HR 2.03, P=0.033). FOLFOX-treated PPI pts had a non-significant increase in three-year RFS versus non-PPI pts (82.9 vs. 61.7%, P=0.066), and no significant difference in recurrence or death (HR 0.51, P=0.071). No significant differences were seen in OS. Conclusions: Our results suggest that PPIs negatively impacted RFS in early-stage XELOX-treated CRC pts, and yielded no significant effect amongst FOLFOX-treated patients. Further studies are required to corroborate our findings. [Table: see text]
Differences in molecular profiles of males and females with colorectal cancer (CRC).
Authors: Barzi Afsaneh , Salem Mohamed E. , Xiu Joanne , Korn Wolfgang Michael , Marshall John , Shields Anthony Frank , Lenz Heinz-Josef 
Published: January 2019

623 Background: Females (F) have a lower incidence of CRC and carry a better overall prognosis than males(M). We explored the differences in the molecular profile of CRC as an explanation for the differences in the outcome. Methods: CRC cases submitted to Caris Life Sciences from 2015 to 2017 were analyzed. These cases were tested with next generation sequencing (NGS) of 592 genes and a panel of IHC and copy number variation assessment. Microsatellite instability (MSI) was evaluated with NGS for known MSI loci in the target regions. High Tumor mutational load (TML-H) was defined as ≥17 mutations/megabase. Results: Data from a total of 1768 CRC tumors (F: 859; M: 909) was available for analysis. The mean age at testing was similar between the two groups (F 59 vs. M 60 years). Tumor location was unknown in more than 40% of the cases. For those with known tumor location (1056) F had a higher rate in right sided than left sided and rectal tumors (51% vs. 47% vs. 40%, p = 0.006). Overall, F carried significantly lower frequency of mutation in APC (68% vs. 74%, p = 0.02), higher frequency of BRAF (11% vs. 6.6%, p = 0.003) and BRCA1 (2% vs. 0.6%, p = 0.007). PDL1 expression was higher in F (4.5% vs. 2.1%, p = 0.006) and MGMT expression was higher in M (63% vs. 56%, p = 0.04). There was no significant difference in the TML-H (F:6.4% vs. M:5.9%) and MSI-high (F:6.2% in vs M:4.8%). When primary (877) and metastatic tumors (838) were investigated separately, mutations in APC was higher in M primary tumors (74% vs. 68% p = 0.03) while not different in metastatic sites. On the contrary, BRCA1 mutations were higher in the metastatic sites for F (2% vs. 0.2%, p = 0.02). PD-L1 was higher in the primary tumor of F (5.2% vs. 1.8%, p = 0.008) and PD-1 on tumor infiltrating lymphocyte in metastatic tumors in F (48% vs. 30%, p = 0.01). Conclusions: The profile of female patients (higher rates of PDL1 in primary and PD1 in metastatic tumors) supports a higher degree of immune evasion. The differences in the profile of metastatic vs. primary sites may be due to the differences in the mechanism of metastasis in females vs. males and may have implications for PDX models.
Analysis of RAS/BRAF mutations in a randomized phase II WJOG6510G study of panitumumab plus irinotecan versus cetuximab plus irinotecan in chemorefractory metastatic colorectal cancer.
