bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphotoxin alpha functional germline genetic variant: A future prognostic factor in colorectal cancer?
Authors: Rocha Mariana , Leite-Pinheiro Fátima , Cardoso Beatriz , Del Rio Maria José , Lojo Teira Antonio , Pires Maria Anjos , Bastos Estela , Ribeiro Ricardo
Published: January 2019

603

Background: Lymphotoxin alpha (LTa) is a proinflammatory cytokine expressed by inflammatory cells with a role in the regulation of tumor microenvironment (TM). A putatively functional genetic polymorphism in LTA, at locus +80 (Thr26Asn, rs1041981), has been associated with altered expression of LTa. Here, we sought to evaluate whether this polymorphism associates with two main endpoints (progression-free survival (PFS) and overall survival(OS)) in colorectal cancer (CRC). Methods: This retrospective cohort study was conducted in 166 CRC patients from a single tertiary hospital. Whole blood was used to isolate genomic DNA. Genotyping of LTA + 80 C > A was performed through real time-PCR allelic discrimination using specific Taqman probes, and confirmed by sequencing. Retrospective data and long-term outcomes were reviewed. Age and gender-adjusted logistic regression analyses were undertaken. Analyses were conducted after stratification by baseline lymphocyte count (LC) (LC < 1x103/µL vs. > 1x103/µL). Kaplan-Meier curves with Log-Rank test were used. Subsequent multivariate Cox regression proportional hazards models were calculated (P for retention > 0.1). Results: Participants’ median age was 65.9 (IR, 57.5-74.3) years, the majority were males (63%), and 58% with colon cancer. At diagnosis, 45,2% were stage III and 18,1% stage IV. The median follow up time was approximately four years (IQR, 25.5-67.0 months). We found a significant association in carriers of the A-allele to have lower LC on linear trend analysis (P for trend = 0.013). Multivariate comparisons between LTA genotypes of additive model showed an independent protective effect for heterozygous compared with C-homozygous in the association with disease progression (HR = 0.5, 95 CI = 0.3-0.97, P = 0.041), only in subjects with baseline LC >1x103/µL. In this group, a significant independent protective effect for all-cause mortality was observed in A-carriers (HR = 0.4, 95 CI = 0.1-0.97, P = 0.042). Conclusions: This LTA genetic variant in subjects with baseline LC > 1x103/µL is associated with PFS and OS in CRC. The understanding of the impact of this polymorphisms on the evolution of the disease can bring us new information on TM regulation.
Risk score and prognosis modeling based on mRNA expressivity in the tumor microenvironment of GI cancers.
Authors: Lee Sunyoung S. , Jerez Jessica , Elkhanany Ahmed , Farrukh Fateeha , Baird Andrew , Baird Stuart , Dolan Jillian
Published: January 2019

608

Background: Stromal elements in the tumor microenvironment (TME) impact prognosis and response to therapy. Advances in mRNA-seq improved understanding of gene expressivity, but few models exist to model prognosis in association with mRNA expression. Methods: Clinical data and mRNA-seq of 1,715 patients (pts) – pancreatic adenocarcinoma (PAAD), colorectal adenocarcinoma (CRC), hepatocellular carcinoma (HCC), gastric adenocarcinoma (GAAD), esophageal adenocarcinoma (EsoAd), and esophageal squamous cell carcinoma (EsoSCC) – were obtained from TCGA. The expressivity of 191 genes enriched in cellular and structural components of the TME and clinical data were analyzed using machine learning, multivariable COX model, and Kaplan-Meier (KM) analysis to model risk score (RS) to predict prognosis. Results: Genes associated with good and poor prognosis were identified via machine learning and statistic methods. Higher RS represents worse prognosis with max RS = 1 (Table). In all 6 cancers, high P/G (the expression ratio of genes associated with poor to good prognosis) and old age are related to worse survival except EsoAd with younger pts having worse prognosis. The location of tumors in CRC and sex in HCC impact RS. When pts are grouped into 3 pt groups in each cancer, KM curves in pts with low, intermediate, and high RS are statistically different (p < 0.0001) with high hazard ratio (HR > 2). Conclusions: Analysis of large data was assisted by machine learning and statistics, identifying genes associated with survival and creating RS as a tool to predict prognosis. This provides valuable information about prognosis for pts encountered in the clinic when genomic profiles are given. Computational modeling to predict response to chemotherapy and immunotherapy is underway. [Table: see text]
A KRAS mutation is associated with an immunosuppressive tumor microenvironment in mismatch-repair proficient colorectal cancer.
Authors: Marco Michael , Chen Ching-Tung , Choi Seo-Hyun , Pelossof Raphael , Shia Jinru , Garcia-Aguilar Julio
Published: January 2019

