bluuebunny/crossref_metadata_2025 huggingface dataset:
Levels of oxidative stress and telomeres in Lynch syndrome-associated malignancies.
Authors: O'Kane Grainne , McGarrigle Sarah A. , Rehill Nadia , Farrell Michael P. , O'Sullivan Jacintha , Muldoon Cian , Mac Mathuna Padraic M. , Carney Desmond N. , Gallagher David James
Published: February 2017

582

Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair genes (MMR) genes which are critical in maintaining cellular integrity. Failure of the MMR pathway in LS culminates in the hypermutable phenotype of Microsatellite Instability. LS confers an increased risk of malignancy of which colorectal cancer (CRC) is most common. Carriers exhibit significant phenotypic variation in the age of onset of malignancy which cannot be predicted. Telomere length attrition is considered an early step in carcinogenesis and may be accelerated by oxidative stress. We investigated an association between relative telomere length (RTL) and levels of DNA oxidative damage in LS affected carriers (AC), unaffected carriers (UAC) and in patients with MMR- proficient colorectal cancer (MPC). Methods: Peripheral blood mononuclear cells were isolated from patients within each group. DNA was extracted and RTL measured by quantitative polymerase chain reaction (PCR). Real-Time PCR was used to quantitate expression levels of TERT, TERC and DKC1 (telomerase components) from RNA. Serum levels of 8-hydroxydeguanosine (8-OHdG) were measured from patients using the ELISA technique. Pearson’s correlation was used to compare mean RTL, telomerase levels and 8-OHdG between groups. Results: RTL and telomerase components were measured in 27 AC (median age 50yrs) 27 UAC (median age 40yrs) and 27 MPC (median age 66yrs). Corresponding RTLs were 0.89, 0.91 and 1.69 respectively. AC had significantly shorter RTL compared to UAC (p = 0.03) and MPC (p < 0.0001). There we no differences in the mean expression of TERT, TERC or DKC between groups. Younger age of tumour onset was associated with shorter telomere length in both AC (p = 0.0006) and MPC (p < 0.0001). 8-OHdG levels have been measured in 17 AC, 19 UAC and 14 MPC. The mean levels of AC and UAC were not statistically different. However the mean MPC level was significantly less than UAC (p = 0.03) and AC (p < 0.0001). Conclusions: Shortened telomere length is an important step in carcinogenesis. Affected LS patients have shorter telomeres and evidence of higher levels of DNA oxidative stress than patients with MMR-proficient CRC.
Therapeutic impact and timing of gastrointestinal malignancy genomic profiling: A single-institution experience.
Authors: Koenig Kristin Lynn , Burkart Jarred , Mikhail Sameh , Wu Christina Sing-Ying , Noonan Anne M. , Goldberg Richard M. , Bekaii-Saab Tanios S. , Ciombor Kristen Keon
Published: February 2017

584

Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.
Serum amyloid α (SAA-1) SNP rs12218 to predict outcome for mCRC patients treated with FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Berger Martin D. , Stintzing Sebastian , Heinemann Volker , Yang Dongyun , Sunakawa Yu , Ning Yan , Matsusaka Satoshi , Okazaki Satoshi , Miyamoto Yuji , Suenaga Mitsukuni , West Jordan David , Zhang Wu , Petasis Nicos , Lenz Heinz-Josef
Published: February 2017

586

Background: The formyl peptide receptor 2 (FPR2) plays a key role in regulating inflammatory processes and host defense by binding a variety of both pro- and anti-inflammatory ligands. As inflammatory mediators may represent a favourable soil for tumor initiation and progression, we hypothesize that genes encoding for FPR2 and its ligands may predict outcome in patients with metastatic colorectal cancer (CRC). Methods: Three hundred and one patients with CRC enrolled in the randomized phase III FIRE-3 Trial and treated with FOLFIRI and Bevacizumab were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. Eight functional SNPs in 8 genes (FPR2, ANXA1, ALOX5, ALOX12, ALOX15, SAA1, PLCB3 and PRKCB1) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: The SAA1 rs12218 variant showed significant association with progression-free survival (PFS). Patients harboring any T allele had a significantly longer PFS than those with a CC genotype in both univariate (p = 0.013) and multivariate analysis (p = 0.010). Conclusions: This is the first report demonstrating that the SAA1 polymorphism rs12218 might serve as a predictive marker in patients with metastatic CRC treated with FOLFIRI and Bevacizumab in the first line setting. Targeting SAA1, a proinflammatory ligand of FPR2, might be a promising approach to enlarge our treatment armamentarium against mCRC.
Predictive value of ERCC1 and KRAS in colorectal cancer patients with FOLFOX chemotherapy.
Authors: Lee In Kyu , Choi Sung-Bong , Cheung DaeYoung , Kim Jin Il
Published: February 2017

