bluuebunny/crossref_metadata_2025_split huggingface dataset:
cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.
Authors: Harle Alexandre , Gavoille Celine , Bouche Olivier , Ben Abdelghani Meher , Plaza Jérôme Edouard , Lambert Aurélien , Spaeth Dominique , Boudrant Axelle , Ghiringhelli François , Villing Anne-Laure , Borg Christophe , Rouyer Marie , Husson Marie , Gilson Pauline , Polet Fabienne , Jones Frederick S. , Edelstein Dan , Baumard Florian , Salleron Julia , Merlin Jean-Louis 
Published: May 2019

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.
ctDNA as a potential prognostic marker for locally advanced rectal cancer patients with ‘watch and wait’ approach.
Authors: Yang Lifeng , Wang Yaqi , Bao Hua , Wan Juefeng , Fan Xiaojun , Bao Hairong , Shen Lijun , Guan Yun , Wu Xue , Shao Yang , Zhu Ji , Zhang Zhen 
Published: May 2019

3544 Background: ‘Watch and Wait’ policy has currently led to growing interest for organ-preservation after neoadjuvant chemoradiation (nCRT) to improve quality of life. However, how to predict and select patients who may achieve clinical complete response is still an unsolved issue. We conducted a pilot study to evaluate the potential role of ctDNA as a biomarker to predict treatment outcome and improve risk stratification in locally advanced rectal cancer (LARC). Methods: In this study, we recruited 119 patients with LARC receiving nCRT. 595 serial plasma samples were collected at d0, d15, d25 of radiotherapy as well before and 7 days post surgery. The level of ctDNA was calculated by dynamic monitoring the mutant allele frequency of somatic mutations in plasma. Plasma and tissue samples were subjected to targeted-NGS using a 422 cancer-related genes panel. We followed up patients with concomitant CT until disease progression or death. Results: Detected mutation of TP53 and APC gene in pre-treatment samples was negatively correlated with patients’ response to nCRT. Alterations in homologous recombination and adherens junction pathways were associated with a better response (P < 0.05). Detection of pre-treatment mutations in any time points during nCRT was significantly (P = 0.03) decreased from TRG3 to TRG0 group (33%, 29%, 22% and 4%, respectively); while detection of acquired mutations showed an opposite trend (P = 0.04). A predictive model based on support vector machine was developed for prediction of pCR achieving a mean AUC of 0.85 assessed by repeated cross validation. Further, detection of pre-treatment mutations after completion of nCRT was significantly associated with worse disease-free survival (DFS) (P < 0.05). Through tracking clonal extinction, persistence and emergence, patients were grouped into four evolutionary subtypes with distinct TRG and DFS. Conclusions: Our data showed the prognostic value of ctDNA on DFS. Dynamic monitoring of ctDNA can be used to predict TRG and prognosis in LARC patients receiving nCRT. ctDNA sequencing depicts the evolutionary trajectories of sensitive and resistant clones during nCRT in LARC. CtDNA could potentially be used to guide patient selection for W&W strategy.
Randomized phase II trial of adjuvant hepatic arterial infusion (HAI) + systemic FOLFIRI +/- panitumumab (Pmab) in patients with resected RAS wild type colorectal cancer hepatic metastases (CRLM).
Authors: Kemeny Nancy E. , Hauser Haley , Capanu Marinela , Kingham T. Peter , Jarnagin William R. , DeMatteo Ronald P. , Cercek Andrea , Balachandran Vinod P. , Drebin Jeffery A. , D'Angelica Michael Ian 
Published: May 2019