609

Background: KRAS-mutant (KRASmut) colorectal cancers (CRCs) are associated with worse prognosis and resistance to therapy. We have previously shown that KRASmut CRCs have different transcriptomic signature of stromal and immune-related genes compared to KRAS-wild type (KRASwt) tumors. Here, we validated the immune-related changes in the tumor microenvironment associated with the KRAS mutation in CRC to guide the design of novel immunotherapy strategies. Methods: The expression of different immune markers (T cells, B cells, macrophages, natural killer cells, and immune check ligands) were assessed using multiplex immunofluorescence (M-IF) technique in both tumor core (TC) and invasive margin (IM). Sequential slides were cut from paraffin blocks of CRC resected at our institute. Each slide was stained with 4 immune markers using M-IF technique. The stained slides were scanned, and quantification of immune cells was done using ImageJ software. Student’s t test was used for statistical analyses. DNA was extracted from each tumor and profiled for 420 cancer genes using targeted exome-capture sequencing (MSK-IMPACT assay). DNA mismatch-repair (MMR) proteins deficiency were analyzed by immunohistochemistry. Only MMR-proficient (pMMR) tumors were included. Results: A total of 39 patients with pMMR CRC were included. AJCC stages (I-III) were not different between KRASmut (n = 15) and KRASwt (n = 25) tumors. M2-macrophages (CD68+CD163+ cells) and IL-17-producing cells (IL17+ cells) were significantly higher (p = 0.002, and 2.9e-6 respectively), while T-helper cells (CD3+CD4+cells) were significantly lower (p = 3.9e-4) in TC of KRASmut tumors compared to KRASwt. Treg (CD3+CD4+FOXP3+cells) were significantly higher in IM of KRASmut tumors (p = 0.01). KRASmut tumors had significantly higher ratios of Treg:T-helper cells, and Treg:T cytotoxic cell (p = 0.008, and p = 0.04; respectively). Conclusions: KRAS oncogene is associated with more pro-tumorigenic (M2 macrophages, IL17 and Treg) and less anti-tumorigenic (CD4 T-helper) immune cells in CRC. These results can be used to guide further research to design novel immunotherapy strategies against KRASmut CRC.
Proteomic analysis to identify markers for response to treatment in esophageal cancer.
Authors: Zlotnik Oran , Goshen-Lago Tal , Brenner Baruch , Kundel Yulia , Menasherov Nikolai , Kashtan Hanoch , Ben-Aharon Irit
Published: January 2019

61

Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery represents a key therapeutic strategy for locally advanced esophageal cancer (LAEC). Former studies addressed the clinicopathological patterns of patients who demonstrated good response to NCRT compared with inferior response. Nevertheless, there is paucity of data regarding potentially involved cellular pathways that account for tumor response to NCRT. We performed a comprehensive proteomic analysis to identify the key differences in protein function and pathway activation between patients with a poor response and those with a favourable response to treatment. Methods: Patients diagnosed with LAEC who were treated with NCRT and operated at our institution were included in the study. Patients were defined as good responders (GR) upon the tumor regression grade (TRG) in the pathological specimen: GR defined as TRG 0/1 and no evidence of recurrence at 1-year post surgery. Bad responders (BR) were defined as TRG 2/3 and recurrence < 1year. Tumor was isolated from the surgical specimen and proteins were extracted and processed for mass spectrometry-based analysis. Clinical data of demographics, response to treatment, and survival was retrieved from electronic medical records. Difference in protein expression between GR and BR were analysed using validated gene expression pathways tools and correlated to clinical data. Results: Forty-four patients were included in the cohort. Mean age was 66.7 years, male predominance (33/44). Thirty-five patients had adenocarcinoma – 17 GR and 18 BR. Nine patients had squamous cell carcinoma – 6 GR and 3 BR. Protein expression patterns significantly differed between GR and BR regardless of histology, mainly in cellular pathways account for nucleic acid metabolism (p < 10-9), whereas BR had overexpression of these genes. Conclusions: Our study indicate that lack of response to NCRT may derive from overexpression of unique cellular pathways. Former studies imply these cellular pathways may play a role in resistance to cisplatin. Larger transcriptomic studies are warranted for future analysis to extend these observations.
The effect of adjuvant chemotherapy for stage III colon cancer in elderly patients.
Authors: Hayashi Naomi
Published: January 2019

611

Background: Adjuvant chemotherapy (ACT) has been recommended for stage III colon cancer patients in NCCN guidelines. However, the benefit of ACT is still controversial in elderly patients. Methods: We retrospectively included stage III colon cancer patients with aged over 70 that were operated between 2008 and 2015 in Tosei general hospital from Japan. We calculated 3 years recurrence rate and performed a multivariate analysis to estimate the risk of recurrence. The model was adjusted by including the following 7 confounders: Age, ECOG-PS (0-1 or ≥ 2), tumor site (right or left), T stage (T1-3 or T4 ), N stage (N1 or N2), pathological type (por-sig or other), and complete ACT (yes or no). No complete ACT was defined as discontinuation ACT and surgery alone. Results: 182 patients were identified (87 patients aged < 70 and 95 patients aged ≥ 70). ACT was performed in 58 patients (61.1%) and complete rate was 67.2% in elderly patients. The median follow up was 36.0 months. 29 patients (30.0%) had relapse. 3 years recurrence rate was 24.3% and 37.8% with complete ACT or no complete ACT (p = 0.29). In multivariate analysis, N2 was only the risk of recurrence (HR 6.95, p < 0.01). In further analysis, addition of oxaliplatin was significant risk factor of recurrence in elderly patients (HR 10.4, p < 0.01). On the other hand, in young patients, no complete ACT was only risk of recurrence (p = 0.01). 3 years survival rate was 89.1% and 81.0% with complete ACT or no complete ACT (p = 0.27). Conclusions: The multivariate analysis showed that ACT did not reduce the risk of recurrence in elderly patients. Moreover, addition of oxaliplatin suggested not only futile but harmful in those patients. These results support the previous reports (MOSAIC study and PETACC-8 trial) that microsatellite instability and RAS status may affect the effect of oxaliplatin.
What is the role of the anti-angiogenic therapy in BRAF (V600E) mutant metastatic colorectal cancer patients in a real-world setting?
Authors: Martinez Lago Nieves , Covela Rúa Marta , Brozos Vazquez Elena , Fernandez Montes Ana Fernandez , De La Camara Gomez Juan Cruz , Méndez Méndez Carlos , Jorge Fernández Mónica , Cousillas Castiñeira Antia , Suárez Begoña Graña , Quintero Aldana Guillermo Alfonso , Candamio Folgar Sonia , Salgado Fernandez Mercedes , Pellon Augusto Maria Luz , Gonzalez Villarroel Paula , Gallardo Martin Elena , Carmona Campos Marta , Vazquez Rivera Francisca , Grande Ventura Carlos , Carral Maseda Alberto , Reboredo Lopez Margarita
Published: January 2019

