bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of irinotecan and oxaliplatin as adjuvant chemotherapy for patients with resectable synchronous colon cancer plus liver-confined metastases: A retrospective nationwide database study.
Authors: Liang Yi-Hsin , Shao Yu Yun , Chen Ho-Min , Cheng Ann-Lii , Lai Mei-Shu , Yeh Kun-Huei 
Published: March 2017

624 Background: Although irinotecan and oxaliplatin are both standard treatment for advanced colon cancer, it was unclear whether either was effective for patients with resectable synchronous colon cancer plus liver-confined metastasis (SCCLM) after curative surgery. Methods: We established a population-based cohort of patients diagnosed with de novo SCCLM between 2004 and 2009 by searching the database of Taiwan Cancer Registry and National Health Insurance Research Database of Taiwan. Patients who received curative surgery as the first therapy followed by chemotherapy doublets were classified into two groups: irinotecan group, or oxaliplatin group. Patient who received radiotherapy or did not receive chemotherapy doublets were excluded. Results: We included 6533 patients with de novo stage IV colon cancer, and 309 of them received chemotherapy doublets after surgery; 77 patients received irinotecan, and 232 patients received oxaliplatin as adjuvant chemotherapy. Patients in the irinotecan group and patients in the oxaliplatin group exhibited similar overall survival (OS) (median: not reached vs. 40.8 months, p = 0.151) and time to the next line of treatment (median: 16.5 months vs. 14.3 months, p = 0.349) in both univariate and multivariate analyses. Patients with resectable SCCLM had significant shorter median OS than patients with stage III colon cancer who received curative surgery and subsequent adjuvant chemotherapy but longer than patients with de novo stage IV colon cancer who received surgery only to the primary site and standard systemic chemotherapy ( p< 0.001). Conclusions: Either irinotecan or oxaliplatin exhibited similar efficacy for patients who received curative surgery for resectable SCCLM. [Table: see text]
Systematic assessment of intra- and peri-metastatic tumor budding in patients with stage IV colorectal cancer.
Authors: Blank Annika , Burren Sandra , Zlobec Inti , Dawson Heather , Lugli Alessandro 
Published: March 2017

626 Background: Tumor budding is a strong independent prognostic factor in primary colorectal cancer (CRC). The prognosis of stage IV CRC is still poor and there is need for biomarkers to facilitate the clinical management. Data on tumor budding in colorectal cancer distant metastases (CRDM) are still missing. Therefore, the aim of this study was to analyze its role in tumor progression. Methods: 73 stage IV CRC with clinico-pathological data were retrieved from a cohort of 331 CRC patients, surgically treated between 2002 and 2013 at the University Hospital of Bern. Tumor budding was visualized immunohistochemically by pan-cytokeratin staining. Tumor budding was defined as intra- and peri-tumoral budding in the primary tumor (ITB = buds in the tumor center; PTB = buds at the tumor margin), intra- and perinodal budding (INB and PNB) and intra- and peri-metastatic tumor budding (IMB and PMB). Overall tumor budding was defined as tumor buds independent of the center and margin (OTB, ONB, OMB). The tumor bud count was assessed by calculating the mean number of tumor buds in 10 high power fields. For survival analysis a cut off of 10 tumor buds was applied to subdivide the tumors with low and high numbers of tumor buds. Results: In lymph nodes and CRDM, the tumor bud count was lower compared to primary tumors (PNB: 13; INB: 18; ONB: 21 vs PMB: 10; IMB: 21; OMB: 22 vs PTB: 23; ITB: 24; OTB: 33). For PTB/PNB and OTB/ONB, there were significant differences between primary tumor and lymph node metastasis (PTB/PNB: p < 0.001; OTB/ONB: 0.008) and primary tumor and distant metastases (PTB/PMB: p < 0.001; OTB/OMB: 0.007). The presence of PMB was predicted by INB, PNB and V1 (p = 0.032, p = 0.001 and p = 0.003). A trend towards a worse prognosis in patients with a high OMB number was observed. Conclusions: Tumor budding is present in lymph node and distant metastases of CRC, but its number is lower compared to the corresponding primary tumor. As tumor budding in local and distant metastases seems to be a predictor of tumor progression, these novel data should be considered as a basis for further analysis in large and multicentric clinical trials.
The role of sidedness, EGFR gene copy number (GCN) and EGFR promoter methylation in RAS/BRAF wild type (WT) colorectal cancer (CRC) patients receiving irinotecan/cetuximab.
Authors: Puzzoni Marco , Giampieri Riccardo , Demurtas Laura , Pusceddu Valeria , Mandolesi Alessandra , Faloppi Luca , Loretelli Cristian , Zaniboni Alberto , Falcone Alfredo , Cascinu Stefano , Scartozzi Mario 
Published: March 2017

