bluuebunny/crossref_metadata_2025 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.
Prognosis and chemosensitivity of non-V600E BRAF mutations in metastatic colorectal carcinoma (mCRC): An AGEO French multicenter retrospective cohort.
Authors: Derosiere Aline , Nicolai Vincent , Malka David , Pozet Astrid , Lazartigues Julien , Turpin Anthony , Tougeron David , Walter Thomas , Artru Pascal , Bachet Jean-Baptiste , Phelip Jean Marc , Lepage Come , Lievre Astrid , Caulet Morgane , Norguet Emmanuelle , Lourenco Nelson , Coriat Romain , Sefrioui David , Dremaux Julie , Hautefeuille Vincent
Published: May 2019

3575

Background: BRAF mutations are present in 5-15% of mCRC. V600E BRAF mutations account for ~80% of cases and are mostly found in right-sided tumors. Non-V600E BRAF mutations are rare (~2% of mCRC), mostly left-sided. Although BRAF V600E mutations are associated with a dismal prognosis, some studies suggest that non-V600E BRAF mutations may be associated with a favorable outcome. The chemosensitivity of non-V600E BRAF-mutated mCRC has never been studied. Methods: From 2017 to 2018, all consecutive patients (pts) with non-V600E BRAF-mutated mCRC (next generation sequencing) treated in the participating centers were included. Survival analyses were performed using Kaplan-Meier method and LogRank test. Results: A total of 108 pts in 34 centers in France were included between October 2017 and August 2018 (median age, 66 years [range, 58-77]; ECOG performance status 0-1, 86%). The primary was mostly left-sided (66%). Main metastatic sites were the liver (73%), lungs (33%), lymph nodes (39%) and peritoneum (26%). D594 (34%), G469 (15%), K601 (11%), N581 (7%) and L597 (7%) were the most frequent mutations. A concomitant RAS mutation was found in 22% of pts. Microsatellite instability (MSI) was found in 3/67 pts (4.5%). First-line chemotherapy (CTx) (n = 69) efficacy was (overall response rate/disease control rate) 49%/77% (anti-EGFR-containing CTx [n = 20], 75%/85%; antiangiogenic-containing CTx [n = 22], 55%/73%). Median overall survival (mOS) was 25.6 months (95% CI : 17.1-43.8) overall; it was 8.0 months with best supportive care alone (n = 10), 16.0 months with palliative CTx alone (n = 63), and attained 105.1 months with curative-intent management of metastases (n = 35). mOS did not differ according to sidedness (p = 0.22), type of mutation (p = 0.52), or its functional impact on BRAF (p = 0.19). Conclusions: Non-V600E BRAF-mutated mCRC retain sensitivity to CTx + biologics and harbor a good prognosis (especially when amenable to curative-intent surgery), regardless of the type of mutation and its impact on BRAF kinase function. Contrarily to BRAF V600E mutations, non-V600E mutations may occur along with RAS mutations, but uncommonly with MSI.
High incidence of advanced stage cancer and prolonged rectal bleeding history before diagnosis in young-onset patients with colorectal cancer.
Authors: Sandhu Gurprataap Singh , Anders Rebekah , Walde Amy , Leal Alexis Diane , King Gentry Teng , Leong Stephen , Davis S. Lindsey , Purcell William T. , Goodman Karyn A. , Herter Whitney , Meguid Cheryl Lauren , Birnbaum Elisa H , Ahrendt Steven Arthur , Gleisner Ana , Schulick Richard D. , Delchiaro Marco , McCarter Martin , Patel Swati , Messersmith Wells A. , Lieu Christopher Hanyoung
Published: May 2019