620

Background: Activating B-type Raf kinase (BRAF) mutations, mostly missense V600E, occur in approximately 8% to 12% of patients with metastatic colorectal cancer (mCRC). BRAF (V600E)mt is a strong predictor of a poor prognosis, with distinct clinical and pathological features. However, it is unknown whether this mutation is predictive of any treatment benefit in a real world setting. Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university Spanish hospitals in NW Spain, belonging to GITuD (Galician Research Group on Digestive Tumors). Demographic, clinic and pathological characteristics, overall survival (OS) and first-line progression free survival (PFS) were retrospectively collected and analyzed. Results: Data from 65 patients treated between November 2010 to June 2018 were recorded in this study. Median age was 62.8 years (range 30-83 years), 55.4 % female, 75.4% ECOG PS0-1, 49.2% right-sided, 35.2% high grade, 69.2% synchronous presentation, 66.2% primary tumor resection and median metastatic locations was 2 (range 1-5). With a median follow up of 64.6 months, median OS was 12.9 months (95% CI, 9.8-16.0 months) and first line PFS was 4.1 months (95% CI, 2.7-5.5 months). First line PFS according treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 6.2 vs 4.8 vs 2.9 vs 2.1 months (p = 0.020). Bevacizumab based chemotherapy was associated with a prolonged first line PFS (median 5.0 vs. 2.1 months, HR, 0.406; 95% CI, 0.20-0.81; p = 0.005). Nevertheless, no statistical differences between bevacizumab based regimes, (Triplet-CT vs Doublet-CT (HR 0.830; 95% CI 0.4-1.9; p = 0.666)) or between Doublet-CT with or without a antiEGFR were found (HR 0.511; 95% CI 0.2-1.6; p = 0.223). Conclusions: Our study confirms the negative prognostic impact of BRAF V600Emt in mCRC and encourage the use of anti-angiogenic based chemotherapy in this subgroup of patients.
“Should we be generous in peritonectomy?”: First prospective comparative analysis of total versus involved field parietal peritonectomy in CRS-HIPEC for peritoneal surface malignancies from COLO-rectal cancer—ISPSM collaboration study.
Authors: Somashekhar S.P. , C Rohit Kumar , Zaveri Shabber , Rajgopal Ashwin K , Rauthan Amit , Ahuja Vijay , Yethadka Ramya
Published: January 2019

633

Background: Peritonectomy is the important components in management of peritoneal surface malignancies (PSM). Immunofluoresecne study done after involved field peritonectomy (IFP) has showed diease in areas not suspected on gross examination stressing the need for total parietal peritonectomy (TPP) for complete cytoreduction. The aim of this study was to assess the morbidity & mortality, recurrence pattern & oncological outcomes of extent of parietal peritonectomy with CRS & HIPEC for colorectal carcinoma. Methods: Patients with PSM from CRC underwent TPP or IFP with CRS- HIPEC. Pre & intraoperative data were analyzed with main focus on postoperative morbidity, mortality, recurrence pattern and oncological outcomes. Results: 40 cases of CRC of which four upfront, 17 interval and 19 recurrent cases. 19 & 21 patients underwent TPP & IFP respectively. Base line characteristics were comparable except median PCI (17 versus 12). TPP group had longer duration of surgery (11 vs 9), more blood loss (1300 vs 700 ml) increased diaphragmatic resections ( 46.2% vs 14.2%), multivisceral resection ( 46.2% vs 28.5%). Number of bowel resections, anastomosis and stoma were comparable. Overall TPP group had more G3-G5 morbidity (46.1% vs 35.7%) & surgical morbidity (30.7% vs 21.5%) . TPP group had increased pleural & intra-abdominal collections which needed intervention. With a median follow up of 30 months, DFS was significantly higher in TPP group (12months vs 8months, p < 0.01) and median overall survival was 21 months in IFP group (yet to be achieved in TPP group). TPP group had most of the recurrences in visceral liver & lung (50.0%) followed by peritoneal (37.5%) & nodal (12.5%) whereas in IFP it was peritoneum (42.8%), visceral ( 38.4%) & nodal (15.3%). Conclusions: It is the first prospective comparative study done on total parietal peritonectomy in PSM of colorectal cancer origin. TPP group had significantly higher DFS, with comparable postoperative morbidity. However, longer follow up and a prospective multi-institutional randomized study needs to be designed for more evidence of the same.
Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Long-term follow-up.
Authors: Overman Michael J. , Lonardi Sara , Wong Ka Yeung Mark , Lenz Heinz-Josef , Gelsomino Fabio , Aglietta Massimo , Morse Michael , Van Cutsem Eric , McDermott Raymond S. , Hill Andrew G , Sawyer Michael B. , Hendlisz Alain , Neyns Bart , Svrcek Magali , Atasoy Ajlan , Zhao Huanyu , Lei Ming , Kopetz Scott , Andre Thierry
Published: January 2019