Authors: Nishina Tomohiro , Taniguchi Hiroya , Sakai Daisuke , Kawakami Hisato , Sugimoto Naotoshi , Hara Hiroki , Esaki Taito , Denda Tadamichi , Makiyama Akitaka , Tsuda Masahiro , Okuda Hiroyuki , Izawa Naoki , Hosokawa Ayumu , Yamazaki Kentaro , Tokunaga Shinya , Moriwaki Toshikazu , Tsuji Akihito , Koh Yasuhiro , Kishimoto Junji , Muro Kei 
Published: January 2019

624 Background: A randomized phase II WJOG6510G study demonstrated non-inferiority of panitumumab (Pmab) plus irinotecan (IRI) to cetuximab (Cmab) plus IRI in terms of progression-free survival (PFS) in wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we performed exploratory analyses of updated survival data using KRAS exon 2 and RAS/BRAF statuses. Methods: In this trial, patients with WT KRAS exon 2 mCRC who progressed after failure of fluoropyrimidine, IRI, and oxaliplatin were randomized to receive Pmab or Cmab in combination with IRI. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence specific oligonucleotide method which can detect 48 types of KRAS/NRAS and 34 types of BRAF mutations. Results: In the ITT population, patient characteristics included the following (Pmab/Cmab): number 61/59; male 69%/63%; median age 64 y/64 y; ECOG PS 0 62%/54%; left-sided primary tumor 85%/88%; multiple sites of metastases 51%/66%. At the time of updated analysis, 113 (94%) and 117 (98%) out of 120 patients had OS and PFS events, respectively. Median PFS was 5.42 months in the Pmab arm and 4.27 months in the Cmab arm (HR 0.674, unstratified log-rank p = 0.035). Median overall survival (OS) was 14.85 months in the Pmab arm and 11.53 months in the Cmab arm (HR 0.675, p = 0.037). In 83 patients, RAS/BRAF tests revealed 19 patients (23%) with RAS and 4 patients (5%) with BRAF mutations (two with V600E, two with non-V600E). Patients with RAS and BRAF mutations did not respond to the treatments. In the RAS WT population, a better PFS trend was observed for Pmab treatment (median 6.06 months vs. 5.26 months, HR 0.629, p = 0.08); however, OS was similar in both arms (median 14.85 months vs. 11.26 months, HR 0.818, p = 0.449). Conclusions: In this analysis, a modest survival benefit was found to be associated with Pmab plus IRI compared to Cmab plus IRI in WT KRAS exon2 mCRC, which warrants further evaluation in the WT RAS population. The number of analytic cases of RAS/BRAF status will be updated in the presentation. Clinical trial information: UMIN000006643.
Phenotypic subtypes as a novel validated prognostic classification system for patients with colorectal cancer.
Authors: Roseweir Antonia K. , Park James Hugh , ten Hoorn Sanne , Powell Arfon GMT , Roxburgh Campbell SD , McMillan Donald C , Horgan Paul G. , Vermeulen Louis , Edwards Joanne 
Published: January 2019

625 Background: There has been enormous effort to develop a prognostic genomic classification of colorectal cancer (CRC). As a result, mismatch repair (MMR) status was established as a prognostic marker in addition to TNM-staging. Phenotypic subtypes were recently proposed that stratified patient survival, however their clinical utility had not been compared to other proposed classification systems including consensus molecular subtypes (CMS) or current prognostic markers including MMR status. Methods: Three patient cohorts, a pilot cohort of 237 stage I-III CRC patients, a validation cohort of 879 stage I-III CRC patients, and the AMC-AJCCII-90 cohort with 81 stage II colon cancer patients were utilised to investigate associations between phenotypic subtypes, MMR status, CMS and patient survival. Results: In the pilot cohort, phenotypic subtype stratified cancer-specific survival (P < 0.001). In the validation cohort, phenotypic subtype stratified overall (p = 0.003) and cancer-specific survival (CSS, p < 0.001) independent of tumour location. MMR status associated with right-sided colon cancer (p < 0.001), therefore further analysis was restricted to this subset of patient (n = 380). The immune subtype had the highest MMR deficiency (p = 0.001). Phenotypic subtype (p < 0.001) more effectively stratified CSS than MMR status (p = 0.023). Furthermore, in left-sided colon cancer (p = 0.007) and rectal cancer (p < 0.001) only phenotypic subtype stratified CSS. Phenotypic subtype and not MMR status was independently prognostic in the full cohort (p < 0.001) and right-sided colon cancer (p < 0.001). In the AMC-AJCCII-90 cohort phenotypic subtypes aligned with CMS (p < 0.001) and stratified overall survival better than CMS (p = 0.125 v p = 0.487 respectively). Conclusions: Phenotypic subtype is a more effective prognostic classification than CMS and MMR status. Phenotypic subtypes should be incorporated alongside MMR status as a clinical aid for the prognosis of patients with CRC.