3576

Background: In contrast to the older population, the incidence of colorectal cancer (CRC) in younger patients (aged < 50 years) has been increasing in the last three decades. Younger patients tend to present with more advanced disease, thought to be in part related to lack of routine screening colonoscopies. The goal of this study was to examine characteristics of young-onset CRC and potentially identify factors that may aid in earlier diagnosis and treatment. Methods: We collected data for patients available through the University of Colorado Cancer Center Cancer Registry. Inclusion criteria included: 1) Diagnosis of colon or rectal cancer between the years 2012-2018 and 2) age at diagnosis of less than 50 years. Pertinent data including baseline characteristics, clinical presentation, family history, pathology, molecular testing, staging, and treatment were collected. Results: 211 patients with young-onset CRC were available for review. Mean age at diagnosis was 42.4 years and 55.5% were males. A total of 42.1% had rectal cancer and a majority of the colon cancer diagnoses had left-sided tumors (66%). Regarding clinical presentation, 52.2% presented with rectal bleeding prior to diagnosis. Of those who presented with rectal bleeding, the average time from the onset of bleeding to diagnosis was 271.17 days. 42.9% of young-onset CRC were stage IV at the time of initial diagnosis. Evaluation of the pathology specimens showed that 89.6% were adenocarcinomas and 63.5% were grade 2 or higher. At diagnosis, the mean BMI was 26.6 and the mean CEA was 135.5. A total of 72.5% of young-onset patients had a positive family history of any cancer. KRAS or NRAS mutations were present in 49.6% of patients, BRAF V600E mutations were present in 3.8%, and 10.8% were MSI-H. Conclusions: Prolonged rectal bleeding history prior to diagnosis was noted in a significant proportion of young-onset patients with colorectal cancer. Patients and primary care physicians should be made aware of this finding in order to facilitate timely referral for colonoscopy which may lead to earlier diagnosis, less advanced disease at diagnosis, and improved outcomes.
Retrospective analysis of overall survival (OS) by subsequent therapy in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving irinotecan ± cetuximab in the EPIC study.
Authors: Sobrero Alberto F. , Lenz Heinz-Josef , Eng Cathy , Scheithauer Werner , Middleton Gary William , Chen Wen-Feng , Esser Regina , Nippgen Johannes , Burris Howard A.
Published: May 2019

3580

Background: The multicenter, open-label, randomized, phase 3 EPIC study (EMR 062202-025) investigated cetuximab + irinotecan vs irinotecan as a second-line (2L) therapy in pts with EGFR-detectable mCRC. A retrospective analysis in the EPIC RAS wt population showed improved overall response rate (29.4% vs 5.0%) and progression-free survival (5.4 vs 2.6 mo) upon the addition of cetuximab to irinotecan. Median OS (mOS) was similar in both treatment arms, possibly due to differences in subsequent therapies. We present OS by post-study therapy in the RAS wt population. Methods: 1298 RAS-unselected pts were enrolled from May 2003 to February 2006. The primary endpoint was OS. RAS status was determined retrospectively in 2018 from existing DNA samples using BEAMing technology; wt status was defined as having a sum of mutated RAS allele frequencies of ≤5%, with all relevant alleles being analyzable. Results: Among the 452 pts with RAS wt mCRC, 231 received cetuximab + irinotecan and 221 received irinotecan. Baseline characteristics were similar in both arms. OS data by post-study therapy are summarized in the Table. No new or unexpected safety signals were observed. Conclusions: Post-study cetuximab was associated with improved OS in both treatment arms compared with post-study therapy without cetuximab and no subsequent therapy, suggesting that cetuximab-based therapy may be suitable as a standard treatment for pts with RAS wt mCRC in the rechallenge setting. Study limitations include a potential bias due to the differences in proportion of subsequent therapies with and without cetuximab between arms (almost 50% of pts in the irinotecan arm received post-study cetuximab) as well as the likelihood for pts who live longer to receive cetuximab in any subsequent therapy line. [Table: see text]
Is the predictive and prognostic impact of sporadic and familial microsatellite instable stage III colon cancer different? A pooled analysis of the PETACC8 and NCCTG N0147 (Alliance) trials.
Authors: Zaanan Aziz , Shi Qian , Taieb Julien , Alberts Steven R , Meyers Jeffrey P. , Smyrk Thomas C. , Julié Catherine , Zawadi Ayman , Tabernero Josep , Mini Enrico , Goldberg Richard M. , Folprecht Gunnar , VAN Laethem Jean Luc , Le Malicot Karine , Sargent Daniel J. , Laurent-Puig Pierre , Sinicrope Frank A.
Published: May 2019