588

Background: To determine the clinical significance of KRAS mutation and ERCC1 overexpression as a predictive factor of resistance in oxaliplatin based treatment. Methods: We retrospectively analyzed the clinicopathologic features, status of KRAS mutation and ERCC1 overexpression of 386 colorectal cancer patients who received curative intent surgery. Among them 84 patients were treated by FOLFOX regimen as the first line. Their disease-free survival and overall survival according to the KRAS and ERCC1 were analyzed. Results: About a quarter of patients (25.5%) were represented KRAS wild type with ERCC1 overexpression. Among the patients who treated by FOLFOX regimen, 73 patients were evaluated both of the KRAS and ERCC1. There were no significant differences of disease-free survival and overall survival according to KRAS status and ERCC1 expression each. Under the subgroup analysis, overall survival of ERCC1 overexpression group in wild type KRAS was poor than ERCC1 negative group (p=.029), but no significant difference was in mutant KRAS group (p=.671). Conclusions: Our results suggest that the KRAS wild type with ERCC1 overexpression would be associated with the resistance of oxaliplatin.If oxaliplatin based chemotherapy would beconsidered, status of KRAS mutation and ERCC1 overexpression should be evaluated.
Novel mutational and pathway signatures in relapsed/refractory colorectal cancer patients.
Authors: Johnson Benny , Cooke Laurence , Mahadevan Daruka
Published: February 2017

591

Background: In the management of metastatic colorectal cancer (mCRC), all RAS (KRAS, NRAS) and BRAF V600E mutation status guides therapeutic options and identify a unique cohort of patients (pts) with a more aggressive clinical course. We hypothesized that relapsed/refractory CRC pts develop unique mutational signatures that guide standard and targeted therapy but also predict for therapeutic response, identify novel driver mutations and highlight key signaling pathways for clinical decision making. Methods: Relapsed/refractory mCRC pts (N=31) were molecularly profiled by NGS Caris Molecular Intelligence (IHC, FISH/CISH, NGS) and/or Foundation One (NGS, copy number). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation, domain, topology, and mutation count. Web-based bioinformatics tools (Enrichr/IntAct) were utilized to analyze mutational profiles, identifying pathway-networks. Results: Pts included progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab. Most common histology was adenocarcinoma followed by squamous cell carcinoma (colon N=28; rectal N=3). TP53 was the most common mutation followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average >5 unique gene mutations. High mutational burden was not predictive for PD-1 (5 pts) or PD-L1 (1 pt) positivity. The most common activated signaling pathways were: ERRB2/HER2, FGFR, p38 activation through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant oncogene mutations do not always equate with oncogenic dependence, therefore understanding the pathologic interactome in each patient is important to both identification of clinically relevant targets and choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to 1). Evaluate functional investigation in the laboratory, 2). Predict response to drug therapy, and 3). Guide rational drug combinations in relapsed/refractory mCRC pts entering targeted and immune checkpoint trials.
Post-operative C-reactive protein concentration: A potential therapeutic target following surgery for colorectal cancer?
Authors: Watt David G. , Park James Hugh , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C
Published: February 2017

597

Background: Post-operative C-reactive protein concentrations (CRP) have been reported to be associated with the development of complications following surgery for colorectal cancer (CRC). The development of complications and an exaggerated post-op CRP are associated with poor long term survival. However, whether this is due to the complication or to the CRP concentration remains unclear. Therefore, the aim of the present study was to determine whether post-op CRP concentrations, independent of post-op complications, were associated with poor long term survival following surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (1999-2013). The relationship between post-op CRP concentrations and overall survival (OS) was examined using Cox regression analysis. Results: 813 patients were included. The majority of patients were > 65 yrs (67%), male (55%) and underwent elective surgery (90%). 257 patients (32%) suffered a complication. Median follow up was 49 months with 314 deaths. In those undergoing elective surgery, 508 patients had an uncomplicated post-op course. In these patients, post-op CRP was significantly lower, on post-op days 2, 3 and 4 (p < 0.001) compared to those with complications. On univariate survival analysis, CRP concentrations on day 2 (HR 1.003, p = 0.008), 3 (HR 1.003, p = 0.024) and 4 (HR 1.003, p = 0.019) were associated with poorer overall survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 2 CRP (HR 1.003, p = 0.006), age (HR 1.70, p < 0.001) and TNM stage (HR 1.61, p < 0.001) were independently associated with poorer survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 3 CRP (HR 1.003, p = 0.030), age (HR 1.70, p < 0.001) and TNM stage (HR 1.63, p < 0.001) were independently associated with poorer survival. Conclusions: In patients undergoing elective surgery for CRC who have an uncomplicated post-op course, the post-op day 2 and 3 CRP concentrations were independently associated with poorer survival. Therefore, CRP could be considered a potential therapeutic target in future attempts to try and improve outcomes following surgery for CRC.
Oxaliplatin associated neurotoxicity outcomes among older adults with colorectal cancer: A population-based study.
Authors: Raphael Michael J. , Fischer Hadas , Fung Kinwah , Austin Peter , Booth Christopher M. , Anderson Geoffrey , Singh Simron
Published: February 2017

