bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical, pathological and prognostic features of rare BRAF mutations (MTs) in metastatic colorectal cancer (mCRC): A bi-institutional retrospective analysis (REBUS study).
Authors: Di Stefano Brunella , Calegari Maria Alessandra , Basso Michele , Orlandi Armando , Boccaccino Alessandra , Lombardo Fiorella , Zurlo Ina Valeria , Bensi Maria , Camarda Floriana , Vivolo Raffaella , Cocomazzi Alessandra , Martini Maurizio , Auriemma Alessandra , Pozzo Carmelo , Bria Emilio , Salvatore Lisa , Tortora Giampaolo 
Published: May 2019

3554 Background: Recently, 3 classes of BRAF MTs have been described. BRAF V600 MTs, which identify mCRC with poor prognosis and not benefitting from anti-EGFR drugs, belong to class 1. Class 2 and 3 include BRAF non-V600 MTs, which occur in about 1-2% mCRC and are associated to favourable prognosis and specific clinicopathologic features. Class 2 and 3 differ in kinase activity and sensitivity to anti-EGFR: class 2 are activated and RAS-independent MTs; class 3 are kinase-dead and sensitive to inhibition of This study aims to retrospectively evaluate features and prognostic role of rare BRAF non-V600 compared to BRAF V600E MTs in mCRC pts treated at 2 Italian Institutions. Methods: mCRC pts harboring BRAF MTs, assessed by means of NGS, pyrosequencing or RT-PCR, treated between Jan-13 and Dec-18 at 2 Italian Institutions, were retrospectively analyzed. Clinico-pathological and treatment characteristics and survival data were collected. Results: 55 pts bearing BRAF MTs were identified. Of those, 46 (84%) harbored a V600E and 9 (16%) a non-V600 MT. Within the non-V600 group, 3 MTs (K601E, G469A, G469R) belonged to class 2, while 5 MTs (G466E, G466A, 2 D594G, D594N), belonged to class 3. One pt harboured a T599I MT, whose kinase activity is unknown. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided ( p .017) and displayed a lower grade ( p .045). In addition, non-V600 mCRC pts had a lower tumor burden (involving one metastatic site) ( p .026) and underwent more frequently to resection of metastases with radical intent (77.7 vs 18%; p .000175). mOS was significantly longer in the non-V600 compared to the V600E group (61.3 vs 20.4 m; HR 0.41, 95%CI 0.18-0.93; p .05). No difference in activity and efficacy of anti-EGFR agents was observed between class 2 and 3. Conclusions: Despite the small size of our retrospective analysis, the results were consistent with previous evidences. BRAF non-V600 MTs identified a subgroup of mCRC, differing both in terms of clinicopathologic characteristics and prognosis from BRAF V600 mCRC. Interestingly, the better prognostic features allowed more frequently radical resection of metastases, positively impacting on survival.
Chemotherapy rechallenge or reintroduction (CTr/r), regofenib (REG) and TAS-102 for metastatic pretreated colorectal cancer (mCRC) patients (pts): A propensity score analysis of treatment beyond second-line (PROSERpINA Study).
Authors: Calegari Maria Alessandra , Zurlo Ina Valeria , Basso Michele , Orlandi Armando , Bensi Maria , Camarda Floriana , Di Stefano Brunella , Vivolo Raffaella , Pozzo Carmelo , Sperduti Isabella , Bria Emilio , Salvatore Lisa , Tortora Giampaolo 
Published: May 2019