3583

Background: The Microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually taken as a single biological entity whereas no data are available concerning prognosis and response to chemotherapy between sporadic and familial dMMR cases. Methods: Resected KRAS exon 2 wild-type (WT) tumor stage III colon cancers (N = 4596) from patients (pts) randomly assigned to FOLFOX +/- cetuximab in two adjuvant large phase III trials were prospectively analyzed for MSI status and dMMR mechanism (sporadic vs familial). Stratified Cox models were used to assess prognostic and predictive values of dMMR mechanism by treatment arms, adjusting for age, gender, tumor grade, ECOG PS, pT/pN stage and primary tumor location. Results: Among dMMR patients with complete data for dMMR mechanism analysis (N = 354), there were 255 (72%) sporadic ( BRAF mutated or WT with MLH1 methylation) and 99 (28%) familial (loss of MSH2 or MSH6, or loss MLH1 with BRAF WT and unmethylated MLH1) cases. A large proportion of dMMR sporadic cases were mutated for BRAF (n = 200; 80%). In pts treated with FOLFOX, the disease-free survival (DFS) was not statistically different by dMMR mechanism, while for pts treated with FOLFOX + cetuximab, the sporadic cases did worse than familial cases (DFS; adjusted (adj) HR, 2.69; 95% CI, 1.02-7.08; P= 0.04). Considering the predictive value, a deleterious effect of adding cetuximab to FOLFOX was observed in sporadic (DFS; adjHR, 1.68; 95% CI, 1.01-2.79; P= 0.04) but not in familial dMMR pts (interaction P value regarding treatment effect = 0.03). Furthermore, a non-significant trend to a deleterious effect of adding cetuximab to FOLFOX was observed in BRAF mutant (DFS; adjHR, 1.66; 95% CI, 0.95-2.92; P= 0.07) but not in BRAF WT pts. Conclusions: The addition of cetuximab to FOLFOX was associated with reduced DFS in patients with sporadic dMMR cases. Further studies including the methylator phenotype (CIMP) analysis are needed to validate these results. Clinical trial information: NCT00265811 and NCT00079274.
Association of MAPK signaling subtypes with prognostic benefit for bevacizumab in left-sided metastatic colorectal cancer (mCRC) patients treated with FOLFIRI + cetuximab / bevacizumab (FIRE-3 trial).
Authors: Stahler Arndt , Stintzing Sebastian , Modest Dominik Paul , Jelas Ivan , Heinrich Kathrin , Miller-Phillips Lisa , von Einem Jobst C. , Vehling-Kaiser Ursula , Decker Thomas , Kiani Alexander , Fischer von Weikersthal Ludwig , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Moehler Markus H. , Wirapati Pratyaksha , Kirchner Thomas , Jung Andreas , Heinemann Volker
Published: May 2019

3584

Background: We investigated the role of the MAPK pathway by mRNA expression profiles in microarrays of the FIRE-3 trial as it was formerly associated with prognosis. Methods: 451 patients provided eligible mRNA material for subsequent analyses of the MAPK pathway (295 genes). Non-negative matrix factorized (NMF) clustering for normalized mRNA microarray data (Almac Inc, Xcel Array) was performed for 2 to 6 ranks against randomized controls. Linear models with adjustment for multiple testing showed differential gene expression between groups. Single sample gene set enrichment analysis (ssGSEA) was used to compare differentially enriched hallmarks of cancer gene sets. Kaplan Meier method, log rank test and Cox regression analyses were performed to estimate overall (OS) and progression free survival (PFS) between MAPK subtypes. Results: NMF clustering built two groups of MAPK mRNA expression (coph: 0.91, silh: 1.00) without cohort-based bias in principal component analysis. Group MAPK1 (n = 238) was significantly associated with CMS2 (66.4 %), group MAPK2 (n = 213) with CMS4 (67.6 %, p < 0.0001). 5.551 of 23.561 genes were significantly differentially expressed between MAPK subtypes. 49 cancer hallmark gene sets were significantly differentially enriched in ssGSEA ( MAPK1: myc targets, DNA repair, cell cycle, PI3K- AKT- mTOR pathway upregulation; MAPK2: EMT-related signatures, TGFß pathway, angiogenesis upregulation among others). In overall analysis, MAPK1 showed slightly better outcome than MAPK2 (OS: HR: 0.80, 95% CI: 0.65 – 0.99, p = 0.049; PFS: HR: 0.81, 95% CI: 0.66 – 1.00, p = 0.05). However, MAPK1 was significantly more favourable for bevacizumab treatment in OS ( MAPK1: 30.8 m, MAPK2: 19.4 m, HR: 0.56, 95% CI: 0.39 – 0.81, p = 0.002) and PFS ( MAPK1: 11.7 m, MAPK2: 9.8 m, HR: 0.68, 95% CI: 0.48 – 0.98, p = 0.038) in left sided tumors, while no difference was seen for cetuximab treatment, RAS and BRAF status. Conclusions: mCRC subtypes by MAPK mRNA expression might contain prognostic information for the treatment with bevacizumab beyond mutational status in patients with left sided tumors of the FIRE-3 trial.
Molecular landscape of colorectal cancers harboring R-spondin fusions.
Authors: Seeber Andreas , Kocher Florian , Xiu Joanne , Spizzo Gilbert , Puccini Alberto , Swensen Jeffrey , Ellis Michelle , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Battaglin Francesca , El-Deiry Wafik S. , Tokunaga Ryuma , Naseem Madiha , Philip Philip Agop , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef , Gatalica Zoran
Published: May 2019