601

Background: The addition of oxaliplatin to fluorouracil-based regimens in the adjuvant treatment of colorectal cancer (CRC) has been shown to improve overall survival at the expense of increased toxicity. Toxicity may be higher among older patients who may also derive less benefit from oxaliplatin. The incidence of toxicity in the elderly is unknown. Methods: A cohort of patients ≥ 66 years old diagnosed with Stage II and III CRC between 2007 and 2011 in Ontario, Canada was identified using the Ontario Cancer Registry. Linked administrative databases were used to identify patients treated with oxaliplatin who were subsequently diagnosed with peripheral neuropathy (PN) or received a new prescription for a neuropathic pain medication. Patients were stratified into two age strata, ages 66-69 and ages ≥ 70, and each group was compared to a control cohort receiving non-oxaliplatin-based adjuvant chemotherapy (AC). Cause-specific hazard models were used to estimate the effect of Oxaliplatin exposure on the cause-specific hazard of PN and associated neurotoxicity outcomes after accounting for the competing risk of death. Results: We identified 3,607 patients aged ≥ 66 with Stage II and III CRC, of whom 1,541 were treated with an oxaliplatin-based AC regimen. Compared to control subjects receiving non-oxaliplatin based AC, patients ≥ 70 years old treated with oxaliplatin were more likely to be diagnosed with PN (cause-specific hazard ratio (CHR) age ≥ 70, 2.07 [95% CI, 1.43-3.00; p < 0.001]) and receive a new prescription for a neuropathic pain medication (CHR age ≥ 70, 1.86 [95% CI, 1.43-2.42;p < 0.001]). In patients aged 66-69, oxaliplatin use was not associated with a new diagnosis of PN (p = 0.903), but was associated with an increased likelihood of receiving a prescription for a neuropathic pain medication (CHR age 66-70, 1.92 [95% CI, 1.22-3.03; p = 0.005]). By the end of one year, the cumulative incidence of PN was 3.21% (95% CI, 2.02-4.81) for ages 66-69 and 5.51% (95% CI, 4.14-7.15) for age ≥ 70. Conclusions: In this population-based cohort of CRC patients ≥ 70 years old, treatment with oxaliplatin is associated with a significant risk of developing PN and requiring treatment with neuropathic pain medications.
Prognostic impact of primary tumor location on survival time in patients (pts) with metastatic colorectal cancer (mCRC) treated with cetuximab plus oxaliplatin-based chemotherapy: A subgroup analysis of the JACCRO CC-05/06.
Authors: Sunakawa Yu , Ichikawa Wataru , Tsuji Akihito , Denda Tadamichi , Segawa Yoshihiko , Negoro Yuji , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Tanioka Hiroaki , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Takeuchi Masahiro , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

613

Background: Sub-analyses of US and European randomized trials have demonstrated that primary tumor location is a critical prognostic factor in mCRC treated with 1st-line chemotherapy; moreover, left-sided tumor location may be a predictor of cetuximab efficacy in KRAS exon 2 wild-type tumors (Loupakis F, et al. J Natl Cancer Inst 2015; von Einem JC, et al. J Cancer Res Clin Oncol 2014). We therefore investigated the prognostic impact of primary tumor location on outcomes of Japanese pts enrolled in JACCRO CC-05 or CC-06 trial, which evaluated efficacy of cetuximab in combination with FOLFOX or SOX, respectively, for mCRC with KRAS exon 2 wild-type tumors. Methods: This study evaluated the association of tumor location with overall survival (OS) and progression-free survival (PFS) in mCRC pts from 2 phase II trials of 1st-line therapy; JACCRO CC-05 of cetuximab plus FOLFOX (n= 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n= 67, UMIN000007022). Tumors proximal or from left flexure to rectum were defined as right-sided or left-sided, respectively. Results: In total of 124 pts of the 2 trials, 110 pts were assessable for the primary tumor location: 90 pts with left-sided tumors and 20 pts with right-sided tumors. In the population consists of 110 evaluable pts, median PFS was 9.4 months, and median OS was 33.9 months. Left-sided tumors were significantly associated with longer OS (36.2 months vs. 12.6 months, HR 0.28, 95%CI 0.15-0.53, p< 0.0001) and PFS (11.1 months vs. 5.6 months, HR 0.47, 95%CI 0.29-0.82, p= 0.0041) compared to right-sided tumors. The association was evident in the group of FOLFOX (p< 0.0001 for OS and p= 0.0002 for PFS), while there was a trend in OS of the group of SOX (p= 0.079). In the FOLFOX-group, median OS and PFS were 5.7 and 3.0 months, respectively, for right-sided tumors (n= 9) and 42.8 and 11.3 months, respectively, for left-sided tumors (n= 43). Conclusions: Our study demonstrates that primary tumor location may serve as a predictor of prognosis of mCRC pts treated with cetuximab plus oxaliplatin-based therapy, potentially confirming the prognostic impact of tumor location.
Relations of T-cell and B-cell area ratios and the number of natural killer cells (NK cells) in lymph nodes (LNs) to outcomes in patients with stage II colon cancer.
Authors: Okada Kazutake , Sadahiro Sotaro , Miyakita Hiroshi , Saito Gota , Tanaka Akira , Suzuki Toshiyuki , Masuda Shinobu
Published: February 2017