635

Background: In the phase II CheckMate-142 trial, NIVO + low-dose IPI (1 mg/kg) provided meaningful clinical benefit in previously treated MSI-H/dMMR mCRC pts after a median follow-up of 13.4 mo. Here, we present long-term follow-up (median 25.4 mo) of these pts. Methods: Pts received NIVO 3 mg/kg + low-dose IPI Q3W (4 doses) followed by NIVO 3 mg/kg Q2W until disease progression. Primary endpoint was investigator (INV)-assessed objective response rate (ORR; RECIST v1.1). Results: Of 119 treated pts, 76% had ≥ 2 prior lines of therapy. ORR and disease control rates (DCR) were 58 and 81%, respectively (Table). Complete response (CR) rate increased with long-term follow-up from 3 (13.4 mo) to 6% (25.4 mo). Median duration of response (DOR) was not reached, with 68% of responses ongoing at data cutoff. At 24 mo, progression-free survival (PFS) and overall survival (OS) rates were 60 and 74%, respectively; OS rates were 96, 56, and 29% in pts with CR or partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 31% of pts; 10% (grade 3–4) and 13% (any grade) of pts had TRAEs leading to discontinuation. Conclusions: Long-term follow-up with NIVO + low-dose IPI provides durable clinical benefit with deepening of response and a manageable safety profile with no new safety signals, demonstrating long-term benefit of NIVO + low-dose IPI for previously treated pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Multicenter phase Ib/II study of biweekly trifluridine/tipiracil with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study).
Authors: Kotaka Masahito , Satake Hironaga , Oba Koji , Kagawa Yoshinori , Yasui Hisateru , Nakamura Masato , Watanabe Takanori , Matsumoto Toshihiko , Kii Takayuki , Terazawa Tetsuji , Makiyama Akitaka , Takano Nao , Yokota Mitsuru , Okita Yoshihiro , Matoba Koreatsu , Hasegawa Hiroko , Tsuji Akihito , Nagata Naoki , Sakamoto Junichi , Kato Takeshi
Published: January 2019

647

Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bmab) combination therapy has shown a promising activity with manageable safety profile in patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC). The aim of this multicenter, phase Ib/II study was to assess the activity and safety of biweekly FTD/TPI with Bmab combination for pts with mCRC who were refractory or intolerant to standard therapies. Methods: Inclusion criteria were ≥ 20 years; histologically confirmed unresectable mCRC; refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type RAS); ECOG PS 0 or 1; evaluable lesion according to the RECIST version 1.1. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and pts received the RP2D in phase Ib part were included in efficacy and safety populations. The primary endpoint in phase II part was an investigator assessed progression-free survival rate at 16 weeks (16w-PFS) with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. Results: From October 2017 to January 2018, totally 46 pts were enrolled (6 pts in phase Ib and 40 pts in phase II). The RP2D was determined to be 5 mg/kg for Bmab and 30 mg/m2 for FTD/TPI in phase Ib. Of the 44 eligible pts (median age, 69; male, 55%; PS 0, 57%; right-sided primary, 29.5%), 16w-PFS rate was 40.9 % (95% CI: 26.3 to 56.8 %) and the null hypothesis of 16w-PFS rate ≤ 15% was rejected (p < 0.0001). Response rate and disease control rate were 0 % (95 %CI: 0 to 6.6 %) and 59.1 % (95%CI: 43.3 to 73.7 %), respectively. With a median follow up of 5.86 months (range, 1.53-9.79), median PFS was 4.25 months (95% CI: 2.54 to 5.57). Grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %), leucopenia (11.4 %), anemia (9.1 %), anorexia (9.1 %), nausea (6.8 %), hyperbilirubinemia (6.8 %) and proteinuria (6.8 %). Conclusions: Bi-weekly FTD/TPI plus Bmab showed promising anti-tumor effect with acceptable toxicities. Clinical trial information: UMIN000029198.
National trends in intensity modulated radiation therapy (IMRT) use for rectal cancer.
Authors: Horne Zachary D. , Abel Stephen , Hasan Shaakir , Kirichenko Alexander V. , Wegner Rodney E
Published: January 2019

648

Background: Neoadjuvant chemoradiation represents the current standard of care for locally advanced rectal cancer prior to surgical resection. Traditionally, 3D conformal radiation therapy (3D CRT) was used in this setting. With advancing technology, intensity modulated radiation therapy (IMRT) was developed with the goal of delivering a more conformal radiation dose, with the potential for reduced toxicity providing a potential advantage across many disease sites. We sought to use the national cancer database (NCDB) to examine trends and predictors for IMRT use in rectal cancer. Methods: We queried the NCDB from 2004-2015 for patients with rectal adenocarcinoma treated with neoadjuvant concurrent chemoradiation to a standard doses (50.4-54Gy) followed by surgical resection. Odds ratios were used to determine predictors of IMRT use. Univariable and multivariable cox regressions were used to determine potential predictors of overall survival (OS). Propensity matching was used to account for any indication bias. Results: We identified 21,490 patients satisfying eligibility criteria, of which 3,131 were treated with IMRT. IMRT use increased from 1% in 2004 to 22% in 2014. Predictors for IMRT use included increased N stage, more recent treatment year, treatment at an academic facility, increased income, and higher educational level. On multivariable analysis including propensity score male gender, increased distance to facility, higher comorbidity score, IMRT technique, government insurance, African American race, and non-metro location were predictive of worse OS. Of note, the complete response rate at time of surgery was 28% with non-IMRT and 21% with IMRT. Conclusions: IMRT use has steadily increased in the treatment of rectal cancer, but still remains only a fraction of overall treatment technique. IMRT use correlated with worse survival likely due to utilization in higher stages and patients with worse disease features.
Systematic review of three decades of clinical trials in metastatic colorectal cancer: Making lemonade out of lemons?
Authors: Tannenbaum Daniel , Raghav Kanwal Pratap Singh , Horn Robert Asa , Overman Michael J. , Eng Cathy , Kopetz Scott , Johnson Benny , Morris Van K. , Parseghian Christine Megerdichian , Chang George J. , Rogers Jane Elizabeth , Parker Susan , Lopez-Olivo Maria de los Angeles , Dasari Arvind
Published: January 2019

