bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of genomic alterations and biomarker expression patterns of gastrointestinal cancers using a multiplatform molecular profiling tool.
Authors: Suero-Abreu Giselle Alexandra , Gonzalez Velez Miguel , McKenna Marshall , Duma Narjust , Krishnasamy Shalini R , Proverbs-Singh Tracy Ann , Gutierrez Martin
Published: January 2019

594

Background: Given the heterogeneity of gastrointestinal cancers (GICs), molecular profiling is becoming part of the standard of care for many solid tumors. The aim of this study was to evaluate the molecular profile of patients (pts) with GICs using a multiplatform profiling tool and to assess how the pattern of detected molecular alterations could guide clinical decision-making in these tumors. Methods: We retrospectively analyzed samples of 85 pts with GICs via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) in order to evaluate clinically relevant genomic alterations (CRGAs) and clinically relevant biomarker expression (CRBs) in GICs. Results: A total of 85 pts with GICs were analyzed. 45 (53 %) were males and 40 (47%) were females. Tumors were colorectal 43 (51%), pancreatic 11 (13%) esophageal 11 (13%) gastric 8 (9%), hepatobiliary 8 (11%), anal canal 3 (4%), and small intestine 1 (1%). 80 cases (94%) had adequate sample for profiling. CRGAs were identified in 71 cases (89%) with a median of 3 CRGAs in the cohort. The most commonly detected CRGAs were TP53 45 (56%), APC 35 (44%), KRAS 32 (40%), ATM 14 (18%) and PTEN 5 (6%). The median number of CRBs was 9 and high expression levels were seen of mismatch repair biomarkers (MLH1, MSH2, MSH6, PMS2) in 45 (56%), TOPO1 in 44 (55%), PTEN in 27 (34%), TOP2A in 20 (25%), ERCC1 in 19 (24%), and both TS and TUBB3 in 17 (21%). Based on actionable CRGAs and CRBs, 94% of pts matched at least one FDA approved treatment with proven clinical benefit, with a median of 4 available therapies per pt. In addition, there was a median of 189 chemotherapy and 64 targeted therapy clinical trial opportunities available for these pts given the molecular blueprint of their GICs. Conclusions: Multiplatform molecular profiling identified a high frequency of actionable CRGAs and CRBs in GIC pts. This approach has the potential to aid in clinical decision-making by providing a stratification of beneficial therapeutic alternatives individualized to the molecular framework of tumor. Larger prospective studies are warranted to further investigate the impact of profiling guided treatment decisions on patient outcomes.
Polyp burden in Lynch syndrome patients ascertained via multigene panel testing.
Authors: Roberts Maegan , Marshall Megan L. , Webb Erica M , McGill Anna K. , Susswein Lisa R. , Xu Zhixiong , Klein Rachel T. , Hruska Kathleen S.
Published: January 2019

596

Background: Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), is a hereditary colorectal cancer syndrome thought to present with few or no polyps. It has been suggested that the majority of LS patients with colon polyps will develop 1-9 cumulative adenomatous polyps in their lifetime, while approximately 10% will develop ≥10. Our aim was to describe polyp burden in a cohort of LS patients who were ascertained via multi-gene cancer panel testing. Methods: We retrospectively reviewed the personal history for all individuals with a pathogenic or likely pathogenic variant (collectively, PV) in MLH1, MSH2 (including 3’ EPCAM deletions), MSH6, or PMS2. Individuals with more than one PV in a LS-associated or other gene were excluded. All polyp data was obtained from provided test requisition forms and/or pathology reports. Results: A total of 131 individuals reported to have colon polyps were molecularly confirmed as having LS. Of these individuals, 55% (72/131) reported a history of colorectal cancer. Overall, polyp burden was reported as follows: 83% (109/131) with 1-10 polyps, 13% (17/131) with 10-19 polyps, and 4% (5/131) with 20-50 polyps. Of the 5 individuals reporting 20-50 polyps, the average was 31.2 polyps (range 21-50). Adenomatous pathology was reported for one or more polyps in 69% (91/131) of individuals. When limited to those with adenomatous polyps, 85% (77/91) reported 1-10 polyps, 11% (10/91) reported 10-19 polyps, and 4% (4/91) reported 20-50 polyps. When breaking down by presence and absence of colorectal cancer, 18% (13/72) and 15% (9/59), respectively, reported a polyp burden ≥10. Overall, 17% (22/131) of all LS patients reported ≥10 polyps. Conclusions: Similar to previously published data, the majority of LS patients with colon polyps report a polyp burden of < 10. However, our data suggest that the proportion of LS patients with a polyp burden of ≥10 may be higher than previously reported (17% vs. 10%) stressing the importance of including the LS-associated genes for these patients. While LS has historically been referred to as a “non-polyposis” syndrome, a subset of patients actually present with an attenuated polyposis-like phenotype.
Prospective randomized controlled trial comparing efficacy of 1-L Peg-Asc with prucalopride and 2-L Peg-Asc for the bowel preparation.
Authors: Choi Seong Ji , Jeen Yoon Tae , Kim Eun Sun , Kim Woojung , Min Geeho , Lee Jae Min , Kim Seung Han , Yoo In Kyung , Choi Hyuk Soon , Keum Bora , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck
Published: January 2019