3556 Background: The optimal treatment for mCRC beyond 2nd line is still questioned. Recently, REG and TAS-102 showed to improve survival compared to BSC. While in real-world practice CTr/r is often considered in this setting, supporting evidences are limited. In absence of studies comparing all these strategies, we aimed to compare the prognostic performance of CTr/r, REG and TAS-102 in mCRC treated beyond 2nd line. Methods: mCRC pts progressing after at least 2 lines of CT, treated with CTr/r, REG or TAS-102 between Jan-10 and Jan-19 were considered eligible. The primary endpoint was OS; secondary endpoints were PFS and RR. Cox’s proportional hazard models for survivals were estimated. A propensity score (PS) adjustment for baseline characteristics was further accomplished for survival analysis. Results: The clinical data of 341 pts (CTr/r 133, REG 150, TAS-102 58) were retrospectively collected. At multivariate analysis type of treatment, ECOG PS, number of metastatic sites and treatment line independently correlated with OS ( p < .001, p .001, p < .001 and p .029, respectively). The mOS was 18.5 (95% CI, 14.3–22.7), 6 (95% CI, 5.6–9.5) and 7.6 months (95%CI, 5.6–9.5), for CTr/r, REG and TAS-102 group, respectively (log-rank p < .0001). mOS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (15.8 vs 7.1 months; adjusted HR 1.96, 95% CI 1.44-2.66; p < .0001) at the PS analysis, adjusted for ECOG PS, number of metastatic sites and treatment line; 2-yrs OS was 34% and 11.6% for CTr/r and REG/TAS-102, respectively. PFS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (5.5 vs 3.9 months; HR 1.45, 95% CI 1.11-1.91; p .006) at the PS analysis. Accordingly, RR was higher in pts receiving CTr/r compared to REG/TAS-102 (29.0 vs 1.5%; Chi-square p < .00001). Conclusions: Our analysis, although underpowered, generates the hypothesis of a superiority of CTr/r in comparison to REG or TAS-102, in both efficacy and activity. Given the retrospective nature of our analysis, and the potential role of selection bias in treatment assignment, a prospective validation is mandatory.
Predictive factors for early mortality after initiation of regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer.
Authors: Masuishi Toshiki , Moriwaki Toshikazu , Fukuoka Shota , Takashima Atsuo , Kumekawa Yosuke , Kajiwara Takeshi , Yamazaki Kentaro , Esaki Taito , Makiyama Akitaka , Denda Tadamichi , Satake Hironaga , Suto Takeshi , Sugimoto Naotoshi , Katsumata Kenji , Ishikawa Toshiaki , Kashiwada Tomomi , Oki Eiji , Komatsu Yoshito , Yoshimura Kenichi , Shimada Yasuhiro 
Published: May 2019

3560 Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been recognized as standard treatments for patients (pts) with refractory metastatic colorectal cancer (mCRC). Because these drugs have limits on efficacy benefit for some pts, we are necessary to select pts who may be better not to receive REG or FTD/TPI. However, no reports are available on how to predict pts with early mortality after initiation of these drugs. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG or FTD/TPI. Predictive factors for early mortality (≤ 12 weeks from initiation of REG or FTD/TPI) were evaluated by multivariate analysis for survival with all variables with P values of <0.05 from the univariate analysis, using the Cox proportional hazards model. In this analysis, the pts who lived at first 15 weeks were defined as censored case. Results: A total of 523 pts (REG, 212; FTD/TPI, 311) were eligible. Predictive factors for early mortality were without primary tumor resection [adjusted hazard ratio (aHR), 1.56; p = 0.02], the low level of albumin (aHR, 2.31; p < 0.0001), the high level of CRP (aHR, 2.31; p < 0.0001), and short time from diagnosis of mCRC (aHR, 1.77; p = 0.002) by multivariate analysis. The pts harboring all these poor factors were classified into the high (H) risk of early mortality group. Two groups of pts with H and non-H were identified, with 12-week mortality rate of 39 and 14%, with 14-week mortality rate of 70 and 18%, and with median survival time (MST) of 2.9 and 7.8 months, respectively (HR of H/non-H, 4.02; p value < 0.0001). In pts treated with REG, H and non-H groups had 12-week mortality rate of 38 and 16%, 14-week mortality rate of 79 and 18%, and MST of 2.8 and 7.8 months, respectively. In pts treated with FTD/TPI, H and non-H groups had 12-week mortality rate of 41 and 13%, 14-week mortality rate of 63 and 18%, and MST of 3.2 and 7.7 months, respectively. Conclusions: Our predictive model for early mortality after initiation of REG or FTD/TPI might be useful for selecting pts who should not receive either these drugs.
Utilization and reach of the Fight Colorectal Cancer Late Stage MSS CRC Clinical Trial Finder.
Authors: Garcia Reese , Dwyer Andrea , Worrall Sharyn , Heery Christopher Ryan , Deming Dustin A. , Benson Al Bowen , Davis Anjee 
Published: May 2019