656

Background: Despite multiple trials of new agents in metastatic colorectal cancer (mCRC), long term outcomes remain poor. This study explores the changing trends in the design, interpretation and outcomes of phase III randomized controlled trials (RCT) in mCRC over time. Methods: Phase III RCTs of systemic therapy for mCRC with enrollment between 1986 and 2016 were identified through 4 electronic databases and grouped into 3 time periods (1986-1996 – T1; 1997-2006 – T2 & 2007-2016 – T3). Study selection, quality appraisal and data collection were performed by 2 independent investigators. Study characteristics, primary and secondary endpoints, and authors’ interpretation of results and conclusions were analyzed. Improvement in overall survival (OS) was the difference between experimental and control arms. A study was deemed positive if it met its end point, was recommended for further study or for adoption for clinical use (p ≤ 0.05 significant for all analyses). Results: One hundred fifty trials (T1=36, T2=62, T3=52) with 77494 patients (T1=12406, T2=39158, T3=25930) were included. Although 1st line therapy trials continued to be the most common across all T, the percentage (%) of trials evaluating 3rd line and beyond (T1=0, T2=3, T3=27) have increased significantly over time as have trials with targeted agents (T1=11, T2=34, T3=79). Although OS remains the most common primary end point, more trials in T2 & T3 have used progression-free survival instead (14 vs 47 & 44). The % of trials with negative results but interpreted as positive increased over time (T1=18; T2=42; T3=35). Across all T, the median improvement in OS (months, m) of these trials was significantly lower compared to the trials that met primary end point across all T (T1 = 0 vs 1.8 m, T2 = -0.1 vs 3.25, T3 = -0.25 vs 2.55). Conclusions: A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced CRC. Any interpretations of potential survival benefits from trials that have not met primary end point must be made with significant caution.
Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes in patients with BRAF non-V600 mutated metastatic colorectal cancer.
Authors: Kotani Daisuke , Mondaca Sebastián , Parikh Aparna , Bando Hideaki , Van Seventer Emily , Taniguchi Hiroya , Yoshino Takayuki , Corcoran Ryan Bruce , Yaeger Rona , Ebi Hiromichi
Published: January 2019

659

Background: BRAF non-V600 mutations occur in 2-3% of colorectal cancer. These mutants can be classified as RAS independent (class 2) or RAS dependent (class 3). We reported BRAF non-V600 mutations could be a negative predictive factor for anti-EGFR therapy in patients (pts) with pretreated metastatic colorectal cancer (mCRC), while mCRC pts with class 3 BRAF mutations could respond to anti-EGFR therapy because of its dependency on receptors and RAS. Methods: This study evaluates the efficacy to anti-EGFR therapy in a large cohort of pts with BRAF non-V600 mutated mCRC. Pts with mCRC referred to the participating centers from 2010 to 2017 were included. Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes were stratified by BRAF mutational class. Results: One hundred seventeen pts with BRAF non-V600 mutated mCRC were identified. Median age was 58 years (range, 27-83), 68 pts (58%) were male, and 38 pts (33%) had right-sided tumors. Mucinous histology was seen in 11 cases (9%); concurrent RAS mutations occurred in 31 cases (27%), and 3 cases (3%) were MSI-H. Also, TP53 mutations were detected in 74 pts among 90 analyzed cases (82%). Regarding BRAF mutation subtype, 25/63/29 pts were classified as class 2/3/not reported (NR), respectively. Median OS in RAS wild-type/mutant were 44.8/34.6 months, respectively (p=0.082). The median OS in RAS wild-type pts with BRAF non-V600 mutations for class 2, 3, and NR were 25.7, 44.2, and 79.1 months, respectively (class 2 vs. 3, p=0.219). Among 40 pts treated with anti-EGFR therapy, response rates were 14%, 44%, and 40% for class 2, 3, and NR, respectively. Median PFS was 4.4, 8.3, 4.0 months for class 2, 3, and NR, respectively. Moreover, in 25 pts receiving anti-EGFR therapy as third or later line, response rate was 0%, 27%, and 50% in class 2, 3, and NR, and median PFS was 2.8, 3.7, and 4.0 months (p=0.762), respectively. Conclusions: Pts with class 2 BRAF mutations tend to have a poor prognosis compared to those with class 3 mutations. While almost half of pts with class 3 BRAF mutations responded to anti-EGFR therapy, response was rare for pts with class 2 BRAF mutations, and none achieved objective response in the third or later line.
Ambulatory 5FU infusion pumps: Patient perceptions and quality of life.
Authors: Al-Kadhimi Munaf , Hill Marisa E. , Fine Elita , Adess Matthew Eric , Polish Ari , Wiebe Lauren Allison , Whalen Margaret , Van Pelt Eileen , Callahan Teresa , Gustafson Cory , Collins Kathleen , Marsh Robert de Wilton
Published: January 2019