597

Background: Though numerous researches enabled decrease of the bowel preparation solution volume, it is still a major complaint of patients preparing colonoscopy. There have been studied that additional administration of laxatives could lessen the amount of aqueous formula with prokinetic effect. Prucalopride is a serotonin (5-HT4) receptor agonist which stimulate colonic mass movements and provide main propulsive force for defecation. The aim of this study is to compare 2-L PEG-Asc and 1-L PEG-Asc plus prucalopride for quality of bowel cleansing while preparing for colonoscopy and patient compliance. Methods: Two hundred patients were prospectively enrolled. Patients referred for colonoscopy were divided into group A (the split-dose 2-L PEG-Asc) and group B (1-L PEG-Asc + prucalopride) randomly. During colonoscopy, each patient’s bowel preparation quality was evaluated with The Boston Bowel Preparation Scale (BBPS) and Aronchick Preparation Scale (APS). The tolerability and satisfaction of patients was determined based on a questionnaire-based survey. Results: One hundred patients received either 2-L PEG-Asc or 1-L PEG-Asc with prucalopride. Regarding colon cleansing outcome (BPPS and APS), the 1-L PEG-Asc with prucalopride group showed similar, but non-inferior results compared to the 2-L PEG-Asc group on both BBPS (7.65±1.27 vs 7.52±1.40, p = 0.586) and APS scales (93.3% vs 95%, p = 0.717). Tolerability was similar for both 1-L PEG-Asc with prucalopride and 2-L PEG-Asc. Conclusions: 1-L PEG-Asc plus prucalopride preparation showed comparable result to traditional 2-L PEG-Asc preparation. 1-L PEG-Asc plus prucalopride preparation method could be an alternative method for bowel preparation which can relieve patient’s discomfort. Clinical trial information: KCT0002409.
Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.
Authors: Khushman Moh'd M. , Patel Girijesh K. , Hosein Peter Joel , Laurini Javier , Cameron Daniel , Clarkson David Roland , Butler Thomas Wayne , Norden Carole , Baliem Wilma , Jones Vanessa , Bhadkamkar Sanjyot , Nelson Cindy , Lee Frances , Singh Ajay , Taylor William R.
Published: January 2019

598

Background: The correlation between DPYD*9A (c.85T > C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines. Methods: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher’s exact test was used for statistical analysis. Results: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N = 28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P = 0.0055). Conclusions: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea).
Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: A randomized controlled trial.
Authors: Van Der Sluis Pieter Christiaan , van der Horst Sylvia , May Anne Maria , Schippers Carlo , Brosens Lodewijk , van Dijk Wouter , Joore Hans , Kroese Christiaan , Haj Mohammad Nadia , Mook Stella , Vleggaar Frank P. , Borel Rinkes Inne , Ruurda Jelle , van Hillegersberg Richard
Published: January 2019