3555 Background: HAI therapy has improved recurrence free (RF) survival in several randomized trials after resection of CRLM. The purpose of this trial was to determine whether systemic Pmab added to adjuvant HAI + FOLFIRI in RAS WT pts increases 15 months RF survival (RFS) after liver resection. Secondary endpoints are evaluation of overall survival, toxicity, and predictive biomarkers. Methods: RAS WT pts with resected liver mets were randomized to HAI + SYS (+/-) Pmab after stratification by clinical risk score (≥ 3 or < 3) and previous chemotherapy (Y/N). For a particular arm, if 24 or more patients (pts) were alive and RF at 15 months, the regimen in that arm would be considered worthy of further investigation. The initial dose of HAI FUDR 0.12mg/Kg + dexamethasone was infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 (irinotecan 125 mg/m2, LV 400 mg/ m2, 5FU 1000 mg/m2 48-hour continuous infusion and +/- Pmab 6mg/kg). Patient characteristics were compared between arms using Fisher’s exact test and Wilcoxon rank-sum test. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: After randomization of 75 pts, the arm receiving + Pmab met the decision rule of having ≥ 24 patients alive and RF at 15 months. The two arms had similar pt characteristics and toxicity, with the exception of Pmab related rash (Table). The 15-month RFS is 79% and 67% in +/- Pmab arms, respectively. With a median follow-up of 45 months, 3-year RFS is 65% [CL 0.45-0.78] and 42% [CL 0.24-0.57], and 3-year survival is 96% and 90% in +/-Pmab arms, respectively. Conclusions: In this trial, the addition of Pmab to HAI and SYS showed promising activity without increase in biliary toxicity and should be further investigated in a larger study. Predictive biomarkers will be presented. Clinical trial information: NCT01312857. [Table: see text]
A phase I study of PolyPEPI1018 vaccine plus maintenance therapy in patients with metastatic colorectal cancer with a predictive biomarker (OBERTO).
Authors: Hubbard Joleen Marie , Cremolini Chiara , Graham Rondell P , Moretto Roberto , Mitchelll Jessica L , Wessling Jaclynn , Toke Eniko Rita , Csiszovszki Zsolt , Lőrincz Orsolya , Molnar Levente , Somogyi Eszter , Megyesi Mónika , Pantya Kata , Tóth József , Miklós István , Lisziewicz Julianna , Lori Franco , Falcone Alfredo 
Published: May 2019

3557 Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequently expressed in mCRC. These epitopes were designed to be Personal EPItopes (PEPIs), i.e. predicted by our novel PEPI test to bind to at least three autologous HLA alleles and more likely to induce T-cell responses than epitopes presented by a single HLA. Methods: mCRC patients in the first line setting received the vaccine (dose: 0.2 mg/peptide) just after the transition to maintenance therapy with a fluoropyrimidine and bevacizumab. Vaccine-specific T-cell responses were first predicted by the PEPI test (using the patient’s complete HLA genotype and antigen expression rate) and then measured by ELISpot after one cycle of vaccination. Results: Eleven patients were vaccinated with PolyPEPI1018. The most common adverse events were transient skin reactions (local inflammation at the site of the injections, e.g. erythema, redness and itchiness) and flu-like syndrome. No grade 3 or higher adverse events related to the vaccine occurred. Initial analysis on 4 patients demonstrated that T-cell responses were elicited by 96% of vaccine peptides. The overall percentage agreement between PEPI test-predicted and Elispot-measured CD8+ T cell responses was 71%, consistent with our retrospective analysis on 64 vaccine clinical trials involving 1,790 patients. Two of these 4 patients had unexpected tumor size reduction. Based on these encouraging results, the trial was amended to administer 3 doses of PolyPEPI1018 given 12 weeks apart. Conclusions: PolyPEPI1018 combined with maintenance therapy was safe and well-tolerated in mCRC patients. Unprecedented immune responses were induced after single dose, with broad CRC-specific T cell responses and high accuracy prediction of CD8+ T cell responses. This promising activity in mCRC patients led to a trial amendment to administer 3 doses of PolyPEPI1018 in combination with systemic therapy. Clinical trial information: NCT03391232.
Feasibility of a national expert panel to determine resectability in patients with initially unresectable colorectal cancer liver metastases (CRLM).
Authors: Bolhuis Karen , Huiskens Joost , Dejong Cornelis H.C. , Engelbrecht Marc R.W. , Gerhards Michael F. , Grunhagen Dirk J. , de Jong Koert P. , Kazemier Geert , Klaase Joost M. , Liem Mike S.L. , van Lienden Krijn P , Molenaar I. Quintus , Patijn Gijs A. , Rijken Arjen M. , Ruers Theo M. , Swijnenburg Rutger-Jan , Verhoef Cornelis , de Wilt Johannes H.W. , Punt Cornelis J. A. , van Gulik Thomas M 
Published: May 2019