663

Background: Infusional-5-fluorouracil (inf-5FU), administered over 48 hours every 2 weeks, is frequently prescribed for the treatment of gastrointestinal cancers. A portable infusion device (ID) may be used for this purpose to enable treatment at home. At our institution, patients are educated by an oncology nurse as to what to expect, and how to function once they leave the infusion center. However, there is no formal process in place to report their experience and to record and analyze the results. The intended goal of this study was to accomplish this, such that the data could improve the education and experience of future patients. Methods: After verbal consent, a sequential cohort of patients, who had received 2 or more treatments with inf-5FU for gastrointestinal cancer, was invited to complete a de-identified paper questionnaire concerning their experience. Eleven specific questions suggested by the GI group were included, with an opportunity to add comments. The surveys were then collated and reviewed. Results: See table. Conclusions: While most patients felt well prepared by their medical team as to what to expect from the ID (93.1%), ≥ 25% had issues with bathing (73.6%), sleep (37.5%), exercising (30.6%), intimacy (26.4%), social interactions (25%) and anxiety (25%). These insights will be used to improve the education of future patients and a second assessment will follow. 72/72 patients approached over 6 months completed the survey with results below: [Table: see text]
Retrospective analysis of clinical characteristics of mCRC patients receiving three or more lines of chemotherapy.
Authors: Garcia Alfonso Pilar , Martínez Delfrade Íñigo , Soto Alsar Javier , Bringas Beranek Marianela , Gutiérrez Alonso Natalia , Ortega Laura , Torres Gabriela , Muñoz Martín Andres J. , Blanco-Codesido Montserrat , Calvo Aitana , Martin Miguel
Published: January 2019

682

Background: Prognostic and predictive factors are becoming more important in mCRC patients, and may have an impact in overall survival and in the number of lines of chemotherapy that a patient can receive. Methods: We conducted a retrospective analysis of 334 patients with mCRC. We analyzed the clinical characteristics of 113 (33.8%) mCRC patients who received ≥3 lines of chemotherapy. We apply the statistical test Chi square in order to identify significant association. Results: Several characteristics were significantly associated with receiving ≥ 3 lines of chemotherapy (n = 113): age < 80 years (n = 93, OR = 3.07, p = 0.001), ECOG 0-1 (n = 98, OR = 3.21, p = 0.055), primary tumor resection (n = 62, OR = 2.36, p = 0.000) and resection of metastases (n = 56, OR = 2.07, p = 0.002). Partial or complete response rate in the first line of chemotherapy was also significantly associated with receiving ≥ 3 lines of treatment (n = 65, p = 0.011). Tumor mutational status was analyzed in 333 patients: KRAS mutation was detected in 163 over 333 patients genotyped (48.9%), NRAS in 25/206 (12.1%), BRAF in 15/217 (6.9%) and PI3K in 31/213 (14.5%). In the group of patients receiving ≥ 3 lines of chemotherapy (n = 113): KRAS mutation was found in 60/113 patients (53.1%), NRAS in 5/77 (6.5 %), BRAF in 5/84 (5.9%) and PI3K in 8/80 (11.1%). Tumor mutations were not significantly associated with ≥ 3 lines of chemotherapy. No significant association was found between sex, tumor location (right [n = 33, 29.2%] or left [n = 76, 73%]), liver or lung isolated metastases and 3 or later lines of chemotherapy. We also performed in our database a survival analysis in the 334 patients: those who received ≥3 lines of chemotherapy had significantly higher survival rates (median OS 18 m in the group of < 3 lines of treatment vs. 37.2 m in the group of ≥ 3 lines of chemotherapy, HR = 1,6; CI 95% 1,2-2.1; p < 0,001). Conclusions: This retrospective analysis showed that mCRC patients with < 80 years, ECOG 0-1, primary tumor and or metastases resected and those with complete or partial response in the first line of treatment have a higher probability of receiving ≥ 3 lines of chemotherapy. [Table: see text]
Trecc: Re-challenge therapy with anti-EGFR in metastatic colorectal adenocarcinoma (mCRC).
Authors: Karani Amanda , Felismino Tiago , Diniz Lara Azevedo , Macedo Mariana Petaccia , Machado Larissa , De Brito Sales Diogo , Mello Celso Lopes
Published: January 2019

683

Background: Anti-EGFR plus chemotherapy (CT) promotes high response rates (RR) and median overall survival (OS) surpasses 30 months in RASwt/BRAFwt mCRC. After disease progression (PD), resistance mechanisms have been described. The aim of our study was to evaluate efficacy of anti-EGFR re-challenge (TRECC). Methods: We retrospectively analyzed a cohort of patients (pts) with mCRC. All pts had received anti-EGFR plus CT and were discontinued for different reasons. During the treatment, there was re-challenge with an anti-EGFR + CT. We aimed to evaluate progression-free survival (PFS) and OS after re-challenge and prognostic factors associated with PFS. Results: Sixty eight pts met the study criteria. Median follow-up after re-challenge was 39.3m. Discontinuation after first exposure was 25% due to PD; 75% for other reasons. Median anti-EGFR free interval was 10.5m. At re-challenge, main CT regime was: FOLFIRI 58.8%, Cetuximab and Panitumumab were used in 59 and 9 pts respectively. mPFS after re-challenge was 6.6m; mOS was 24.4m. Objective response rate (CR + PR) at re-challenge was 42.6%. In an univariate analysis, adverse prognostic factors related to PFS were: absence of objective response at 1st EGFR exposure (HR 2.12, CI:1.20-3.74 p = 0.009); PD as reason for 1st discontinuation (HR 3.44, CI:1.88-6.29 p < 0.0001); re-challenge at fourth or later lines (HR 2,51, CI:1.49-4.23 p = 0.001); panitumumab use (HR 2.26 CI:1.18-5.54 p = 0.017). In a multivariate model, only PD as reason for 1st discontinuation remained statistically significant (HR = 2.63, CI:1.14-6.03 p = 0.022). mPFS was 3.3m and 8.4m and mOS was 7,5m and 33,4m in patients with PD as reason for 1st discontinuation and other reasons respectively. Conclusions: Re-challenge therapy is commonly used due to paucity of effective lines of treament for mCRC. In our analysis, pts that stopped 1st anti-EGFR therapy due to PD have shorter survival, suggesting these pts do not benefit from TRECC. However, interruption due to treatment holiday after PR/CR resulted in longer PFS. In conclusion, for a selected group of pts, TRECC could be considered a strategy of treatment. Due to the limited number of pts, our data should be evaluated in a prospective cohort of patients.
Impact of sarcopenia on outcomes in patients with rectal carcinoma treated with trimodality therapy.
Authors: Sandoval Maria Luisa , Yuan Zhigang , Grass G. Daniel , Felder Seth , Sanchez Julian , Dessureault Sophie , Imanirad Iman , Kim Richard D. , Hoffe Sarah E. , Frakes Jessica
Published: January 2019