6

Background: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) may reduce perioperative complications and improve functional recovery. Methods: In this randomized controlled trial, 112 patients with resectable intrathoracic esophageal cancer were randomly assigned to RAMIE or OTE. The composite primary endpoint was the occurrence of overall postoperative complications (modified Clavien–Dindo classification (MCDC) grade 2-5). Results: Postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) (RR 0.74 (0.57-0.96; P = 0.02). RAMIE resulted in a less median blood loss (400ml versus 568ml, P < 0.001), a lower percentage of surgery-related complications (RR 0.74 (0.57-0.96; P = 0.02), pulmonary complications (RR 0.54 (0.34-0.85; P = 0.005) and cardiac complications (RR 0.47 (0.27-0.83; P = 0.006)) and lower mean postoperative pain (visual analogue scale, 1.86 versus 2.62; p < 0.000) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group (RR 1.48 (1.03–2.13; P = 0.038)) with better quality of life score at discharge (mean difference quality of life score 13.4 (2.0-24.7, p = 0.02) and 6 weeks post-discharge (mean difference 11.1 quality of life score (1.0-21.1; p = 0.03)). Mean costs for RAMIE were €34.892 and mean costs for OTE were €39.463 (p = 0.07). Oncological outcomes at short term (radicality, number of lymph nodes) and long term (overall and disease-free survival) were equal at a medium follow up of 38 months. Conclusions: RAMIE resulted in a lower percentage of overall, surgery-related and (cardio)pulmonary complications with lower postoperative pain, better quality of life and a better short term postoperative functional recovery compared to OTE. Oncological outcomes were equal. This randomized controlled trial provides evidence for the use of RAMIE to improve postoperative outcome in patients with resectable esophageal cancer. Clinical trial information: NCT01544790.
Association of minimally invasive colorectal resection with elevated levels of plasma B7 homolog 1 (B7-H1) during the first month after surgery and effect on immune suppression and growth of residual metastases.
Authors: Kumara Hmc Shantha , Pettke Erica , Winkler Carl S , Jaspreet Sandhu K , Yan Xiaohong , Vesna Cekic , Gandhi Nipa Dilip , Whelan Richard L
Published: January 2019

602

Background: The co-stimulatory molecule B7 homolog 1 (B7-H1) is a ligand for PD-1 which is an immunoinhibitory receptor of activated lymphocytes. PD-1 expression is upregulated on tumor infiltrating lymphocytes (TILs), and B7-H1 expressed on cancer cells may inhibit T-cell activation and proliferation. B7-H1 is also expressed on endothelial (EC) and intestinal epithelial cells as well as activated macrophages. B7H1 in EC is rapidly induced by IFN-gamma and TNF. B7-H1 silencing with siRNA inhibits tumor cell proliferation/invasion. B7H1 expression in keratinocytes (KC) directly downregulates CD8(+) T-cell effector function via PD-1 binding at sites of inflammation. Shed B7-H1 can be found in the blood. Surgery’s impact on plasma B7H1 levels is unknown. This study’s purpose was to evaluate plasma B7H1 levels during the first month after MICR for colorectal (CRC). Methods: MICR CRC patients in an IRB approved data/plasma bank with adequate plasma available were eligible. Clinical and pathological data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41). B7-H1 levels were analyzed in duplicate using ELISA. The Wilcoxon test was used for analysis. Results: 88 CRC patients who had a MICR met inclusion criteria (28% rectal and 62% colon lesions). The mean PreOp B7-H1 level was 51.9±20.9 pg/ml. Significantly elevated mean plasma levels were noted on POD1 (64.9±24.2 pg/ml, n = 86, p = < 0.0001), POD3 (67.3±24.6 pg/ml, n= 72, p = < 0.0001), POD7-13 (69.2±22.6 pg/ml, n = 65, p = < 0.0001), POD14-20 (72.5±28.9 pg/ml, n=23,p=0.001), POD 21-27 (79.4±66.6 pg/ml, n = 13, p = 0.001), and on POD 28-41 (56.3 ±22.7 pg/ml, n = 20, p =0.02), when compared to PreOp levels. Conclusions: Plasma B7-H1 levels are elevated for over a month after MICR for CRC. The etiology of the early increase may be the acute inflammatory response whereas late elevations may be related to wound healing-related tissue remodeling. Elevated plasma B7-H1 may suppress TIL’s which may result in increased tumor growth. Further studies are warranted.
Time to adjuvant chemotherapy in CEA-positive colon cancer: An NCDB analysis.
Authors: Zhang Yang , Aurit Sarah J , Satish Mohan , Chau Eugene , Silberstein Peter T.
Published: January 2019