3562 Background: Decision on optimal treatment strategy for CRLM remains complex because uniform (un)resectability criteria are lacking. We hypothesize that the use of an expert panel can improve the identification of patients with potentially resectable CRLM. The Dutch Colorectal Cancer Group (DCCG) Expert Panel was established in conjunction with the CAIRO5 study (Huiskens J et al. BMC Cancer 2015), a multicenter, randomized, phase-3 trial, investigating optimal systemic induction treatment in patients with initially unresectable CRLM. Here, we present the feasibility of this panel. Methods: The DCCG Expert Panel consists of 13 liver surgeons and 4 radiologists. Consensus was reached on predefined (un)resectability criteria at baseline. An online platform allowed resectability-assessment by 3 surgeons in case of inter-surgeon agreement, and 5 surgeons if they disagreed. CRLM were assessed as 1) resectable 2) potentially resectable, or 3) permanently unresectable. Patients with initially unresectable CRLM were evaluated at baseline and subsequently every 2 months as long as CRLM were considered potentially resectable. Results: Overall, 397 panel evaluations in 183 patients were analyzed. Median time to panel conclusion was 7 days (IQR 5-11 days) and 204 (51%) evaluations showed inter-surgeon disagreement, with major disagreement (resectable versus permanently unresectable) in 24 (14%) and 12 (29%) evaluations after 2 and 4 months of systemic treatment. Ultimately, 84 (79%) patients with resectable CRLM underwent resection and 23 (27%) resections included portal vein embolization or 2-stage procedures. In resectable CRLM with inter-surgeon agreement versus disagreement, R0 resection was achieved in 39 (75%) versus 28 (52%) patients, p = 0.013. Median time to recurrence was similar between resections with panel agreement versus disagreement, 8 versus 6 months, p = 0.447. Conclusions: This study shows the feasibility of a national Liver Expert Panel for prospective resectability assessment of patients with initially unresectable CRLM. High inter-surgeon disagreement supports the use of a panel. We aim to further validate the panel with outcome parameters. Clinical trial information: NCT02162563.
Factors affecting differential outcomes in the definitive treatment of anal cancer between HIV+ and HIV- patients.
Authors: Susko Matthew , Kim Stephanie , Lazar Ann , Laffan Angela , Feng Mary Uan-Sian , Venook Alan P. , Atreya Chloe Evelyn , Van Loon Katherine , Anwar Mekhail 
Published: May 2019

3572 Background: Anal cancer is an uncommon malignancy with numerous factors that influence treatment outcomes. Historically, HIV+ patients were restricted from entering clinical trials, limiting data on their outcomes to small retrospective reports. This study seeks to understand the factors related to anal cancer outcomes, specifically the differences between HIV+ and HIV- patients. Methods: Inclusion criteria was non-metastatic anal squamous cell carcinoma treated with a definitive course of chemotherapy and radiation between 2005 and 2018 at a single institution. Clinical data related to baseline characteristics, treatment parameters, and post-treatment follow-up were extracted for calculation of freedom from local recurrence (FFLR) and overall survival (OS). Univariate analysis (UVA) and multivariate analysis (MVA) were done using cox proportional hazard model, and FFLR and OS were calculated using the Kaplan-Meier method. Results: During the study period, 111 patient initiated definitive treatment for anal cancer. Median age was 56.7 years (IQR: 51.4-63.5), and 47% (N = 52) were HIV+. At median follow-up of 28 months, 12 and 24-month FFLR was 84.1% and 78.2% respectively, with 24-month OS of 87.3%. MVA demonstrated significant association between FFLR and T-stage HR 4.02 (95% CI: 2.14-7.55) p < 0.001, elapsed treatment time (median of 50 days) 1.08 (95% CI: 1.04-1.12) p < 0.001, and diagnosis to treatment start (median time of 15 weeks) 1.05 (95% CI: 1.01-1.08) p = 0.005. Additional analysis with log-rank test for FFLR demonstrated significant difference between patients taking < 50 days to complete treatment (p = 0.03), and < 15 weeks from diagnosis to treatment completion (p = 0.006). In HIV+ patients, post-treatment CD4 < 150 was significantly associated with worse OS on log-rank test (p = 0.016), with pretreatment CD4 values being non-significant. Conclusions: This study represents the largest single institution report of HIV positive patients treated for anal cancer. No difference in local recurrence or overall survival between HIV+ and HIV- patients was elucidated; however, HIV+ patients with lower post-treatment CD4 counts had worse OS. The most significant predictors of local recurrence were advanced T-stage, increased time from diagnosis to treatment initiation, and prolonged treatment time.
Combination of tissues analysis and immune infiltrate in localized colon cancer using artificial intelligence in PETACC8 study.
Authors: Reichling Cynthia , Taieb Julien , Derangere Valentin , Le Malicot Karine , Emile Jean Francois , Gornet Jean Marc , Becheur Hakim , Fein Francine , Cojocarasu Oana , Kaminsky Marie-Christine , Lagasse Jean-Paul , Luet Dominique , Nguyen Suzanne , Etienne Pierre-Luc , Gasmi Mohamed , Vanoli Andr , Perrier Herve , Klopfenstein Quentin , Lepage Come , Ghiringhelli Francois 
Published: May 2019