618

Background: In stage II colon cancer, patients with many retrieved LNs have good outcomes. We previously reported that the longest diameter of retrieved LNs correlates with the number of LNs and can be used as a prognostic factor (Int J Colorectal Dis 2015). LNs can be divided into three main regions, cortex, paracortex, and medulla, and consist mainly of T cells, B cells, NK cells, and histiocytes. We studied the relations of the T-cell, B-cell area ratios, and the number of NK cells in longest-diameter LNs to the number of retrieved LNs and outcomes. Methods: The subjects were 320 patients with stage II colon cancer who underwent curative resection. One LN with the maximum long-axis diameter was selected, and was immunostained with CD3 as a T-cell marker, CD20 as a B-cell marker, and CD56 as an NK-cell marker. Positive area ratio was determined by image analysis. The number of CD56-positive cells were examined and the mean number per 0.093 mm2was calculated. The relations were evaluated with the use of Spearman’s rank correlation coefficient. The cut-off values were calculated by ROC curve analysis. Results: The number of LNs was 14.8 ± 10.4 (mean ± SD). The CD3-positive area ratio was 0.39 ± 0.08. The CD20-positive area ratio was 0.42 ± 0.10. The number of CD56-positive cells was 9.9 ± 10.1. The correlation coefficients for the number of LNs with CD3-positive area ratio, CD20-positive area ratio, and the number of CD56-positive cells were respectively -0.07 (p = 0.220), 0.05 (p = 0.360), and 0.33 (p < 0.001). The number of LNs positively correlated with the number of CD56-positive cells. The median follow-up period was 118 months. Patients with a CD20-positive area ratio of 0.43 or greater (n = 160) had a significantly better survival (HR, 0.64; 95%CI, 0.44-0.92; p = 0.015). Patients with 3 or more CD56-positive cells (n = 276) had a significantly better survival (HR, 0.57; 95%CI, 0.37-0.93; p = 0.017). Conclusions: A high number of NK cells in longest-diameter LNs was associated with a higher number of retrieved LNs, a longer LN diameter, and better survival. NK cells in the longest LNs may reflect the host antitumor immune response in patients with Stage II colon cancer.
Frequency of HER2 mutations and amplification in GI malignancies and ability of pertuzumab to overcome neuregulin1 mediated drug resistance to a HER2 tyrosine kinase inhibitor in colon cancer.
Authors: Bose Ron , Ali Siraj , Jain Naveen , Gowen Kyle , Bertotti Andrea , Murray Elisa , Ross Jeffrey S. , Beattie Mary Stanley , Hurwitz Herbert , Hainsworth John D.
Published: February 2017

630

Background: HER2 amplifications and activating mutations are an emerging drug target in the treatment of colorectal cancer (CRC). Ongoing studies, such as MyPathway (Clinicaltrials.gov NCT02091141), include basket trials of targeted therapies for multiple solid tumor types. The frequency of HER2 mutations in GI cancers and a drug resistance mechanism to the HER2 kinase inhibitor, afatinib, are presented here. Methods: The Foundation Medicine database of 53,126 cases was searched and clinical data from patients with GI tumors enrolled in the HER2 basket of MyPathway was included. Results: 10,358 patients with GI cancers and FoundationOne (FO) testing were identified and compared to the HER2 mutation frequency reported by The Cancer Genome Atlas (TCGA). In MyPathway, 28 GI tumors with HER2 alterations are enrolled: CRC (n = 13, all amplified), liver/biliary (n = 5), pancreatic (n =4), small intestine (n = 3), and esophageal (n = 2). Several CRC patients demonstrated responses to trastuzumab/pertuzumab (reported separately). The HER2 mutant CRC cell lines, CW-2 and CCK-81, are highly sensitive to afatinib (IC50=7-20 nM). Addition of the HER3 ligand, neuregulin1 caused afatinib resistance, but pertuzumab prevented HER3/HER2 activation and reversed this drug resistance. Conclusions: HER2 mutations or amplifications are commonly found in a wide range of GI cancers. Pre-clinical data provide rationale for inclusion of pertuzumab in the treatment strategy for these cancers. The MyPathway Trial is testing this approach. [Table: see text]
Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab.
Authors: Cascinu Stefano , Zaniboni Alberto , Lonardi Sara , Rosati Gerardo , Nasti Guglielmo , Giordano Monica , Corsi Domenico C. , Ferraú Francesco , Iaffaioli Rosario Vincenz , Marchetti Paolo , Aglietta Massimo , Bilancia Domenico , Ronzoni Monica , Floriani Irene Claudia , Labianca Roberto
Published: February 2017

632

Background: FOLFOX/FOLFIRI are effective as first-line treatment but FOLFOX might be more effective in second line. The optimal first-line in RAS wild type mCRC is still unclear even after 2 trials comparing chemotherapy with bevacizumab or cetuximab. While bevacizumab seems to loose efficacy across treatment lines, cetuximab has a similar activity across all treatment lines. It might be a better choice for the third-line in the view of an optimal sequence strategy. We designed a phase III randomised trial to compare two different treatment sequences of cetuximab and FOLFOX in mCRC patients refractory to FOLFIRI/bevacizumab first-line. Methods: Pts were randomized to receive Irinotecan/Cetuximab as 2nd line followed by FOLFOX-4 as 3rdline (Arm A) or the inverse sequence. Primary endpoint was progression free survival (PFS); secondary endpoints were overall survival and toxicity. 101 events were required in order to detect an hazard ratio of 0.57, translating in an increase of median PFS from 4 to 7 months (two-sided type I error 5%, power 80%). Results: 110 mCC pts were enrolled in this trial: 64 pts were males and 46 females with a mean age of 61 years. Efficacy results are reported in the table. Treatment was well tolerated with a low number of serious adverse reactions (2 in each treatment arm). Conclusions: Cetuximab is less effective immediately after bevacizumab. This is in accordance with data suggesting that EGFR inhibition is not active after VEGF blockade. The sequence of biological agents seems to be more relevant than the first-line choice. In RAS wild type patients progressing after a first line bevacizumab based therapy cetuximab should be given as first line or third line. Clinical trial information: NCT01030042. [Table: see text]
Real-world cancer regimen costs for metastatic colorectal cancer patients treated with biologics in first- through second-line.
Authors: Johnston Stephen , Riehle Ellen , Varker Helen , Juneau Paul , Wilson Kathleen , Sommer Nicolas , Ogale Sarika
Published: February 2017