3588

Background: Gene fusions involving R-spondin ( RSPO) family members have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Therapies targeting Wnt pathway are being actively investigated for tumors harboring RSPO2/3 fusions. Here we set out to characterize the molecular features of CRC with and without RSPO fusions to gain insight into potential rationale combination therapy strategies. Methods: Tumor DNA sequencing of 592 genes (NextSeq, Illumina), RNA sequencing of 53 gene fusions (ArcherDx FusionPlex) and immunohistochemistry for PD-L1 on tumor cells (SP142) were tested on CRC tumors at Caris Life Sciences, Phoenix, AZ. Molecular profiles of RSPO2/3 positive (pos) were compared with negative (neg) tumors, Fisher-Exact was used for comparative analysis. Results: A total of 1356 CRC samples were analyzed. RSPO3 and RSPO2 fusions were detected in 42 (3.1%) and 4 (0.3%) samples, respectively, including 5 fusion events not previously reported (e.g., IFNGR1-RSPO3). A female predominance was seen in RSPO fusion pos vs. neg tumors (71.7% vs 45.0%, p < 0.001); no association with age or tumor sidedness was seen. RSPO2/3 fusions were mutually exclusive of MSI-high (0 vs. 5%), ERBB2 alterations (0 vs. 1% mutation, 4% amplification) and other Wnt pathway activation drivers including APC (2 vs. 75%), CTNNB1 (0 vs. 1.4%) and RNF43 (0 vs. 5.3%) mutations. Significantly higher BRAF (26 vs. 7%), RAF1 (4.5 vs. 0.4%) and SMAD4 (30 vs. 11%) mutation rates were seen in RSPO pos vs. neg tumors (p < 0.05). A universal co-activation of MAPK pathway ( KRAS, NRAS or BRAF) was seen with RSPO fusions. There was a significantly elevated PD-L1 expression in RSPO3 pos tumors (14%) compared to RSPO neg (6%, p = 0.04) and APC-mutated (5%, p = 0.02) tumors that are MSS. Conclusions: This is the largest series of CRC cases harboring an RSPO rearrangement reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO fusions in CRC and suggested potential combinatorial approach to target Wnt/MAPK pathway. The immune modulatory effects specific to RSPO2/3 fusion revealed by PD-L1 expression suggest co-targeting Wnt pathway with PD1/PDL1 inhibitors in RSPO pos tumors.
Prediction model for detecting circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).
Authors: Pereira Allan Andresson Lima , Parikh Aparna Raj , Van Seventer Emily E. , Jia Jingquan , Loree Jonathan M. , Kanikarla Marie Preeti , Raghav Kanwal Pratap Singh , Morris Van K. , Overman Michael J. , Raymond Victoria M. , Lanman Richard B. , Talasaz AmirAli , Strickler John H. , Corcoran Ryan Bruce , Kopetz Scott
Published: May 2019