Association of genetic variations within the PD-L2 immune checkpoint gene with outcome in stage II and III colon cancer.
Authors: Berger Martin D. , Zlobec Inti , Yang Dongyun , Cao Shu , Sunakawa Yu , Matsusaka Satoshi , Koelzer Viktor H. , Inderbitzin Daniel , Ning Yan , Okazaki Satoshi , Miyamoto Yuji , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Zhang Wu , Lugli Alessandro , Lenz Heinz-Josef 
Published: January 2019

626 Background: Immune checkpoints can either inhibit or stimulate T-cell responses and therefore play a key role in maintaining an equilibrium between self tolerance and autoimmunity. Targeting immune checkpoint molecules can result in increased antitumor immunity by stimulation of the immune system. We hypothesize, that variations in genes encoding for both inhibitory or stimulatory immune checkpoint proteins may predict outcome in stage II and III colon cancer patients. Methods: The impact of 6 functional single nucleotide polymorphisms (SNPs) within the PD1, PD-L1, PD-L2, TIM3, OX40 and CD27 genes on time to recurrence was evaluated in 201 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: female/male ratio = 42.8% / 57.2%; median age = 70y (19-91); median follow-up = 43months. The PD-L2 rs16923189 SNP showed significant association with recurrence rate. Patients with a G/G genotype had a higher 3-years recurrence rate compared to those harboring any A allele (41% vs 19%) in both univariate (HR 2.68, 95% Confidence interval (CI) 1.28-5.61, p = 0.006) and multivariate analyses (HR 3.13, 95% CI 1.42-6.28, p = 0.003). The high recurrence rate was most evident among patients with stage III and left-sided tumors carrying the G/G genotype (53% vs 24% and 65% vs 18%) in both univariate (HR 2.87, 95% CI 1.24-6.66, p = 0.009 and HR 5.28, 95% CI 2.24-12.44, p < 0.0001) and multivariate analyses (HR 4.32, 95% CI 1.76-9.91, p = 0.001 and HR 5.20, 95% CI 2.02-12.75, p = 0.001). Conclusions: Our results provide the first evidence, that polymorphisms within the PD-L2 gene might serve as prognostic markers in patients with stage II and III colon cancer. Interestingly, the prognostic effect is most significant among patients with stage III and left-sided colon cancers. Targeting PD-L2 might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.
BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): Efficacy and tumor markers.
Authors: Van Cutsem Eric , Cuyle Pieter-Jan , Huijberts Sanne , Yaeger Rona , Schellens Jan H. M. , Elez Elena , Tabernero Josep , Fakih Marwan , Montagut Clara , Peeters Marc , Desai Jayesh , Yoshino Takayuki , Ciardiello Fortunato , Wasan Harpreet Singh , Kopetz Scott , Maharry Kati , Christy-Bittel Janna , Gollerkeri Ashwin , Grothey Axel 
Published: January 2019

627 Background: The SLI of the BEACON CRC phase 3 study assessed the safety and efficacy of the combination of the BRAF inhibitor encorafenib (ENCO) + MEK inhibitor binimetinib (BINI) + anti-EGFR antibody cetuximab (CETUX) in pts with BRAFV600E-mutant mCRC after 1 or 2 prior regimens. CEA and CA19-9 are tumor markers that are widely used to monitor the effectiveness of systemic therapies for mCRC; here we report on the association of CEA and CA19-9 changes while on treatment with clinical outcomes in pts from the SLI. Methods: Pts in the SLI received the triplet of ENCO 300 mg QD + BINI 45 mg BID + CETUX 400 mg/m2 (initial dose) then 250 mg/m2 QW in 28-day cycles. Pts were evaluated for safety, radiographic response, and change in tumor markers CEA and CA19-9. Results: 30 pts were treated. The triplet was generally well tolerated, and adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities. The rate of severe skin toxicities (grade 3/4) was lower than generally observed for CETUX in mCRC. Of the 29 pts with a BRAFV600E mutation, the median time on study treatment was 5.6 mo (range, 1.0–9.3 mo), and 22 (76%) remained on study treatment at the time of data cutoff. The confirmed overall response rate (ORR) was 41%, with 1 complete and 11 partial responses. In addition, 9 pts had prolonged stable disease (SD) up to 9.3 mo.CEA and CA19-9 were analyzed in 28 pts. CEA and CA19-9 decreased in 96% and 82% of these pts, respectively. Among 15 pts with treatment duration ≥5.6 mo, median/mean % decreases were 97%/79% for CEA and 92%/82% for CA19-9 in confirmed responders (n=6). Respective decreases in pts with prolonged SD (n=9) were similar: 84%/68% for CEA and 89%/68% for CA19-9. Updated safety, efficacy, and tumor marker results will be provided. Conclusions: ENCO + BINI + CETUX is generally well tolerated and has encouraging clinical activity in BRAFV 600E mCRC, with a confirmed ORR of 41%. In pts with study treatment duration ≥5.6 mo, the tumor markers CEA and CA19-9 decreased markedly and to the same degree in responders vs pts with prolonged SD, providing additional evidence of the meaningful clinical activity of this regimen. Clinical trial information: NCT02928224.