687

Background: Sarcopenia has been identified as a negative prognostic factor in several gastrointestinal malignancies. We sought to evaluate whether total psoas area (TPA) was predictive of grade ≥ 3 toxicity, recurrence and overall survival in patients with rectal carcinoma who received tri-modality therapy. Methods: After IRB approval, a retrospective analysis of 112 patients with biopsy-proven rectal cancer treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy was performed. The L4 vertebra was identified on pre-treatment axial CT and the bilateral psoas muscles were manually contoured to determine the skeletal muscle index, which was normalized by height. Sarcopenia was defined as TPA less than the median of the cohort. (< 1463 mm3/m). Acute toxicity was defined as within 3 months of radiation based on Common Terminology Criteria for Adverse Events version 4. Chi-square was used to assess differences between groups. Time to event analysis was estimated by Kaplan-Meier methods followed by log rank comparison. Predictor variables for outcomes were assessed with Cox regression. Results: Median follow-up was 31 months. Female gender was strongly associated with being sarcopenic (P < 0.001) otherwise no other differences in clinical or treatment characteristics were found. 20 patients (17.8%) developed recurrence (95% distant). Patients with sarcopenia had a decreased risk of recurrence (P = 0.048) as well as a longer time to recurrence from radiation (50 vs. 21.4 months, P = 0.006) and surgery (47.2 vs. 17.9 months, P = 0.006). Gender was not associated with risk of recurrence (p = 0.131). On multivariable analysis, absence of sarcopenia was predictive of time to recurrence following radiation (HR 4.7, 95% CI: 1.2-18.8; P = 0.03). The presence of sarcopenia was not associated with overall survival (P = 0.12) or grade ≥ 3 acute toxicity (P = 0.242). Conclusions: In our cohort, patients with sarcopenia appear to have better tumor control when compared to patients without sarcopenia independent of gender, suggesting this may be a predictor of treatment response. However, sarcopenia was not associated with overall survival or probability of having grade ≥ 3 acute toxicity.
Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Grothey Axel , Yaeger Rona , Cuyle Pieter-Jan AR , Huijberts Sanne , Schellens Jan H. M. , Elez Elena , Fakih Marwan , Montagut Viladot Clara , Peeters Marc , Desai Jayesh , Yoshino Takayuki , Ciardiello Fortunato , Wasan Harpreet Singh , Maharry Kati , Christy-Bittel Janna , Gollerkeri Ashwin , Van Cutsem Eric , Tabernero Josep
Published: January 2019

688

Background: BRAFV600E mutation occurs in 10%-15% of patients (pts) with mCRC and confers a poor prognosis. After first-line therapy, standard second-line therapies provide limited benefit, with objective response rates (ORRs) < 10%, and overall survival (OS) of 46 months (mo). BEACON CRC (NCT02928224) is a 3-arm phase 3 trial of triplet therapy with the BRAF inhibitor ENCO + MEK inhibitor BINI + antiEGFR antibody CETUX vs ENCO + CETUX vs a control arm (irinotecan/FOLFIRI + CETUX) in pts with BRAFV600E mCRC in the second or third-line setting. A safety lead-in (SLI) of the triplet therapy was conducted in 30 pts prior to initiation of the randomized part of the trial. Previously reported confirmed ORR in 29 pts with BRAFV600E mCRC was 48% and median progression-free survival (PFS) was 8.0 mo (Van Cutsem E, et al. Ann Oncol. 2018;29:O-027). Here we present updated safety and efficacy results including mature OS. Methods: All pts in the SLI received ENCO 300 mg once daily + BINI 45 mg twice daily + CETUX standard weekly dose. Assessments included efficacy (ORR, duration of response, time to response, PFS, and OS), safety, and tolerability. Results: Among 30 pts treated, 1 had a BRAF non-V600E mutation and is not included in the efficacy analyses. At data cutoff, the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.521.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95%CI, 29.467.5]; PFS, 8.0 mo [95% CI, 5.69.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 monot reached). The triplet continues to be well-tolerated with no unexpected toxicities. The most common grade 3/4 toxicities were fatigue (13%), anemia, increases in creatine phosphokinase and/or aspartate aminotransferase, and urinary tract infections (each 10%). The rate of grade 3/4 skin toxicities continues to be lower than generally observed with CETUX in mCRC. Conclusions: With longer follow-up, triplet therapy with ENCO + BINI + CETUX continues to be well tolerated. Median PFS and now mature median OS are substantially improved over historical data for current standard-of-care options. Clinical trial information: NCT02928224.
HIPEC scoring system: A preoperative model including clinical and radiographic parameters to improve patient selection.
Authors: Gauvin Gabrielle , Kilcoyne Maxwell , Ang Kwan-Keat , Selesner Leigh T , Egleston Brian L. , Farma Jeffrey M. , Sigurdson Elin R. , Reddy Sanjay S.
Published: January 2019