3590

Background: While tissue-based assays have yields above 90% in solid tumors, there is less known about factors that influence the sensitivity of ctDNA for detecting mutations. Methods:We retrospectively evaluated mCRC patients (pts) who had plasma-derived NGS utilizing a highly-sensitive targeted 68-73-gene ctDNA assay. In a case-control design, pts with a known mutation on tissue and radiologic evidence of metastatic disease but no detectable ctDNA mutation were matched 1:3 with randomly selected pts with detectable mutations and compared according to clinical, laboratory, and radiologic characteristics. A prediction score for ctDNA detection was built using a binary logistic backward stepwise regression analysis and tested in two independent data sets from different institutions. Area under the curve (AUC) from receiver operating characteristics curves (ROC) were used for internal and external validation. Results: From 416 pts who met inclusion criteria, plasma-derived NGS did not find tumor mutations in 66 cases (15.9%); 198 pts with detectable alterations were selected as controls. After multivariate analysis, the detection of ctDNA was associated with increasing age (OR 1.05; 95%CI 1.02-1.09; p = .001), presence of liver (OR 5.82; 95%CI 2.55-12.49; p < .001) and lymph node metastases (OR 3.28; 95%CI 1.51-7.60; p = .004), archival TP53 mutations (OR = 2.88; 95%CI 1.37-6.17; p = .006). A key determinant was timing of collection relative to disease status: plasma collected in newly diagnosed metastatic disease or after evidence of progression was substantially more likely to have detectable alterations (OR 9.24; 95%CI 4.11-22.40; p < .001); The simplified prediction model performed well in internal (AUC = 0.88) and external validation (AUC = 0.95; 163 pts). Conclusions: Our validated prediction model provides clinicians and researchers with a tool to screen for patients in whom ctDNA testing can outperform tissue-based testing in detecting genomic alterations.
Preoperative platelet leukocyte ratio as an independent risk factor for postoperative outcomes in colorectal cancers.
Authors: Ryan Carrie E , Gajdos Csaba , Pourafkari Leili , Nader Nader D.
Published: May 2019

3591

Background: Although preoperative platelet/leukocyte ratio (PLR) is a predictor of postoperative outcomes in various neoplasms, data is lacking for colorectal cancer (CRC). We hypothesized that elevated preoperative PLR would be an independent risk factor for postoperative complications and increased 30-day mortality in patients with surgically resected CRC. Methods: Patients undergoing resections for CRC were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2016 dataset. Logistic regression models for 30-day morbidity and mortality for PLR ≤28.4 and >28.4 (calculated from ROC analyses) were completed. Univariate log-rank test, and multivariate Cox proportional hazards regression were used for time-to-event analyses and data are presented as odds/hazard ratio with confidence interval. Results: 98,398 patients were included in the study. Elevated PLR was an independent predictor of 30-day morbidity and mortality. Patients with high PLR were more likely to have a wound infection (1.022, 1.01-1.04), pneumonia (1.2, 1.17-1.23), require reintubation (1.23, 1.19-127), prolonged ventilation (1.31, 1.26-1.36), have renal insufficiency (1.17, 1.11-1.22), and have a postoperative myocardial infarction (1.23, 1.9-127). PLR value > 28.4 was among independent predictors of mortality (1.67, 1.47–1.87), along with the ASA class, age, perioperative use of steroids, serum albumin and INR. (Table). Conclusions: Elevated PLR is a significant preoperative risk factor for 30-day morbidity and mortality. PLR may be considered as a potential risk assessment tool that predicts postoperative outcome following CRC resections. Multivariate analysis. [Table: see text]
Exploring the genetic basis of Lynch-like syndrome through paired germline and tumor exome sequencing.
Authors: Willis Jason , Mork Maureen E , Chang Kyle , Kinnison Jenniffer , Rodriguez-Bigas Miguel A. , Thirumurthi Selvi , Borras Ester , Taggart Melissa , Lynch Patrick M. , You Y. Nancy , Vilar Sanchez Eduardo
Published: May 2019