628 Background: Data from randomized trials suggested that tumour sidedness could represent a prognostic and predictive factor in CRC patients. Distinctive molecular and clinical features are related to tumour sidedness, however their predictive role has not yet been clearly defined. Methods: Tumour samples from RAS/BRAF WT metastatic CRC patients treated with second-third line irinotecan-cetuximab were analised for EGFR GCN and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Results: Eighty-eightpatients were included in the study, 24/88 (27.3%) had right sided CRC(RSCC), 64/88 (72.7%) had left sided CRC(LSCC); 32/88 (36.4%) had EGFR GCN < 2.12 tumour, 56/88 (63.6%) had EGFR GCN ≥ 2.12 tumour; 44/88 (50%) had EGFR promoter methylated tumour. RSCC were associated with reduced ORR (4.2% for RSCC vs 35.9% for LSCC, p:0.0030), with shorter PFS (3.0 vs 10.29 months, HR:2.74, p < 0.0001) and shorter OS (8.0 vs 13.6 months, HR:2.83, p < 0.0001). EGFR GCN < 2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN < 2.12 vs 39.3% for ≥ 2.12 tumours, p:0.0009), with shorter PFS (3.8 vs 7.0 months HR:2.15, p = 0.0010) and shorter OS (8.5 vs 14.0 months HR:2.59, p < 0.0001). EGFR methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, p = 0.0001), with shorter PFS (3.0 vs 7.67 months HR:3.23, p < 0.0001) and shorter OS (8.0 vs 17.0 months HR:3.57, p < 0.0001). At multivariate analysis EGFR GCN and EGFR promoter methylation mantained their independent role for ORR (respectively p:0.0082 and p:0.0025), PFS (respectively Exp(b):0.40, p:0.0048 and Exp(b):4.52, p < 0.0001) and OS (respectively Exp(b):0.23, p:0.0001 and Exp(b):5.58, p < 0.0001). Conclusions: In our study an accurate molecular selection based on an all RAS and BRAF analisys along with EGFR GCN and EGFR promoter methylation status resulted more relevant than tumour sidedness for the prediction of clinical outcome during cetuximab/irinotecan. We then suggest that molecular selection might overcome the importance of tumour sidedness in this setting.
A phase 2 study of temozolomide in patients affected by pretreated metastatic colorectal cancer with MGMT promoter methylation.
Authors: Calegari Maria Alessandra , Monterisi Santa , Inno Alessandro , Orlandi Armando , Basso Michele , Cassano Alessandra , Santini Daniele , Martini Maurizio , Cenci Tonia , de Pascalis Ivana , Barbaro Brunella , Camarda Floriana , Colosimo Cesare , Larocca Luigi Maria , Tonini Giuseppe , Gori Stefania , Barone Carlo Antonio 
Published: March 2017

629 Background: Presently few options are available for pts with mCRC who failed standard treatments and prognosis remains grim. MGMT promoter methylation is a frequent and early event in CRC tumorigenesis. This epigenetic silencing is a predictor of response to the alkylating drug TMZ in glioblastoma. Preclinical evidences and a couple of clinical cases showed TMZ activity in pts affected by mCRC with MGMT silencing. We designed a study to evaluate the efficacy and safety of TMZ in pts with refractory mCRC harboring MGMT promoter methylation. While the trial was ongoing three analogous studies, reporting discordant results, were published. Methods: This was a 3-institutional, single arm, phase 2 trial, planned according to a 2-stage Simon’s optimal design. The primary endpoint was ORR. Secondary outcomes included DCR, OS, PFS and safety. A first cohort of 21 pts was accrued: if more than 1 response was observed a second cohort of 20 pts would be enrolled; if 4 or fewer responses were observed by the end of stage two, then no further investigation would be warranted. MGMT promoter methylation was assessed on archival tissue samples by MS-PCR. Patients affected by MGMT methylated mCRC, who failed 2 or more prior treatments, received TMZ, provided by TEVA Pharmaceutical Industries, at a dose of 150-200 mg/mq/day once a day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 pts were screened and 80 showed MGMT promoter methylation, among those 42 met the inclusion and exclusion criteria and were enrolled. ORR was 10% with no CR and 4 (10%) PR. SD was achieved in 9 (22%) pts, accounting for a DCR of 32%. At a median FU of 9 months all pts experienced PD and 88% died. Median PFS and OS were 2.6 months (95% CI 2.1-3.2) and 7.1 months (95% CI 5.1-9.2) respectively. Overall, any-grades AEs were reported in 75.6% pts, most of them were G1-2 (84%). The most frequent AE were nausea (56%) and platelet count decreased (39%). 4 pts discontinued study treatment due to AE. No SAE neither toxic death was recorded. Conclusions: The study did not meet its primary endpoint, however an interesting DCR (32%) and 4 PR were achieved. The role of TMZ in mCRC treatment remains still controversial and might warrant further analysis. Clinical trial information: 2012-002766-13.
Characterization of the number and site of APC mutations in sporadic colorectal cancer.
Authors: Joseph Ranjit , Little Paul , Hayes David N. , Lee Michael Sangmin 
Published: March 2017