3561 Background: Colorectal cancer (CRC) remains one of the most lethal cancer killers worldwide. Recently, research has shown great strides in the treatment of MSI-H mCRC using immunotherapy, however, these treatments have not been effective in MSS patients, who make up a majority of CRC cases. Due to numerous barriers, clinical trial enrollment numbers remain as low as 9% of the eligible populations, despite the reliance of many late stage CRC patients on clinical trials for treatment. Perhaps greatest of these barriers is the lack of meaningful patient-facing clinical trial matching, making advances in MSS mCRC IO clinical research extremely slow. Methods: In May 2017, Fight Colorectal Cancer (FightCRC) launched its web-based trial finder, The Late Stage MSS Trial Finder (TF) with the late Dr. Tom Marsilije, a stage IV CRC patient and researcher, and Flatiron Health. The TF is a publicly available immunotherapy-based repository of clinical trials. An algorithm automatically codes for a subset of trials from ClinicalTrials.gov to be uploaded into the tool, and trained FightCRC advocates follow a strategic logic flow to prioritize trials of highest potential benefit and lowest risk for patients. Results: Between 30 and 100 trials are uploaded into the TF for curation each week. A total of 378 trials have been indexed in the TF to date. In February 2019, a mobile application was introduced. From May 2017 to January 2019, the tool has seen > 15,000 users, yielding 26,000 searches in 105 countries; primarily from the United States, China, the United Kingdom, Canada, and France. On average, users navigate to 2.5 pages and spend > 2.5 minutes per use. Providers are using this as a tool to find clinical trials and to discuss these options in real time. CRC patient feedback confirmed the platform functionality. Conclusions: The Trial Finder is a unique tool for MSS mCRC patients pursuing clinical trials. The success of the tool may be attributed to patient focused selection of therapies that show promise. The FightCRC late stage MSS CRC trial finder is being widely utilized, in diverse settings. With our patient curators and Medical Advisory Board, FightCRC will improve the search features and outcome tracking with user feedback. The goal for the TF is to address key barriers to patient entry into clinical trials and promote patient-provider discussions to inform decision making.
Association between gene fusions and anti-EGFR resistance signature in colorectal cancer.
Authors: Rich Thereasa A. , Clifton Katherine , Raymond Victoria M. , Dasari Arvind , Raghav Kanwal Pratap Singh , Parseghian Christine Megerdichian , Lanman Richard B. , Kopetz Scott , Morris Van K. 
Published: May 2019

3564 Background: Acquired resistance to anti-EGFR therapy in metastatic colorectal cancer (mCRC) has been characterized by a circulating tumor DNA (ctDNA) signature including any sub-clonal RAS mutation, co-existing RAS mutations, or co-existing EGFR mutations. Here, we investigated if fusions in ctDNA are associated with this anti-EGFR signature for CRC patients (pts). Methods: 4289 advanced stage CRC pts underwent molecular profiling using a plasma-based NGS assay that included FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1 fusions. Available clinical histories were reviewed. Correlations between fusions and clinicopathological features were measured with a Fischer exact test. Relative frequencies of genomic alterations were compared between fusion-present vs -absent cases with an unpaired t-test. Clonality for a given alteration was called for a relative variant allele frequency (rVAF) > 50 %, while subclonal was defined as < 50% rVAF. Results: 44 unique fusions were detected in 40 (1.1%) of the 3808 pts with alterations present: RET (N = 16), FGFR3 (N = 12), ALK (N = 10), NTRK1 (N = 3), ROS1 (N = 2), and FGFR2 (N = 1). Relative to non-fusion variants detected, fusions were more likely to be subclonal (OR 8.2, p < 0.0001). Mutations associated with a previously reported anti-EGFR resistance were found in FGFR3 (7/12 pts), RET (7/15 pts) and ALK (5/10 pts). In fusion-present cases, co-existing RAS mutations were more likely to be subclonal than non-fusion cases (OR 14, p < 0.0001). EGFR mutations were more common in fusion present cases (OR 3.7, p = 0.0001) and predominantly subclonal (97%). EGFR mutations aggregated to ectodomain sites (85%) previously linked to acquired anti-EGFR resistance. For 27 pts with available clinical histories, 21 (78%) received anti-EGFR treatment prior to ctDNA testing. Conclusions: Actionable fusions using a ctDNA NGS assay were predominantly subclonal and co-existed with subclonal RAS and EGFR mutations. These clinicopathologic features are consistent with a previously validated signature linked to resistance to anti-EGFR therapies in CRC. We hypothesize that fusions may arise as a previously undescribed mechanism of acquired resistance to anti-EGFR therapies in CRC pts.
Survival according to mutations in BRAF, KRAS, or microsatellite instability (MSI-H) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases from colorectal cancer.
Authors: Larsen Stein G , Dueland Svein , Goscinski M , Steigen Sonja , Hofsli Eva , Flatmark Kjersti , Sorbye Halfdan 
Published: May 2019