3592

Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age <50 years) dMMR colorectal or uterine cancers were selected from a familial cancer registry. The absence of deleterious germline MMR mutation and/or somatic MLH1inactivation was confirmed by standard clinical testing. We performed whole-exome sequencing (Illumina HiSeq) of germline (peripheral blood) DNA. Variant calls, quality-control, allele-frequency filtering (<1% in reference cohorts), and in silicoannotation were performed using the GATK and polyphen/SIFT tools. Pathway analysis was performed using the DAVID suite. For 16 of 18 patients, targeted exon sequencing of 408 cancer-related genes was performed on paired tumor/normal tissue samples (Ion Torrent AmpliSeq) and analyzed with VarScan 2. Results: 237,055 rare germline variants were detected in our cohort. We enriched a subset of 758 variants with putative frameshift (45.1%), stop gain or loss (25%), or splice site alteration (29.9%). Pathway analysis of genes altered by this subset revealed excess events in DNA damage repair (e.g. ERCC5, POLM, POLN, EXO5) and mRNA splicing (e.g. SCAF1, SRSF4) pathways. Preliminary analysis of somatic mutations profiles shows frequent alteration of known drivers including APC(64%) and NOTCH1(36%). Conclusions: Our exploratory analysis provides novel evidence that LLS patients may harbor an excess of deleterious germline mutations in DNA damage repair- and mRNA splicing-related genes. Future studies will identify genes which are targeted by both germline and somatic mutation with the goal of nominating putative causal genes. Defining additional mechanisms of dMMR in LLS cancers may help to refine prevention strategies for (un)affected individuals.
Comparison of HER2 overexpression with total Her2 mutation on resistance of EGFR-targeted therapy in Ras wild-type mCRC patients.
Authors: Chang Wenju , Huang Wenbai , Chen Yijiao , Ren Li , Wei Ye , Xu Jianmin
Published: May 2019

3594

Background: Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type Ras, however, only partial patients respond to cetuximab treatment. The effect of human epidermal growth factor receptor 2 (HER2) protein overexpression and Her2 gene mutant on the efficacy of cetuximab treatment was not well elucidated in patients with Ras wild-type unresectable mCRC. Methods: From June 2008 to December 2014, we identified 216 patients with Ras wild-type unresectable liver-limited mCRC base on our previous study (ClinicalTrials: NCT01564810.), whose Her2 gene mutation was analyzed by next-generation sequencing for single nucleotide polymorphism (SNP) of Her2 gene and HER2 protein overexpression was determined by immunohistochemistry and fluorescence in situ hybridization (FISH). Results: Of these 216 patients, 103 were received cetuximab plus chemotherapy (cetuxima group) and 113 were received chemotherapy alone (chemotherapy group). The total rate of HER2 overexpression was 8.8%, including 9.7% in cetuximab group and 7.9% in chemotherapy group. HER2 overexpression caused impaired survival compared with HER2 non-overexpression patients in cetuxima group, with a median progression-free survival (PFS) of 4 months (95% CI 2.482-5.518) versus 10 months (95% CI 8.963-11.037; P< 0.0001), and a median overall survival (OS) of 15 months (95% CI 7.5-22.2) versus 36 months (95% CI 31.4-40.5) ( P< 0.0001). While, HER2 overexpression had no effect on treatment efficacy in chemotherapy group, when compared with HER2 non-overexpression paitents, with a median PFS of 5 months (95% CI 2.228-7.772) versus 5 months (95% CI 4.004-5.996; P= 0.615), and a median OS of 21 months (95% CI 6.975-35.025) versus 21 months (95% CI 17.772-24.228; P= 0.629). Meanwhile, we observed 25.5% of total Her2 mutant (24.2% in cetuximab group and 26.5% in cetuximab group), among of them 5 patients are HER2 overexpression. Total Her2 mutation has no impact on survival compared with Her2 wild-type ones in neither cetuximab group nor chemotherapy group. In further bioinformatics analysis is underdoing, and which subgroup or type of Her2 mutant potential affect cetuximab treatment need confirm. Conclusions: We show HER2 overexpression rather than total Her2 mutant contribute to resistance of cetuximab treatment in patients with mCRC harboring wild-type Ras. Next, the subgroup mutant in total Her2 mutant needs further analysis to confirm their roles in survival after cetuximab treatment.