603

Background: It is well accepted that positive serum carcinoembryonic antigen (CEA) levels are associated with inferior survival in patients with advanced non-metastatic colon cancer; however, it is not fully elucidated whether this prognostic factor can inform clinical decisions, specifically for the optimal timing of adjuvant chemotherapy after definitive surgical treatment. This study was aimed to determine the relationship between onset of adjuvant chemotherapy and rate of survival in stage III colon cancer patients who tested CEA-positive, and thus, potentially identifying the optimal timing to increase survivorship. Methods: We identified 19,180 patients from the NCDB with TNM pathologic stage IIIB and IIIC adenocarcinoma of the colon who also had a recorded CEA test result and whom had received adjuvant chemotherapy. We examined unadjusted overall survival based on CEA status with the Kaplan-Meier method. A multivariable Cox regression model was estimated to determine the association of CEA status and overall survival after controlling for site, stage, days from surgery to chemotherapy, demographic background, and facility characteristics. All analyses were conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC) with a statistical threshold of p < 0.05. Results: Based on the log-rank χ2 test, a positive CEA test result was significantly associated with worse survival. We adjusted for patient and facility level characteristics, and found a 49.7% increased risk of death for a patient with a positive CEA result (95% CI: 41.7% to 58.2%). We found a median number of 43 days from definitive surgery to initiation of chemotherapy; after adjusting for all other variables, we found for every ten-day delay in receiving adjuvant therapy after definitive surgical intervention, there was a 1.6% increased risk of death (95% CI: 1.0 to 2.2%). Conclusions: In this cohort of patients who tested CEA-positive, delays in receiving adjuvant chemotherapy had a negative linear association on survival. Adjuvant therapy should be considered as soon as patient’s clinical condition permits.
Oxaliplatin desensitization after hypersensitivity reaction: A single-center experience on more than 300 procedures.
Authors: Le Roy Florence , Rigault Eugénie , Regnault David , Hubert Nicole , Burtin Pascal , Hollebecque Antoine , Malka David , Boige Valerie , Ducreux Michel
Published: January 2019

610

Background: Oxaliplatin is an essential drug in gastrointestinal oncology. Hypersensitivity reactions (HSR) occur frequently (incidence varying from 10% to 25%), leading to permanent treatment discontinuation. The present study aimed to report our experience of oxaliplatin desensitization in patients with history of HSR to oxaliplatin. Methods: We retrospectively reviewed all patients who received at least one infusion of oxaliplatin according to a desensitization protocol after prior history of HSR to oxaliplatin, from June 2011 until June 2017. HSRs were classified from NCI CTC-AE grade 1 (transient rash, fever < 38°C) to grade 4 (anaphylaxis). We applied in all cases a desensitization protocol in which the oxaliplatin infusion rate is gradually increased from 1mL/hr. to 150mL/hr., on an inpatient basis. Intravenous or hepatic arterial infusion was used depending on clinical setting. Results: Overall, 54 patients were included in this study, in whom HSR to oxaliplatin occurred after a median of 9 infusions (range, 1-31). The severity of HSRs was grade 1-2 in 33 patients (61%) and grade 3-4 in 21 patients (39%). A total of 305 oxaliplatin infusions according to a desensitization protocol were performed in these 54 patients (median, 5 infusions; range, 1-20). These infusions were by intravenous route in 42 patients (78%), by hepatic arterial route in 11 patients (18%), and both in 2 patients (4%). Infusions were well tolerated in 41 patients (76%), without new HSR. The remaining 13 patients (24%) experienced HSR recurrence (grade 2, 9 patients [69%]; grade 3, 4 patients [31%]). No anaphylaxis or oxaliplatin-related death occurred. In the 21 patients with a prior history of severe (grade 3-4) HSR, oxaliplatin desensitization procedure was effective and sustained in 16 patients (79%). Among 32 evaluable patients, 23 (72%) experienced disease control (14 partial responses, 9 stable diseases). Conclusions: Rechallenging Oxaliplatin desensitization procedure was successful in three out of four patients with prior history of HSR to oxaliplatin. Our retrospective study confirms that oxaliplatin desensitization is safe, and allows patients who developed HSR to continue an effective treatment.
Evaluation of lesion-based response at 12 weeks (LBR12) of treatment (Rx) in metastatic colorectal cancer (mCRC): Findings from 9,092 patients (pts) in the ARCAD database.
Authors: Ou Fang-Shu , Lou Yiyue , Van Cutsem Eric , Saltz Leonard , Schmoll Hans-Joachim , Goldberg Richard M. , Hoff Paulo , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Punt Cornelis J. A. , Bokemeyer Carsten , Fuchs Charles S. , Diaz-Rubio Eduardo , Tebbut Niall , Falcone Alfredo , Kabbinavar Fairooz F. , De Gramont Aimery , Grothey Axel , Shi Qian
Published: January 2019