3565 Background: Patients with metastatic colorectal cancer (mCRC) and mutations in BRAF V600E (mutBRAF) or KRAS (mutKRAS) have a worse prognosis after liver or lung surgery/ablation, whereas the impact of microsatellite instability (MSI-H) has not been well studied. Few patients with mutBRAF receive liver or lung surgery (1-4%), whereas mutBRAF is present in 5-12% of mCRC trial patients and in up to 20% of the general mCRC population. The frequency and prognostic role of mutBRAF, mutKRAS and MSI has not been well studied after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases from colorectal cancer. Methods: The Norwegian Radium Hospital is the only center offering CRS and HIPEC in Norway. From 2004 to 2015 257 patients with histology proven peritoneal metastasis from colorectal cancer, appendiceal cancer excluded, was consecutively enrolled. Molecular analyses of KRAS, BRAF and MSS/MSI in mutBRAF were done. Fourteen patients were excluded due to missing tumour blocks (7), unsuccessful analysis (4) and other malignant disease (1). Results: 180 of 243 patients obtained complete cytoreductive surgery and received HIPEC for 90 minutes with Mitomycin C (45-70mg). Median survival for the 180 patients was 47 months and 5-year survival rate 40.1%. Median disease-free survival was 10 months. mutBRAF was found in 23.4% of cases, mutKRAS 35.1% and double-wild type 41.5%. mutBRAF with MSS was found in 16.4%, mutBRAF with MSI-H in 7.0%. 3-year disease free survival (DFS) and median overall survival (OS) was 38.9% and 59 months with mutBRAF with MSI-H, significantly higher compared to 24.2% and 30 months in patients with double wild type, 13.2 % and 41 months in mutKRAS and 17.9% and 22 months in mutBRAF with MSS. Conclusions: A surprisingly high frequency of mutBRAF was seen in mCRC patients after CRS and HIPEC for peritoneal metastatic disease. Patients with mutBRAF and MSI-H had a significantly better DFS and OS after CRS and HIPEC. DFS for patients with mutBRAF and MSS was numerically lower but not statistically different from patients with mutKRAS or double wild type.
Tumor and microenvironment evolution during chemotherapy combine with bevacizumab in colorectal cancer liver metastasis.
Authors: Liao Wangjun , Shi Min , Zeng Dongqiang , Huang Na , Wang Yuqi , Li Jing , Wang Chunlin , Rong Xiaoxiang , Fang Yisheng , Zheng Siting , Xue Yichen , Wang Jiao , Guo Jian 
Published: May 2019

3568 Background: Identifying patterns of pathological tumor resistant to treatment regimens and improving tumor’s chemotherapy sensitivity from longitudinal and multi-omics data integration are of paramount importance in order to provide the best chances of cure, especially, for colorectal cancer liver metastases. Methods: We elucidated genomic (ctDNA and whole exome sequencing), immunomic (DNA-based T cell receptor sequencing) and transcriptomic changes from liver metastases, peripheral blood and match primary tumors that accompany the evolution of colorectal cancer liver metastases. In total, 197 histopathologically distinct areas of liver metastases and 72 peripheral blood samples at multiple time points from 15 patients with colorectal cancer were analysis in this study. Results: In responding patients, mutation load from plasma were reduced from baseline ( P < 0.001), but changed slightly in tumor tissues ( P = 0.351). Transcriptomic analysis and immunohistochemistry revealed that increased infiltration of neutrophils and monocytes were associated with worse outcomes and insensitive response to chemotherapy (Neutrophils: P = 0.003; Monocytes: P = 0.032). Activation of fatty acid metabolism, JAK-STAT, PPAR, insulin and TGF-β signaling pathway were observed in progressive tumor. TCR diversity in response metastatic regions was significantly increased compared with non-responder ( P = 0.008). Combination of bevacizumab with chemotherapy facilitated T cell infiltrating to the tumor microenvironment which might consequently benefit from checkpoint immunotherapy ( P = 0.006). Conclusions: Our integrative and comparative genomic analysis provides a new paradigm for understanding the evolution and treatment resistance of colorectal cancer liver metastases, with implications for identifying ways to advance treatment regimen and monitoring treatment response of colorectal cancer liver metastases.
Serial ctDNA analysis as a real-time indicator of neoadjuvant chemoradiotherapy in rectal cancer.
Authors: Zhou Jiaolin , Lin Guole , Gong Yuhua , Zhang Yanyan , Guan Yan-Fang , Xia Xuefeng , Yi Xin , Xue Xiaoqiang , Bai Xueshan , Yang Ling 
Published: May 2019