695

Background: Most studies looking at long-term outcomes in patients undergoing cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CS/HIPEC) are based on scoring systems performed at the time of the operation. With a morbidity as high as 67%, it is crucial to carefully choose the patients who will benefit from this procedure. In this study, we evaluated preoperative factors that could impact patient outcomes. Results were used to create a predictive model for patients considered for CS/HIPEC. Methods: Patients assessed for CS/HIPEC at our tertiary cancer center between 2012 and 2017 were considered for this study. Postoperative complications, recurrence free survival (RFS) and overall survival (OS) were used as endpoints, and multivariable analysis accounting for demographics, clinical, bloodwork, radiologic and pathologic findings was performed. Results: Sixty-eight patients were considered for CS/HIPEC. Preoperative elements found to have an impact on OS were lymph node involvement (p = 0.001) and high extent of carcinomatosis (p < 0.001) on computed tomography (CT) scan. Findings that impacted RFS were lymphovascular invasion (p = 0.042), lymph node involvement (p = 0.061) and omental caking (p = 0.010) on CT. Our preoperative predictive model is presented in table. An increased rate of complications was seen in smokers (p = 0.031), obese patients (p = 0.005) and carcinomatosis diagnosed ≤ 12 months from the primary diagnosis (p = 0.069). In our experience, performing CS/HIPEC did improve OS (p = 0.036) after adjustment for age, race, smoking, and BMI. Conclusions: Preoperative findings could help physicians in their discussions with patients prior to pursue CS/HIPEC. These interesting findings will be used to inform the next step of our study: a prospective clinical trial. [Table: see text]
A multivariate model to define risk groups among patients with curatively resected stage I and II colon carcinoma: Final report of a retrospective cohort study.
Authors: Onate-Ocana Luis F.
Published: January 2019

696

Background: Patients with stage I or II colon carcinoma (CC) have a 10 or 20% risk, respectively, of presenting recurrent disease after a potentially curative surgical resection and adjuvant chemotherapy have not improved survival in this setting. In this study, we present a multivariate model to define risk groups. Methods: Consecutive cases with stage I and II CC treated at a single cancer center in Mexico City, from January 1992 to December 2016, were included in this 25-year cohort. Clinical history and biochemical data were registered, and colon resection was performed with curative intention with standard lymphadenectomy. Standard hematoxylin-eosin slides and CDX2 immunohistochemistry (IHC) slides were analyzed by two independent pathologists. The Kaplan-Meier method and Cox model were used to analyze the association of prognostic factors and overall survival (OS). Results: 3,301 cases of colorectal cancer were treated during this study, but only 556 patients with stage I and II CC were included in the database: 266 women (47.8%) and 290 males (52.2%) (mean age 57.9 years); 52 (9.4%), 431 (77.5%), 36 (6.5%) and 37 (6.7%) were pTNM stages I, IIa, IIb, and IIc, respectively. R0 resection was performed in 548 patients (98.6) and R1 in 8 (1.4%). Location in the left colon (HR 1.63), hemoglobin (HR 0.93), serum albumin (HR 2.45), prognostic nutritional index 0.915), platelet count (HR 0.998), body mass index (HR 0.94), basal carcinoembryonic antigen (HR 1.0), TNM stage [stage I reference category, IIa (HR 5.46), IIb (HR 4.42), IIc (HR 9.28)], R1 residual disease (HR 2.8), negative CDX2 IHC (HR 2.1), and use of adjuvant chemotherapy (HR 0.629) were included in the final model as independent predictors of OS (model p < 0.0001).Predicted survival functions using this model defined three distinct risk groups. Conclusions: This multivariate model adds significant prognostic value to the pTNM classification. This model can be useful for stratifying prognosis in patients with CC and will aid in the design of randomized clinical trials evaluating the usefulness of adjuvant chemotherapy in this subgroup of patients with CC.
Assessing hematologic ratios as biomarkers for psychosocial distress.
Authors: Fong Abigail , Lafaro Kelly , Li Arthur X , Melstrom Laleh Golkar , Rodriguez Jenny , Clark Karen L. , Loscalzo Matthew J. , Warner Susanne
Published: January 2019

699

Background: Psychosocial distress is common among cancer patients and has been shown to have deleterious effects on a patient’s quality of life, treatment, and outcomes. Neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-monocyte ratio (PMR) have been associated with poor outcomes in some cancers. Therefore we hypothesized that these ratios may be correlated to distress. This study looked at request for social work follow up as a surrogate marker for distress and investigated relationships between these ratios and markers of patient distress. Methods: A validated 48 item electronic distress screen was administered to patients in the medical and surgical oncology clinics of a large cancer center from 2009-2015. Patient requests for social work follow up were noted and patient charts reviewed for relevant labs and history. Patient demographics, NLR, LMR, PMR were reviewed. Chi-squared tests and univariate and multivariate regressions were performed to compare groups and relationships of variables and outcomes. Results: 43% of patients surveyed requested social work follow up. Of those, 75% received follow up, at a mean of 8 days. Non-Caucasian patients were more likely to request social work follow up (p = 0.03). Non-English speaking patients (p = 0.06) and those who saw medical oncologists trended towards significant desire for social work follow up. There was no significant correlation between NLR, PMR, LMR and desire to see a social worker. On multivariate analysis, patients with metastatic disease were less likely to want social work follow up (OR 0.43, 95% CI: 0.21-0.9, P = 0.02). Conclusions: In this study, non-white, non-English speaking patients, and those seeing medical oncologists were more likely to request social work follow up. We found no significant correlations between NLR, PMR, LMR and request for social work follow up. This suggests that desire for social work follow up is not a good correlate for physiologic distress in cancer patients. Further work is ongoing to provide better insight into determinants of psychosocial and physiologic stress in this patient population along with relevance of hematologic ratios.