612

Background: mCRC is a heterogeneous disease leading to possible disparate responses among lesions in a single pt. This study assesses the heterogeneity of lesion responses and evaluates the prognostic value of LBR12 and its mortality risk discrimination beyond RECIST responses. Methods: Pts with ≥ 2 lesions and no new lesions at 12 weeks (wks) were eligible. For each pt, after 12 wks of Rx, each lesion was categorized as progressive disease (L-PD: ≥20% increase in the longest diameter [LD]), partial response (L-PR: ≥30% decrease in LD), or stable disease (L-SD: neither L-PD nor L-PR). LBR12 was defined, per patient, by the combination of lesion responses: homogeneous LBR12 (L-PD, L-SD, L-PR only) and heterogeneous LBR12 (mixture of L-PD/L-SD, L-PD/L-PR, L-SD/L-PR). LBR12 and overall survival (OS) were correlated using stratified multivariate Cox models after adjusting for age, gender, and ECOG PS. Results: Among 9,092 mCRCs (Rx: chemo alone 44%; chemo + VEGF inhibitor [VEGFi] 42%; chemo + EGFR inhibitor [EGFRi] 10%) from 16 1st-line studies. Median OS: 2.2 years. Per RECIST at 12 wks, CR 0%; PR 36.1%; SD 60.9%; PD 3.0%. Responses in 52% were heterogeneous (Table). VEGFi and EGFRi treated pts had the highest rate of L-SD/L-PR (45%) and L-PR only (22%) status, respectively. Median OS increased monotonically across pts with more L-PRs and fewer L-PDs (Table). Pts with L-SD/L-PR status, among which 51% had SD per RECIST, had longer OS than those with L-SD only status (HRadj.= .81, padj.< .0001), but shorter OS than those with L-PR only status (HRadj.= 1.46, padj.< .0001). Pts with L-PD/L-SD status, among which 71% were SD per RECIST, had shorter OS than those with L-SD only status (HRadj.= 2.22, padj.< .0001). These associations were consistent across treatment regimens. Conclusions: The lesion-based response captures the heterogeneity of within pt lesion responses and provides refinement in predicting outcome beyond RECIST response at 12 wks. [Table: see text]
Genomic evolution and acquired resistance to preoperative chemoradiation therapy (CRT) in rectal cancer.
Authors: Kamran Sophia C. , Lennerz Jochen K , Margolis Claire , Liu David , Reardon Brendan , Wankowicz Stephanie A , Wo Jennifer Yon-Li , Willers Henning , Corcoran Ryan Bruce , Van Allen Eliezer Mendel , Hong Theodore S.
Published: January 2019

613

Background: Following pre-operative CRT for locally advanced rectal cancer, ~20% of patients achieve a pathologic complete response and 20-40% have little to no response (NR) at time of surgery. Pathologic downstaging after CRT is associated with improved outcomes but molecular predictors of response are poorly understood. The objective of this study was to characterize somatic mutations and derive genomic biomarkers distinguishing complete and excellent partial responders (R) vs NR through whole exome sequencing (WES) in pre- and post-CRT tumor samples. Methods: Rectal cancer patients treated with pre-operative CRT and having either a R or NR were identified. DNA extraction from clinical FFPE samples and WES were performed on pre/post-CRT tumor and matched germline DNA followed by genomic analysis to identify somatic mutations, insertion/deletions, and clonal/subclonal mutational evolution. RNA extraction/sequencing and GSEA was performed in parallel. Results: We identified 34 pre- and post-CRT matched tumor samples from 17 patients treated with pre-operative fluoropyrimidine-based CRT (50.4 Gy) followed by surgery within 8-10 weeks. Nine and 8 patients were classified as NR and R, respectively. All FFPE passed quality control metrics and were successfully sequenced. Mean somatic mutational burden pre-CRT was 3.78 mutations/Mb (rg, 2.25-8.43), which, unexpectedly, was not significantly increased in the post-CRT samples (4.23 mutations/Mb; rg, 1.74-8.96). NR cases had more concurrent KRAS/TP53 (KP) mutations than R cases (67% vs 13%, p < 0.05). Related to this finding, NR was associated with epithelial-to-mesenchymal transition (p < 0.001) and potentially linked to high intra-tumoral heterogeneity pre-CRT (p = 0.08). Conclusions: We have established feasibility and a pipeline for performing WES on pre- and post-CRT FFPE tumor samples. Our data suggest that evolution of CRT resistance is not through hypermutation. In conjunction with recent observations from our group (Hong, JNCI 2017; Wang, Cancer Res 2017), our findings strongly support the clinical utility of the KP genotype as a biomarker of CRT resistance and begin to offer insight into the underlying mechanisms on a genomic level.
Immunoscore to provide prognostic information in low- (T1-3N1) and high-risk (T4 or N2) subsets of stage III colon carcinoma patients treated with adjuvant FOLFOX in a phase III trial (NCCTG N0147; Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Hermitte Fabienne , Heying Erica N , Benson Al Bowen , Gill Sharlene , Goldberg Richard , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Sargent Daniel J. , Galon Jerome , Alberts Steven R.
Published: January 2019