636

Background: This study examined real-world cancer regimen costs for metastatic colorectal cancer (mCRC) patients treated with biologics in first- (1L) through second-line (2L). Methods: Using a large U.S. commercial/Medicare supplemental insurance claims database, patients with mCRC initiating a 1L bevacizumab (BEV) or cetuximab (CET) containing regimen between 1/1/2008-8/31/2014 and transitioning to a 2L biologic-containing regimen (BEV, CET, panitimumab [PAN], regorafenib [REG], or ziv-aflibercept [ZAF]) were identified. Monthly costs of cancer regimens (biologic/administration, chemotherapy/administration) were measured over a follow-up period beginning at initiation of 1L therapy and ending at the discontinuation of 2L therapy, inpatient death, insurance disenrollment, or 9/30/2014. Results: Among 2,352 patients, mean monthly biologic costs for 1L+2L ranged from $6,738 in the 1LBEV-2LBEV group, to $12,568 in the 1LCET-2LOther group (Table). In contrast, chemotherapy costs ranged from $1,898 in 1LCET-2LOther group to $4,070 in the 1LBEV-2LBEV group. Conclusions: Mean total cancer regimen costs per month for the 1L+2L sequence tended to be lower for patients treated with 1L BEV-containing regimens, compared with 1L CET-containing regimens. The majority of 1L-BEV patients also received BEV in 2L (TML). These agents' real-world comparative costs are an important consideration in treatment decisions. [Table: see text]
Conversion to resectability in unresectable metastatic colorectal cancer chemotherapy (mCRC) trials.
Authors: Chrabaszcz Sarah , Rajeev Rahul , Klooster Brittany , Chinn Ashley , Gamblin T. Clark , Johnston Fabian McCartney , George Ben , Banerjee Anjishnu , Turaga Kiran
Published: February 2017

641

Background: Patients with mCRC undergoing surgical metastasectomy have been shown to derive significant survival benefit with a potential for cure. We hypothesized that conversion to resectability (c2r) is correlated with increased overall survival in patients with unresectable mCRC. Methods: Prospectively registered systematic review (PROSPERO CRD42015024104) was utilized to identify randomized clinical trials published after 2003. Exposure of interest was c2r from unresectable disease, while the outcome was overall survival (OS). Clinical trials were classified into three groups based on difference in c2r between the two study groups ( < 2, 2-2.9, ≥ 3 %). Generalized estimating equations(GEE) were used to measure associations while adjusting for multiple observations from the same trial. The Cochrane risk of bias tool was used to evaluate the methodological quality. Results: Out of 2,902 studies reviewed, 30 satisfied selection criteria (n = 13,618 patients). All studies had two arms only (100%). Median c2r was 7.3% (Interquartile Range 5%-12.9%), with maximum c2r in FOLFOX/FOLFIRI+ cetuximab arm (28.6%). The median difference in c2r between two arms of the same study was 2.3% (IQR 1.3 – 3.4%) and the maximum difference was 15.4% seen in FOLFOX/FOLFIRI+ cetuximab vs. FOLFOX/FOLFIRI (Ye, 2013). Median OS for the entire cohort of patients was 20.7 months (IQR 18.9 – 22.7 months), with a between group difference of 1.3 (IQR -1.2 – 3.6 months). The maximum survival benefit between two study arms was 9.9 months. Median survival difference between the two study arms with a minimal c2r difference ( < 2%) was 0.8 months, as compared to 1.6 months with higher c2r ( ≥ 3%). Incremental dose effect response was noted with an increasing c2r leading to improved overall survival in regression models (p = 0.021, r2= 0.16). Higher response rates also correlated with higher c2r rates (p = 0.003, r2= 0.25). Conclusions: Conversion to resectability is positively correlated with an improvement in survival in trials examining therapies for unresectable mCRC. Patient level data examining the contribution of metastasectomy to the overall survival benefit of systemic chemotherapy needs to be further examined.
Effect of combined neoadjuvant chemoradiation on overall survival for patients with locally advanced rectal cancer.
Authors: Sun Zhifei , Adam Mohamed A , Kim Jina , Hsu Shiao-Wen D , Palta Manisha , Czito Brian G. , Migaly John , Mantyh Christopher
Published: February 2017

657

Background: Prospective randomized trials have demonstrated that neoadjuvant chemoradiation improves local control and results in a higher rate of sphincter-sparing surgery for patients with locally advanced rectal cancer. However, neoadjuvant therapy utilization and population-based outcomes are not well defined. Methods: Adults with stage II/III rectal adenocarcinoma within the National Cancer Data Base undergoing surgery between 2006-2012 were analyzed. Patients were grouped by type of neoadjuvant therapy received: no therapy, chemotherapy only, radiotherapy only, or concomitant chemoradiation. Multivariable modeling was used to compare perioperative outcomes and overall survival between groups. Results: Among 32,978 patients included, 9,714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1,170 (3.5%) radiotherapy only, and 21,204 (64.3%) concomitant chemoradiation. 5-year overall survival among groups was 62%, 69%, 71%, and 74%, respectively. Compared to no therapy, chemotherapy or radiotherapy alone was not associated with any differences in perioperative or oncologic outcomes (all p > 0.05). With adjustment for patient and disease characteristics, neoadjuvant chemoradiation was associated with a lower likelihood of margin positivity (OR 0.74, p < 0.001), need for permanent colostomy (OR 0.77, 95% CI 0.70-0.85, p < 0.001), 30-day mortality (OR 0.67, p = 0.003), and overall survival (HR 0.69, p < 0.001). When compared to chemotherapy or radiotherapy alone, neoadjuvant chemoradiation was still associated with improved overall survival (vs. chemotherapy: HR 0.83, p = 0.04; vs. radiotherapy: HR 0.75, p < 0.001). Conclusions: Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter-preservation and survival for patients with locally advanced rectal cancer. Despite this finding, one third of patients with locally advanced rectal cancer are failing to receive this therapy in the United States.
Stereotactic body radiation therapy for local control of liver metastases from colorectal cancer.
Authors: Joo Ji Hyeon , Kim Jong Hoon
Published: February 2017