630 Background: Truncating mutations in the adenomatous polyposis coli ( APC) gene are well-described events in the carcinogenesis of colorectal carcinomas (CRC) and may impact one or both APC alleles. These aberrations often fall within the mutation cluster region (MCR) of the APC gene to preserve a “just right” number of beta-catenin binding sites in the resulting mutant APC protein. Further clinical and genotypic characterization of CRCs based on number and site of mutations in APC determined using modern next generation sequencing methods is needed. Methods: Next generation sequencing of 70 CRC tumors was performed at a single institution via UNCseq to determine mutations in a panel of 247 oncogenes and tumor suppressors, including APC. RNASeq, DNA sequencing, and clinical characteristics from 224 colon and rectal cancer samples in The Cancer Genome Atlas (TCGA) project were also obtained. Results: In the UNCseq cohort, 58 patients (83%) had at least one inactivating APC mutation, and 33 (47%) had two mutations. Of those with at least one mutation, 81% had a mutation in the MCR (residues 1281-1556), but only 5/33 (15%) with two mutations had both in the MCR. In the TCGA cohort, 162 (72%) had at least one inactivating APC mutation, and 52 (23%) had two mutations. Of those with at least one mutation, 59% had a mutation in the MCR, but only 3/52 (6%) with two mutations had both in the MCR. Gene expression of APC was higher in those with no APC mutations vs. 1-2 mutations (p = 0.015), but was not significantly different between those with one vs. two mutations (p = 0.29). The absence of APC mutations was associated with microsatellite instability (p < 0.001) and with right-sided primary tumors (p = 0.001 by chi-square). Conclusions: CRCs have high frequency of biallelic APC mutations, and the majority of tumors with APC mutations had a single mutation within the MCR region of the APC gene. These genotypic factors may impact tumor biology and clinical features.
Combination of TLR9 agonist lefitolimod/MGN1703 with checkpoint inhibitors for cancer immunotherapy.
Authors: Schmidt Manuel , Kapp Kerstin , Volz Barbara , Oswald Detlef , Wittig Burghardt 
Published: March 2017

634 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod/MGN1703 is a covalently-closed dumbbell-like immune surveillance reactivator (ISR) with a broad immunomodulatory potential. After promising data from a phase II trial (IMPACT) as maintenance therapy after first-line induction chemotherapy in patients with metastatic colorectal cancer lefitolimod is recently evaluated in a phase III trial in mCRC patients (IMPALA). Methods: It was previously shown that lefitolimod can reduce tumor growth in several murine tumor models. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors aCTLA-4 or aPD-1/aPD-L1 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, we employed two syngeneic murine tumor models: One with s.c. inoculation of CT26 cells and another with s.c. A20 cell challenge. Multiple doses of lefitolimod were injected s.c. or i.tu. Results: In the colon carcinoma CT26 model i.p. injection of aPD-L1 had no effect on the tumor growth, whereas peritumoral injection of lefitolimod led to a slowed tumor growth. The tumor growth was further inhibited by the combination (tumor growth inhibition, TGI - aPD-L1: no, lefitolimod: 28%, combination: 48%) resulting in prolonged survival of the mice. This combinatory effect was even more pronounced in the lymphoma A20 model: Injections of anti-PD-1 (i.p.) or lefitolimod (i.tu.) alone had a moderate anti-tumor effect which was vastly increased by the combination (TGI - aPD-1: 46%, lefitolimod: 50%, combination: 99%). Conclusions: In conclusion, we showed that lefitolimod, a member of dSLIM family of TLR9 agonists and an ISR, can enhance the limited anti-tumor effects of checkpoint inhibitors in pilot studies in murine colon carcinoma and lymphoma tumor models in vivo. These data show the promising potential for the combination with checkpoint inhibitors. In fact, a clinical trial in cooperation with MD Anderson evaluating the benefit of lefitolimod in combination with ipilimumab is currently ongoing.
A survey of medical oncologist’s opinions and perceptions regarding the management of dermatologic toxicities among mCRC patients treated with panitumumab in the United States.
Authors: Lowe Kimberly , Bergstresser Rachel , Hool Kristina , Kafatos George , Garawin Tamer , McNamara Michelle , Kelsh Michael Anthony , Collins Seth , Bach Bruce A. ,   Skin Tox
Published: March 2017