614

Background: A consensus interpretation of the IDEA colon cancer study results suggested that risk categories based on T/N stage grouping be used to guide decision-making for duration (3 vs 6 months) of adjuvant FOLFOX or CapeOX chemotherapy. Given the prognostic potential of immune biomarkers, we examined the immunoscore and individual T and B lymphocyte markers in low and high risk T/N subsets of stage III colon carcinoma patients (N=600) treated with adjuvant FOLFOX. Methods: Immunoscore (CD3+, CD8+) and individual T-cell and CD20+ B-cell immunostain densities in central tumor (CT) and invasive margin (IM) of FFPE sections were quantified by image analysis. A predetermined immunoscore categorization was used [high (2-4) vs low (0-1)]. Individual markers were analyzed by backwards selection wherein CD3+ IM was most robust for prognosis and an optimized cutoff was then determined. Associations with disease-free survival (DFS) were analyzed by multivariable Cox regression adjusting for age, T/N stage, sidedness, KRAS/BRAF, and DNA mismatch repair. Results: In low and high risk T/N patient subsets, the immunoscore and CD3+ IM were each significantly discriminant for prognosis. Among low risk (T1-3N1) patients, a high vs low immunoscore was associated with a 91% vs 77% 3-year DFS [HR 0.57, 95% confidence interval (CI) 0.34-0.95, adjusted (adj) P= 0.026]. Among high risk (T4 or N2) patients, a high vs low immunoscore was associated with a 68% vs 54% 3-year DFS (HR 0.64, 95% CI 0.42-0.98, Padj= 0.034]. Similarly, a high vs low intratumoral CD3+ density at the invasive margin (IM) was significantly associated with prognosis in low risk [HR 0.37, 95% CI 0.21- 0.66), Padj< 0.0003] and in high risk [HR 0.47, 95% CI, 0.27- 0.80), Padj< 0.0028] patient subsets. Conclusions: Immunoscore and CD3+ IM were shown to prognostically stratify FOLFOX-treated patients within both low and high risk T/N subsets. These data underscore limitations of the T/N risk classification for adjuvant treatment decisions in stage III patients, and demonstrate the ability of T-cell markers to enhance prognostication to guide clinical decision-making.
Impact of microsatellite instability (MSI) on tumor clonal evolution in metastatic colorectal cancer (mCRC).
Authors: Willis Jason , Morelli Maria Pia , Morris Van Karlyle , Loree Jonathan , Lam Michael , Pereira Allan Andresson Lima , Raghav Kanwal Pratap Singh , Kee Bryan K. , Vilar Sanchez Eduardo , Eng Cathy , Manuel Shanequa , Crosby Shadarra , Wolff Robert A. , Lanman Richard B. , Talasaz AmirAli , Janku Filip , Overman Michael J. , Kopetz Scott
Published: January 2019