662

Background: Although possible candidates for surgical treatment are increasing, majority of colorectal cancer patients with liver metastases are ineligible for surgery. In our institution, SBRT for liver metastatic colorectal carcinoma has been adopted since 2005. By reviewing the treatment outcomes of relatively large cohorts treated with homogeneous technique, we aimed to report patterns of recurrence and the most effective dose fractionation schedule. Methods: Seventy patients with colorectal liver metastases were treated with SBRT from 2005 to 2014. Total number of treated lesions was 103. Median tumor size was 2.5 cm, with ≥ 3 cm in 42 (41%) lesions. Prescribed doses were biologically equivalent dose (BED) ≥ 112 Gy10, but, if small bowel is adjacent to target volume, dose was decreased according to the normal tissue tolerance dose. Prescription doses relevant to BED ≥ 112 Gy10 were ≥ 45 Gy in 3 fractions or ≥ 60 Gy in 5 fractions, in this study. Results: Median follow-up period was 34.2 months (range, 5.3-121.8). The 2-year local control rate was 92% when full prescription dose was delivered, and 73% if compromised dose group was included. On prognostic factor analysis for local control, N-stage (P= 0.008), and BED (P= 0.001) were significant factors. Overall survival rate was 86% for BED ≥ 112 Gy10 group, and 73% for total cohort. The major pattern of failure was out-of-field intrahepatic progression. On multivariate analysis, N stage (P= 0.001), lesion size (P= 0.010) and number of treated hepatic lesions (P< 0.001) were significant factors for intrahepatic control. Conclusions: Liver SBRT was an effective treatment option for colorectal liver metastases. If BED ≥ 112 Gy10 was delivered, we could expect long-term survival in substantial portion of patients. Major pattern of failure was out-of-field intrahepatic progression, which was related to number of treated hepatic lesions, lesion size and N-stage.
Assessment of treatment with panitumumab, cetuximab, and bevacizumab among mCRC patients with wild-type RAS or BRAF treated at community cancer centers in the United States.
Authors: Lowe Kimberly , Garawin Tamer , Kelsh Michael Anthony , Bohac Gerry C.
Published: February 2017

663

Background: There is limited observational data on the use of RAS test results and treatment patterns with chemotherapy and biologics among metastatic colorectal cancer (mCRC) patients. Our objective was to use real world data to evaluate the treatment sequences of mCRC patients who have wild-type RAS (KRAS, NRAS), or BRAF and who are treated at community cancer clinics within the United States (U.S.). Methods: The sample included 536 patients in the Oncology Services Comprehensive Electronic Records (OSCER) database who were diagnosed with mCRC between 1/1/2011 and 8/31/2015. All patients had available treatment data and were confirmed to have wild-type RAS or BRAF. Patients were stratified into mutually-exclusive categories based on 1st line treatment with chemotherapy in combination with either bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab), a combination of Pmab, Cmab or Bmab, or no biologics. Descriptive statistics were used to summarize the data. Results: The demographics of the sample were as follows: mean age 67 years (standard deviation = 12), 55% male, 70% White, and 50% with ECOG value of zero. The use of Bmab, Cmab, or Pmab in combination with chemotherapy in 1st line treatment was follows: Bmab only (n = 270, 50%), Cmab only (n = 81, 15%), Pmab only (n = 28, 5%), and a combination of either Bmab, Cmab and/or Pmab (n = 6, 1%). No biologics were administered to 151 (28%) of the sample in 1st line. There were no statistically significant differences in age, gender, race, insurance type, region of the U.S. or ECOG status at mCRC diagnosis across the 1st line treatment categories. Of the 385 patients who received a biologic in 1st line, 94 (24%) of those who survived and selected to continue treatment received a biologic in 2nd line. Of these 94 patients, 25 (27%) of those who survived and selected to continue treatment also received a biologic in 3rd line. Conclusions: Bmab was the most commonly-used biologic among mCRC patients with wild-type RAS or BRAF in this descriptive study. Future research is needed to better understand what factors impact treatment decisions among mCRC patients.
Two-stage hepatectomy for colorectal metastases: Association of a good pathologic response to intensified preoperative chemotherapy with second stage completion and longer survival.
Authors: Quenet François , Pissas Marie-Hélène , Gil Hugo , Roca Lise , Carrere Sebastien , Alline Mathias , Rouanet Philippe , Saint-Aubert Bernard , de Forges Helene , Khellaf Lakhdar , Samalin Emmanuelle , Portales Fabienne , Sgarbura Olivia , Ychou Marc , Bibeau Frederic
Published: February 2017