3574 Background: We used artificial intelligence to perform tissue classification and count CD3 and CD8 in each subclass and determined their role in outcome prediction in PETACC8 cohort of stage III colon cancer treated with FOLFOX or FOLFOX plus cetuximab. Methods: We developed artificial intelligence aimed to detect tumor, healthy mucosa, stroma and immune cells on whole slide of CD3 and CD8 staining. The invasive margin (IM) was also automatically determined. Using a lasso algorithm, the software was able to detect digital parameters within the tumor core (TC) which were related to patients’ outcome (variable called DGMate for DiGital tuMor pArameTErs). CD3 and CD8 lymphocytes density were also quantified automatically by the software in TC and at IM. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for age, T/N stage, sidedness, KRAS/BRAF, DNA mismatch repair (MMR). Results: On 1220 samples collected, data could be generated for 1018 patients. We observed that a high IM stromal area and a high DGMate were associated with a poorer DFS [HR 5.65 (95% CI, 2.34, 13.67), p < 0.0001; HR 2.72 (95% IC, 1.92, 3.85), p<0.001 respectively for the continuous variable]. A higher density of CD3+ TC, CD3+ IM and CD8+ TC were significantly associated with a longer DFS (HR 0.75 (95% IC, .66, .87), p<0.0001; HR 0.78 (95% IC, .68, .88), p<0.0001; HR 0.83 (95% IC, .71, .96), p=0.01). All these immune variables were significantly correlated with each other. ANOVA test demonstrated that CD3+ TC gave a similar prognostic value compared to the classical CD3/CD8 immunoscore (p=0.44). The combination of IM stromal area, DGMate and CD3 outperformed the classical CD3/CD8 immunoscore to estimate patients’ prognosis (C-index= 0.601 vs 0.578, p-value=0.04). Adding this new variable to classical clinical prognostic parameters we generated a nomogram which predicted the risk of relapse of stage III colon cancer with a stronger predictive value compared to clinical parameters or the immunoscore. Conclusions: We propose a new fully automated method of whole slide analysis using a software based on artificial intelligence which classify tissue and determine tumor and immune parameters on one single slide stained with CD3 antibody. This valuable strategy outperforms immunoscore and clinical outcome prediction models.
Dissection of the lateral lymph nodes with short axis of ≥ 5 mm affects the prognosis in rectal cancer patients: A central review of 738 lower rectal cancer magnetic resonance images.
Authors: Hida Koya , Nishizaki Daisuke , Sumii Atsuhiko , Sakai Yoshiharu , Konishi Tsuyoshi , Akagi Tomonori , Yamaguchi Tomohiro , Akiyoshi Takashi , Fukuda Meiki , Yamamoto Seiichiro , Uemura Mamoru , Hasegawa Hirotoshi , Okamura Ryosuke , Yamamoto Michio , Kawada Kenji , Morita Satoshi , Watanabe Masahiko 
Published: May 2019

3578 Background: The usefulness of lateral lymph node dissection (LLND) for lower rectal cancer has been discussed. Concerning relapse-free survival (RFS), in the JCOG0212 trial, the non-inferiority of avoiding LLND for rectal cancer without LLN enlargement of ≥10 mm was not shown; however, the superiority of LLND was also not demonstrated. Methods: To examine whether the difference in dissection effect could be demonstrated by the size of LLN, magnetic resonance imaging (MRI) for the central review of pre-registered patients with stages II/III lower rectal cancer below the peritoneal reflection was performed, and the prognosis of the patients were prospectively investigated as a cohort. The relationship between LLND and RFS was also evaluated. Results: MR images of 738 cases (mean distance from anal verge: 4.5 cm) were evaluated. Twenty patients with LLN enlargement of ≥10 mm were excluded from the analysis. Overall, of 718 patients, 310 did not undergo LLND (non-LLND group), whereas the other 408 underwent LLND (LLND group). The lymph node sizes of ≥5 mm were observed in 10.0% and 21.1% of patients in the non-LLND and LLND groups, respectively. Although there was some bias in the background characteristics of the two groups (non-LLND vs. LLND; median age 66 vs. 61 years; laparoscopic surgery 64.2% vs. 17.9%; preoperative treatment 39.4% vs. 27.9%; circumferential resection margin evaluated by MRI 37.3% vs. 49.9%; and postoperative complications 33.2% vs. 44.4%), almost no difference in the 5-year RFS was observed (63.4% vs. 67.5%).The LLND group had significantly more favorable with ≥5 mm LLN (non-LLND 51.6% vs. LLND 69.0% P = 0.023) than with < 5 mm LLN (non-LLND 64.7%; LLND 67.0%). Conclusions: Oncological benefit of LLND was suggested in patients with enlarged lateral nodes on MRI using a large cohort of clinical stage II/III lower rectal cancer.
Population-based screening for BRAF V600E in metastatic colorectal cancer (mCRC) to reveal true prognosis.
Authors: Chu Jenny E. , Johnson Benny , Morris Van K. , Raghav Kanwal Pratap Singh , Swanson Lucas , Lim Howard John , Renouf Daniel John , Gill Sharlene , Wolber Robert , Karsan Aly , Schaeffer David F. , Kopetz Scott , Loree Jonathan M. 
Published: May 2019

3579 Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text]