639 Background: Dermatologic toxicity can be a limiting factor for the use of anti-EGFR therapy such as panitumumab. There is a paucity of real world data regarding the management of dermatologic toxicity among metastatic colorectal cancer (mCRC) patients treated with panitumumab in the United States (U.S.). The objective of this study is to describe oncologist's opinions regarding timing of skin rash management in relation to the initiation of treatment and perceptions regarding rash management strategies. Methods: A total of 125 oncologists were recruited from a national database via a third independent party. Eligible oncologists (i.e.: licensed and practicing oncologist who had treated at least three new or continuing mCRC patients with panitumumab in the last year) completed an online survey to report their opinions regarding the grade and type of dermatologic toxicities seen and their perceptions about management strategies for mCRC patients who are treated with panitumumab. The timing of rash management initiation was defined as pre-emptive (prior to the appearance of the rash) or reactive (after any signs of skin rash). Results: Based upon their collective experience, oncologists expect that 44% of patients will develop acneiform rash while on treatment. More than half (58%) of the oncologists reported they did not follow any practice guidelines regarding the management of dermatologic toxicities. The oncologists reported that they pre-emptively initiated the management of dermatologic toxicities in 53% of their patients. Skin moisturizer and sunscreen were reported to be the most critical preemptive management approach, while skin moisturizer, over-the-counter topical steroids, and oral antibiotics were reported to be the most critical reactive management tools for Grades 1, 2, and 3, respectively. Conclusions: Despite evidence from randomized controlled trials, a majority of oncologists do not follow guidelines for dermatologic management of EGFR-I rash. There is a clear need for better physician education and awareness of mitigation strategies for skin toxicity management in mCRC patients treated with panitumumab.
A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.
Authors: Townsend Amanda Rose , Hardingham Jennifer , Tebbutt Niall C. , Karapetis Christos Stelios , Singhal Nimit , Joshi Rohit , Yeend Sue , Cooper Pamela , Dorward Hilary , Price Timothy Jay 
Published: March 2017

643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P < 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.
BRAF +/- MEK inhibition in patients (pts) with BRAF-mutant (mut) metastatic colorectal cancer (mCRC): The Sarah Cannon Research Institute UK’s experience.
Authors: Uccello Mario , Moschetta Michele , Mak Gabriel , Martynyuk Nataliya , Hauser Joana , Bassett Sian , Voskoboynik Mark , Lemech Charlotte , Rafii Saeed , Arkenau Hendrik-Tobias 
Published: March 2017

645 Background: Activating V600 BRAF mutations are detectable in around 10% of mCRC pts and are associated with poor prognosis. Low response rates have been reported with anti-BRAF monotherapy in this subset of pts while encouraging data exist on enhanced MAPK pathway inhibition with combination therapy (anti-BRAF + anti-MEK and/or anti-EGFR). Methods: We performed a pooled analysis of BRAF-mut mCRC pts enrolled into different phase 1 trials involving the use of anti-BRAF monotherapy alone (Group A) or in combination with a MEK inhibitor (Group B) at therapeutic doses between June 2012 and August 2016. Demographic, baseline, toxicity and efficacy data were retrospectively reviewed. Results: Twenty BRAF-mut mCRC pts were identified in either Group A (n = 13) or Group B (n = 7). All pts had an ECOG performance status ≤ 1. Median age was 54 years (range 33-74). The primary tumor was right-sided in 10 (50%) pts, left-sided in 9 (45%) pts, and unknown in 1 (5%) subject. Median number of previous treatment lines was 1 (range 1-4). The disease control rate was 55%, with 3 (15%) pts experiencing partial response (PR) and 8 (40%) with stable disease. No complete responses were observed, 8 (40%) pts had progressive disease and 1 subject was considered not evaluable. All PRs were achieved in Group B and had duration of 2-4 months (mo). Median PFS was 3.73 mo (95% confidence interval [CI] 3.06-6.79) in the overall population, and showed a trend favoring the combination arm (2.80 mo for Group A vs. 5.03 mo for Group B, hazard ratio 0.71 [CI 0.26-1.95], p = 0.503). Most common toxicities were skin-related side effects (n = 10; 50%), myalgia/arthralgia (n = 5; 25%), nausea (n = 3; 15%), and pyrexia (n = 3; 15%). Grade 3/4 toxicities were uncommon and manageable: neutropenia (n = 1; 5%), hypophosphatemia (n = 1; 5%), pyrexia (n = 1; 5%), and abdominal pain (n = 1; 5%). Conclusions: Our cohort of pts treated with BRAF +/- MEK inhibitors showed a favorable safety profile. An encouraging activity level was found in the combination arm. In line with existing literature data, our findings supporting further development of combined MAPK inhibition in V600-positive mCRC.