3569 Background: Neoadjuvant chemoradiotherapy (nCRT) is nowadays the standard of care for the locally advanced rectal cancer (LARC). However, there is no effective method to predict patients’ possible benefits from nCRT and monitor the response to it. Methods: Patients with locally advanced middle and low rectal cancer of stage cT3-4N0M0 or cTanyN+M0 were enrolled from August 2017 to July 2018. All patients received nCRT with long-term radiation plus fluorouracil based chemotherapy, followed by the radical surgery. Serial plasma samples were collected pre-nCRT, during nCRT, and preoperatively (8 weeks after the completion of nCRT). Somatic mutations were detected with next-generation sequencing using a 1021-gene panel with peripheral blood lymphocyte DNA as a germline control. Results: This prospective cohort study enrolled 61 patients with rectal cancer. The pathological complete response (pCR) rate and the downstage rate was 31% (19/61) and 80% (49/61), respectively. ctDNA was detectable in 77% (47/61), 18% (11/61) and 13% (8/61) of blood samples obtained pre-nCRT, during nCRT and preoperatively, respectively. No significant association was observed between pre-nCRT ctDNA status with any clinicopathological factors, including age, gender, differentiation or tumor circumferential extent. Among the 8 patients with detectable ctDNA preoperatively, pathological tumor regression grade (TRG) of CAP 2-3 were observed and hepatic metastasis was found in 4 patients within 2 months. For patients with undetectable pre-operative ctDNA, a higher proportion archived pathological downstaging (85% vs 50%). The correlation between preoperative ctDNA status and achievement of pathological downstage was independent of age, gender or differentiation (p = 0.02). In addition, preoperative ctDNA positivity was associated with the persistently involved lymph node (p = 0.02). However, neither pre-nCRT nor during-nCRT ctDNA status was associated with pathological downstaging or persistently lymph node involvement. Conclusions: Detectable ctDNA after the completion of nCRT is a predicator of unsatisfactory curative effect of patients with LARC, which might indicate novel treatment intensification studies. Clinical trial information: NCT03042000.
Outcomes of salvage surgery for anal squamous cell carcinoma: A systematic review and meta-analysis.
Authors: Cyr David Patrick , Savage Paul , Theodosopoulos Evangelia , Chesney Tyler R , Swallow Carol Jane 
Published: May 2019

3571 Background: Following primary chemoradiotherapy for squamous cell carcinoma of the anal canal (A-SCCa), 10% of patients have persistent cancer, and 30% develop local recurrence after initial complete response. Both persistent and recurrent A-SCCa may be amenable to salvage surgery, which typically involves intense health care resource utilization. Because only small cohorts have been reported, we synthesized the evidence for salvage surgery to gain a comprehensive understanding of outcomes. Methods: We systematically searched MEDLINE, Embase, and Cochrane Library (until October 11, 2018) for studies reporting on persistent or recurrent A-SCCa treated with salvage surgery. Quality assessment was performed using the Institute of Health Economics Quality Appraisal Checklist. Overall survival (OS) and disease-free survival (DFS) were pooled using two approaches: survival curve meta-analysis, and exact binomial likelihood random-effects model for survival probabilities. We used meta-regression, subgroup and sensitivity meta-analyses to explore sources of heterogeneity. Results: We identified 39 observational studies that included 1388 patients. Pooled 5-year OS was 45.5% (95% CI 40.6 to 49.9; 33 studies; 1308 patients), and did not differ in patients resected for recurrent (14 studies, n=259 patients) vs. persistent (n=238 patients) disease. There was no association of OS with study year, tumor size, or resection margin at the aggregate-level. Pooled 5-year DFS was 38.3% (95% CI 31.4-43.9; 14 studies; 554 patients). Pooled 30-day complications were 65.3% (95% CI 50.2-77.9; 17 studies; 720 patients): major complications 27.7% (95% CI 22.3-33.8), reoperations 12.7% (95% CI 8.7-18.2), and mortality 1.7% (95% CI 1.1-2.6%). Pooled perineal complications were 32.7% (95% CI 25.0-41.4). Conclusions: Salvage surgery offers 5-year OS of ≈45% and DFS of ≈40% for recurrent/persistent A-SCCa. Major complications and perineal wound complications are common, but postoperative mortality is rare. Presently, there are no reports of patient-reported outcomes such as quality of life after salvage surgery for A-SCCa. Comparative effectiveness studies comparing surgery to other treatments are warranted.