666

Background: The two-stage surgical resection (TSR) of bilobar colorectal liver metastases (CRLM) is widely used and has shown encouraging survival results. The risk of drop-out after the first-stage hepatectomy remains high and associated with poor survival rates. Our objective was to evaluate the predictive factors of long-term survival, based on the pathologic response to an intensified systemic chemotherapy administered preoperatively. Methods: Data from 899 patients treated for CRLM in our institution were collected prospectively between January 2003 and August 2013. We evaluated the pathologic response to preoperative chemotherapy, and its impact on the second-stage completion and on survival. Results: Sixty-seven patients were eligible for the TSR first stage. All patients underwent an intensified chemotherapy in combination with a biotherapy (Bevacizumab or Cetuximab) in 38cases. The Tumour Regression Grade (TRG), the Blazer grade, and the modified-TRG were used to classify patients as responders (TRG and mTRG 1-3, Blazer 0-1) or non-responders (TRG and mTRG 4-5, Blazer 2) after the first stage. Responders in the three classifications (TRG: p = 0.033; mTRG: p = 0.03, Blazer:p = 0.005), and initial metastases number (p = 0.001) were independent predictive factors for the second-stage completion. Triple chemotherapy were associated with responders in the three classifications (TRG and mTRG: 73.7% versus 26.3% p < 0.0001 ; Blazer : 84.2% versus 15.8% p = 0.001). Median overall survival (OS) of patients who completed TSR was significantly different (44, 84 versus18,39 months; p < 0.0001). There was no statistical difference in OS and recurrence-free survival between the responders and non-responders. Conclusions: A good pathologic response to intensified preoperative chemotherapy is associated with completion of the second stage of TSR, and thus with a longer survival. Knowing this response before the first-stage resection may allow avoiding useless resections for patients who will not benefit from this strategy.
Loco-regional outcomes of a population-based cohort of rectal neuroendocrine tumors.
Authors: Tsang Erica S , McConnell Yarrow Jean , Schaeffer David F. , Speers Caroline , Kennecke Hagen F.
Published: February 2017

668

Background: Optimal management of rectal neuroendocrine tumors (NETs) is not well defined. We characterized the clinicopathologic features, loco-regional, and systemic management of a population-based cohort of rectal NETs. Methods: Patients diagnosed with rectal NETs from 1999-2011 were identified from British Columbia provincial databases. NETs were classified as G1 and G2 tumors with a Ki-67 ≤ 20% and/or mitotic count ≤ 20 per high power field. Results: Of 91 rectal NETs, median age was 58 (IQR 48-65) years and 35 (38%) were male. Median tumor size was 6 (IQR 4-8) mm. Median overall survival was 164.7 months, with 3 patients presenting with stage IV disease. Treatment included local excision (n = 79), surgical resection (n = 6), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 (20%) cases. Local relapse occurred in 8 (9%) cases, and one relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and T classification, Ki-67, mitotic count, grade, and perineural invasion (p< 0.01), but not N or M classification, or lymphovascular invasion. Local relapse was not associated with surgical management or margin status. Of 3 patients with metastatic disease, two received systemic management, with capecitabine and temozolomide. Conclusions: Rectal NETs generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. [Table: see text]
ARID1A alterations in gastrointestinal cancers as therapeutic opportunities.
Authors: Basu Gargi D. , White Tracey , LoBello Janine R , Lau Kevin R , Syring Michael , Krishnan Subha , Gonzalez Laura , Royce Thomas , Kurdoglu Ahmet , Halbert Matthew J , Kiefer Jeff , Cherni Irene , Aldrich Jessica , Izatt Tyler , Russell Megan , Nasser Sara , Carpten John D. , Craig David W. , Demeure Michael J
Published: February 2017

671

Background: The gene encoding the AT-rich interacting domain (ARID1A) is a tumor suppressor and a subunit of the Switch/Sucrose Non fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression. Additionally, ARID1A functions to maintain genomic integrity by interacting with ATR. Mutations in ARID1A have been observed in a number of cancers. Inactivation of ARID1A has been reported to lead to increased sensitivity to inhibitors of PARP and PI3K/AKT pathway. We evaluated ARID1A alterations in gastrointestinal (GI) cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed on 55 GI cancer samples with 28 metastatic and 27 primary samples. Targeted sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA samples. Results: ARID1A alterations were noted in 20% (11/55) of GI cancers. Alterations included frameshift and nonsense mutations, INDELs and structural breakpoints which are predicted to cause loss of ARID1A function. Tumor tissues harboring ARID1A alterations included 2/8 gastro-esophageal cancers, 2/2 duodenal cancers, 3/29 colorectal (CRC) cancers, 2/2 small bowel cancers, and 2/7 bile duct cancers. Mutations in the C-terminal half of ARID1A, known to interact with ATR and mediate its recruitment to double strand breakpoints was present in 2/11 samples. No pathogenic changes in the DNA repair genes (BRCA1/2, CHEK1/2, ATM, ATR or PALB2) or MMR genes were present in the tumors harboring ARID1A alterations. Interestingly, ARID1A mutations frequently coexisted with alterations leading to activation of the PI3K pathway. We found 45% (5/11) samples with mutated ARID1A had pathogenic alterations in PIK3CA, AKT, NF1, STK11, TSC1 and TSC2 genes which may increase sensitivity to PI3K pathway inhibitors. Conclusions: Targeted sequencing demonstrated that ARID1A is a frequent event in GI cancer. Our results suggest there may be a correlation between samples with ARID1A alteration and PI3K/AKT pathway activation which may lead to therapeutic opportunities with PI3K pathway inhibitors. The presence of ARID1A mutations especially those in the C-terminal half may predict clinical utility of PARP inhibitors in GI cancer.
Optimal timing for curative surgery after preoperative chemoradiotherapy in locally advanced rectal cancer.
Authors: Kwak Yoo-Kang
Published: February 2017