616

Background: For mCRC, the contribution of clinical and pathologic factors to concordance between formalin-fixed, paraffin-embedded (FFPE) tissue-based and ctDNA-based mutation profiling remains unclear. MSI is hypothesized to confer a higher rate of somatic alteration resulting in clonal evolution over time compared to microsatellite stable (MSS) patients, but this has not been previously confirmed. Methods: All mCRC patients were consented for a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]) using CLIA-certified platforms. Archived tumor DNA from primary or metastatic tissue was sequenced on a 46- or 50-gene panel (Ion Torrent). Paired ctDNA samples were isolated from blood and sequenced with an ultra high-sensitivity assay (Guardant360). Mutation data were normalized by excluding genomic regions not covered on both platforms and were filtered to remove germline or synonymous variants. Results: An initial cohort of 139 patients was included in our analyses, with a median of two lines of intervening chemotherapy between FFPE and plasma DNA collection; 6 (4.3%) of the patients had MSI (MSI-H) mCRC. We detected 472 total mutations in either tissue or ctDNA, with a global concordance rate of 34.5%. Global concordance was not associated with tissue source, nor treatment with specific standard cytotoxic and/or biologic agents. Mutations detected in MSI-H CRC showed significantly greater discordance compared to MSS CRC (OR = 2.5, p = 0.025). This finding was validated using an independent cohort of 17 MSI-H mCRC patients (OR = 2.78, p = 0.00015). Among recurrently altered genes, we found that MSI-H cases were significantly more likely to have gained new TP53 mutations (OR = 8.17, p = 0.001) and to have lost PIK3CA mutations (OR = 8.04, p = 0.036) in ctDNA compared to MSS cases. Conclusions: MSI correlates with discordance between tissue DNA and ctDNA-based mutation profiling, which suggests that MSI-H CRC undergoes distinct patterns of clonal evolution including acquisition of new TP53 mutations. This may have implications for targeted and immunologic therapies in this unique population, and suggests a utility for repeated molecular testing.
Associations of incidence of common adverse events (AEs) and survival outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first line chemotherapy: Findings from 9,812 pts in the ARCAD database.
Authors: Ferraro Danielle Angela , Zalcberg John Raymond , Shi Qian , Meyers Jeffrey P. , Seymour Matthew T. , Saltz Leonard , Maughan Tim , Goldberg Richard M. , Van Cutsem Eric , Heinemann Volker , Hurwitz Herbert , Falcone Alfredo , Diaz-Rubio Eduardo , Chibaudel Benoist , Fuchs Charles S. , Porschen Rainer , Bokemeyer Carsten , De Gramont Aimery , Price Tim , Adams Richard
Published: January 2019

617

Background: There is limited, often conflicting evidence about AE timing, severity or associations with outcomes with the use of cytotoxic agents in cancer treatment. We investigated the impact on overall survival (OS) and progression-free survival (PFS) of selected common AEs (neutropenia, diarrhea, nausea, vomiting, neuropathy) occurring in patients receiving first line oxaliplatin (Oxa)- and/or irinotecan(Iri)-based regimens for mCRC. Methods: The CTCAE grading scores of at least one AE of interest were available on 9812 pts treated with chemotherapy alone (median age 63; 62.4% male, 50.1% ECOG PS 0) from 17 1st-line randomized trials. Patients who also received biologics were excluded in the primary analyses. AEs occurring during the first 6 weeks of treatment and entire treatment were analyzed by stratified multivariable Cox models in relationship to OS/PFS. 55.7% pts received Oxa- regimens, 35.7% Iri-regimens, and 8.6% combined Oxa- and Iri-regimens. Results: Within the first 6 weeks of treatment, G3+ neutropenia (HRadj= 1.3, 95% CI, 1.06-1.59, padj 0.01), diarrhea (HRadj= 1.48, 95% CI, 1.23-1.79, padj < .0001), nausea (HRadj= 1.53, 95% CI, 1.17-1.99, padj 0.002) and vomiting (HRadj= 1.56, 95% CI, 1.18-2.07, padj 0.002) were associated with significantly worse OS for Iri-regimens, but only G3+ nausea predicted for worse OS for Oxa- regimens (HRadj= 1.61, 95% CI, 1.18-2.21, padj 0.003). For AEs experienced at any time, G3+ neutropenia and neuropathy were significantly associated with longer PFS and OS for Oxa-regimens, while G3+ vomiting and nausea were associated with worse OS for both Oxa- and Iri-based regimens. Sensitivity analysis showed largely concordant results by including pts who also received biologics. Conclusions: The association between more severe selected AEs and outcome varies between AEs and is influenced by timing of the occurrence. More severe selected AEs occurring early in treatment are associated with worse outcomes. In contrast, for AEs occurring at any time, G3+ neutropenia and neuropathy predicted for longer PFS and/or OS in Oxa-treated pts.
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.