Identification of mutation biomarkers underpinning colon cancer sidedness and cetuximab sensitivity.
Authors: Yeatman Timothy Joseph , Yang Mingli , Schell Michael J. , Loboda Andrey , Nebozhyn Michael , Li Jiannong , Teer Jamie K. , Rocha Lima Caio Max S. , Pledger Jack 
Published: January 2019

629 Background: Currently, extended RAS testing ( KRAS/ NRAS) in colorectal cancer (CRC) patients identifies only non-responders to EGFR inhibitor (EGFRi) therapies, and accurate prediction of drug-sensitive subpopulations remains problematic in patients, even with wild-type RAS. Moreover, the molecular basis for the laterality of anti-EGFR sensitivity is poorly understood. Methods: 468 CRCs were analyzed by global gene expression analysis, DNA sequencing (1321 cancer related genes) and MSI analysis. Tumors were stratified by a validated gene expression cetuximab sensitivity (CTX-S) score, and then correlated with identified high frequency mutations, resulting in a ranking of CTX-S score-associated mutated genes (see Table). Results: Ranking analysis revealed MSI-H status and KRAS mutation as the most negatively-correlated among all patients and MSS patients, respectively. Conversely, APC and TP53 were the most highly positively-correlated mutant genes in both all patient- and MSS-cases. Deeper analysis revealed that the combination of mutant APC + TP53 ( A + P) was more common in left vs. right CRCs (52% vs 21%), and even more pronounced in MSS vs MSI cases (47% vs 2%). CTX-S scores were highest in mutant A + P patients with WT RAS, but surprisingly, were nearly as high in mutant A + P patients with mutant RAS. CRC PDX models validated these results with a favorable CR/PR/SD vs PD association. Conclusions: Here we report the discovery of a cooperative role of APC and TP53 mutations in identifying EGFRi-sensitive CRC subpopulations. Our data suggest that addition of the routine sequencing of APC and TP53 to extended RAS testing may expand the EGFRi therapeutic opportunity (by up to 25%), regardless of RAS mutation status. [Table: see text]
ColotypeR: A tool to classify colon cancers by consensus molecular subtype and subtype-specific risk of recurrence.