677

Background: This study is a multicenter retrospective analysis conducted by the Korean Radiation Oncology Group (KROG) to identify the optimal operation timing after preoperative chemoradiotherapy (CRT) in rectal cancer. Methods: The study included data of 1786 patients who were diagnosed with locally advanced rectal cancer (cT3-4N0-2M0) and received preoperative CRT followed by curative surgery from 2003 to 2014, at 8 institutions in Korea. Total radiation dose was 50.4 Gy in 28 fractions, delivered in 1.8 Gy per fraction. All patients received total mesorectal resection. Interval time between preoperative CRT and surgery ranged from 1 week to 136 weeks, and median interval time was 7 weeks. Downstaging rate was assessed by comparing clinical pre-CRT and pathological post-CRT stages and downstaging was defined as ypStage 0-I (ypT0-2N0M0). Pathologically complete response (ypCR) was defined as the complete absence of viable tumor (ypT0N0M0). Primary end point of this study was to evaluate the period of highest downstaging and ypCR rates to determine the optimal timing for surgery after CRT. Results: Analyses on downstaging and ypCR rates were done with all patients. Downstaging rates peaked between 6 and 7 weeks and declined afterwards. ypCR rates increased from 5 to 6 weeks and decreased after 9 to 10 weeks. The patients were divided into two arms according to the median interval time between preoperative CRT and surgery. Downstaging rates were similar between the two arms showing 36.9% in the early arm (≤ 7 weeks) and 37.0% in the delayed arm ( > 7 weeks). However, ypCR rates were significantly higher in the delayed arm, compared to the early arm (12.3% vs. 8.6%, p = 0.011). Complete tumor regression was superior in the delayed arm, as compared to the early arm (13.2% vs. 9.1%, p = 0.004). The delayed arm had higher sphincter preservation rates than the early arm with a marginal significance (92.4% vs. 89.9%, p = 0.078). There was no statistically significant difference regarding overall survival and disease-free survival. Conclusions: The optimal timing for surgery for advanced rectal cancer is after 7 weeks and before 10 weeks following preoperative CRT.
Clinical effectiveness of adjuvant chemotherapy (AC) with or without oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) in stage II rectal cancer (RC).
Authors: Loree Jonathan M. , Kennecke Hagen F. , Powell Erin Diana , Goodwin Rachel Anne , Tang Patricia A. , Heng Daniel Yick Chin , Price Hiller Julie A. , Monzon Jose Gerard , Vickers Michael M. , Cheung Winson Y.
Published: February 2017

686

Background: Use of AC in RC following nCRT is controversial because of concerns regarding its potentially small magnitude of benefit. We aimed to 1) examine real-world patterns of AC use in stage II RC and assess its impact on outcomes and 2) determine whether the addition of oxaliplatin to fluoropyrimidines modifies effectiveness. Methods: Using a cohort of yp stage II RC patients from 5 Canadian centers that underwent curative surgery, we assessed the relationship between AC +/- oxaliplatin and overall (OS) and disease free survival (DFS). Cox models adjusting for age, gender, ECOG, and high risk features (T4 lesion, poor differentiation, inadequate lymph node sampling, lymphovascular/perineural invasion, and obstruction/perforation) were constructed. Results: Among 485 pts, 74% received AC of whom 19% received oxaliplatin-based treatment. Median follow up was 4.5 yrs. Pts in the AC group were younger (median age 61 vs 64; P= 0.003) and had higher rates of TME (82% vs 79%; P= 0.049), but they had similar demographics, ECOG, high risk features, preoperative CEA, margin status and nCRT regimen when compared to pts in the non-AC group (all P> 0.05). Multivariate analyses demonstrated that receipt of any AC (OS HR 0.93 95% CI 0.58-1.50 P =0.77; DFS HR 0.91 95% CI 0.58-1.43 P =0.69), fluoropyrimidine AC (OS HR 0.82 95% CI 0.49-1.36 P =0.44; DFS HR 0.83 95% CI 0.51-1.34 P =0.44), or oxaliplatin-based AC (OS HR 1.37 95% CI 0.74-2.55 P =0.32; DFS HR 1.17 95% CI 0.66-2.05 P =0.59) did not improve outcomes versus no AC. In subgroup analyses that stratified pts by high risk features, presence of 1, 2, or 3 high risk factors, preoperative CEA and margin status, AC did not result in better OS or DFS in any subgroup. A further exploratory analysis that focused only on those receiving AC within 12 weeks of surgery did not reveal any consistent correlations between AC and survival. Conclusions: Use of fluoropyrimidine or oxaliplatin-based AC in this multi-institutional cohort of yp stage II RC pts after nCRT did not improve outcomes compared to observation. Conventional high risk features used to risk stratify stage II colon cancer for AC decision making have limited utility in RC after nCRT.