Authors: Buechler Steven Allen , Badve Sunil S. , Gokmen-Polar Yesim , Herring Emily , Ludwig Katelyn , Hummon Amanda 
Published: January 2019

632 Background: Colon cancer is highly heterogeneous in prognosis and response to treatment. The consensus molecular subtypes (CMS1-4, and mixed) partition colon cancers into distinct groups. CMS4 tumors, a mesenchymal subtype, have the worst prognosis and poor response to standard chemotherapies. There is a critical need for accurate molecular subtyping, and subtype-specific management. Methods: Affymetrix microarrays colon cancer datasets (N = 813; GSE39582, GSE14333) were partitioned into training (AT; N = 370) and validation sets (AV; N = 443) balanced for clinical traits. A novel multistate gene methodology was used to predict CMS, and prognosticate subtype-specific relapse-free survival (RFS) in the training set. Accuracy of CMS prediction and prognostic significance was validated in the AV and TCGA colon cancer (COAD; N = 458) sets. Results: In the training set, a 20-gene panel (ColotypeR-CMS) predicts CMS subtype. Mean accuracy for CMS1-4 prediction was 0.87 in AV and 0.81 in COAD. In AV, 5-year RFS is 0.52 (95%CI 0.43 – 0.63) in the predicted CMS4, and 0.70 (95%CI 0.65 – 0.77) in the non-CMS4 samples. The risk of relapse for non-CMS4 samples was refined by a genomic score (ColotypeR-Risk) computed using expression of 25 genes in the training set. ColotypeR-Risk was prognostic of RFS (p = 0.0004) among the AV non-CMS4 samples, and also prognostic (p = 0.0001) among the stage II non-CMS4 AV samples not treated with chemotherapy. The prognostic significance of ColotypeR-Risk among non-CMS4 samples is independent of tumor location (right or left) and CMS subtype (CMS1-3 or mixed). ColotypeR-Risk was also prognostic of RFS in non-CMS4 samples in COAD (p = 0.005). Conclusions: ColotypeR identifies the consensus molecular subtypes (CMS1, CMS2, CMS3, CMS4, or mixed), and assesses subtype-specific risk of recurrence of colon cancer. ColotypeR identifies prognostic risk and molecular features that could help guide the management of colon cancer patients.
Initial therapy with FOLFOXIRI plus bevacizumab (bev) for RAS mutant metastatic colorectal cancer (mCRC) and gene mutations in circulating tumor DNA (ctDNA) as a predictive marker for the efficacy: JACCRO CC-11.
Authors: Sunakawa Yu , Satake Hironaga , Usher Joshua L. , Jaimes Yolanda S , Miyamoto Yuji , Nakamura Masato , Nakayama Hiroshi , Sugano Nobuhiro , Takagane Akinori , Gotoh Masahiro , Watanabe Takanori , Ishigure Kiyoshi , Tanaka Chihiro , Takeuchi Masahiro , Fujii Masashi , DANENBERG KATHLEEN , Lenz Heinz-Josef , Sekikawa Takashi , Ichikawa Wataru 
Published: January 2019

635 Background: We have reported that modified (m)-FOLFOXIRI plus bev was feasible and had a good objective response rate (ORR) for Japanese patients (pts) in a phase II trial of the JACCRO CC-11 (ESMO 2017 #543P). In addition, a pre-planned research was performed to investigate if the change of gene mutations in ctDNA during therapy can serve as a predictor for clinical outcomes in RAS mutant mCRC. Methods: The efficacy of m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², levofolinate 200 mg/m², and fluorouracil 2400 mg/m² repeated biweekly) plus bev was evaluated prospectively in 62 pts (median age 63, 55% male, 92% PS0, and 27% right-sided tumors) with mCRC harboring RAS mutation (mt). The primary endpoint was ORR. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8w, and progression) and analyzed for specific KRAS, NRAS, BRAF, and PIK3CA variants with real-time PCR assays. Results: Updated median follow-up time was 10.2 months. ORR and disease control rate were 75.8% and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.6%. Median PFS was 11.5 months (95%CI 9.5-14.0). KRAS/ NRAS mt from pre-treatment plasma was confirmed in 79% of pts. In 41 pts with RAS mt at pre-treatment, mt status at 8 weeks predicted clinical outcomes (Table). Moreover, combined assessment of mt in ctDNA and ETS served as a refined predictor for efficacy. Pts with PIK3CA mt at pre-treatment had a poor outcome (ORR, 43%; median PFS, 8.8 months). Conclusions: FOLFOXIRI plus bev regimen is active for RAS mutant mCRC. RAS mt in ctDNA and ETS evaluation might potentially be a useful on-treatment biomarker in mCRC pts with RAS mt. Clinical trial information: UMIN000015152. [Table: see text]