bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of patients (pts) with BRAF mutated (BRAF MT) Colorectal Cancer (CRC): The Royal Marsden Experience.
Authors: Kayhanian Hamzeh , Goode Emily , Ang Joo Ern , Gonzalez de Castro David , Sclafani Francesco , Petruckevitch Ann , Rao Sheela , Watkins David J. , Gerlinger Marco , Cunningham David , Chau Ian , Starling Naureen 
Published: February 2017

644 Background: BRAF MT metastatic CRC (mCRC) is associated with a poor prognosis. For the first time, we report outcomes for BRAF MT mCRC at a single tertiary centre, compared to a matched control group, since introduction of routine somatic BRAF and RAS mutation testing. Methods: Pts with BRAF MT mCRC (diagnosed Oct 2010-Nov 2014) were compared to a matched group of BRAF wildtype (WT) pts treated in same time period who were randomly selected after matching for age, sex and stage. Demographic, tumour characteristic and treatment data were collected. Overall (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and comparisons made using χ² test or Cox regression. Results: Of 503 pts tested, 59 (11.7%) had BRAF MT tumours (16 early stage, 16 recurrent and 27 de novo metastatic). Median age (years) at diagnosis was 68 (27-85) compared with 70 (29-85) for BRAF WT pts (p = 0.995). Median OS for pts with mCRC was 18.2 months (m) for BRAF MT and 41.1m for BRAF WT pts (HR 2.73 P < 0.01). For BRAF MT and BRAF WT pts with mCRC, median PFS on first-line treatment (1L) was 8.1m (n = 37) and 9.2m (n = 81) respectively (HR = 1.10 [P = 0.69]), PFS on 2L was 5.1m (n = 21) and 9.0m (n = 49) respectively (HR = 1.84 [P = 0.03]) while PFS on 3L was 1.7m (n = 10) and 6.6m (n = 20) respectively (HR = 2.75 [P = 0.02]). Fluoropyrimidine based doublet regimens were used in 94.6%, 85.7% and 20% of BRAF MT pts in 1L, 2L and 3L respectively compared with 87.2%, 92.5% and 52.4% in BRAF WT pts. Pts with localised disease had a recurrence rate of 50% (16/32) for pts with BRAF MT compared with 52.4% (33/63) for BRAF WT pts (p = 0.83). Conclusions: In this case-control study, poor OS of pts with BRAF MT mCRC is associated with reduced clinical benefit beyond 1L. Sequential doublet chemotherapy remains a reasonable option in these pts. The role of BRAF mutation in predicting recurrence of early CRC warrants further study. [Table: see text]
Survival determinants with matched targeted therapies in BRAF mutant metastatic colorectal cancer (mCRC).
Authors: Sanz-Garcia Enrique , Martinez Ana Maria , Elez Elena , Argiles Guillem , Grasselli Julieta , Macarulla Teresa , Capdevila Jaume , Alsina Maria , Sauri Tamara , Hierro Cinta , Matos Ignacio , Verdaguer Helena , Azaro Analia , Landolfi Stefania , Hernandez-Losa Javier , Rodón Jordi , Nuciforo Paolo , Vivancos Ana , Dienstmann Rodrigo , Tabernero Josep 
Published: February 2017

649 Background: BRAF mutation (mt) occurs in 5-8% of mCRC and is associated with poor prognosis. Matched targeted therapies for this population are increasingly available in clinical trials. Methods: From Nov 2010 to June 2015, a total of 32 chemorefractory BRAF mt mCRC patients (pts) were enrolled in phase I trials with anti-BRAF matched therapy at Vall d´Hebron Institute of Oncology. BRAF mt was determined by real-time PCR (50%), mass spectrometry (Sequenom, 28%) or next-generation sequencing (Amplicon MiSeq, 22%). All demographic, treatment and survival data were retrospectively analyzed. Results: Median age was 60.4 years (range 42.8-73.5), 62% had right-sided CRC primaries and 59% were stage IV at diagnosis. Median treatment lines before matched therapy was 2 (range 1-4). Co-existing RNFA43, PI3KCA and GNAS mt were found in 4, 2 and 1 pts, respectively. Median time from diagnosis to start of anti-BRAF therapy was 18.6 months (m) (CI95% 14-36) and median time from diagnosis of mCRC to death was 28.4m (CI95% 25-50). A total of 41 anti-BRAF matched therapies were delivered, 9 pts received more than 1 regimen. BRAF inhibitor (inh) monotherapy was delivered in 34% of cases; BRAF plus MEK/EGFR/WNT/PI3K/CDK inh doublets or triplets to 37% and 29% pts, respectively. Survival from start of anti-BRAF to death was 8.9m (CI95% 7-15), without significant differences if 1 or more than 1 anti-BRAF regimen was given (HR: 0.82, p=0.6). Partial responses were observed in 7 cases (17%, 4 doublets and 3 triplets) and complete response in 2 cases (5%, 1 doublet and 1 triplet). Median time on treatment (ToT) with anti-BRAF therapy was 2.83m (CI95% 2-5.5). Of note, ToT was significantly longer for triplets compared to mono/doublets: 5.5m (CI95% 2.7-not reached) vs. 1.9m (CI95% 1.6-3.7; HR: 0.46 [CI95% 0.2-1.0], p=0.05). Median BRAFmt allele fraction (adjusted for tumor purity) was 0.25 (0.13-0.68); no correlation with ToT on anti-BRAF therapy was observed (p=0.36). Conclusions: In a selected BRAF mt population enrolled in early trials with anti-BRAF matched therapy at our institution, survival in the metastatic setting was remarkably high. Triplet matched therapies seem to control disease for longer time than mono/doublets.
Comparative effectiveness of panitumumab (P) and cetuximab (C) in metastatic colorectal cancer (mCRC) with wild-type KRAS (WTKRAS).
Authors: Xu Yifan , Hay Joel W , Lenz Heinz-Josef , Sadeghi Sarmad , Barzi Afsaneh 
Published: February 2017

652 Background: In 2015, 140,000 patients will be diagnosed with colorectal cancer (CRC) with 20% diagnosed with mCRC and another 20% developing mCRC during their course. In recent years the outcome of mCRC has improved with survival reaching 30 months in clinical trials. P and C have similar effectiveness as reported in ASPECCT, though their administration and toxicities are different. Availability of more than one agent for one indication makes cost a variable in selection process. We aimed to evaluate the comparative effectiveness of P and C as monotherapy in chemo-refractory mCRC with WTKRAS from a societal perspective. Methods: We developed a Markov model with three states: stable disease, progressive disease and death. Probabilities of each state and transitions were extracted from the ASPECCT trial report. Costs of drug and administration were based on the Veteran Affairs Federal Supply Schedule and Medicare reimbursement rates for a base case of a 61-year-old male. We conducted a literature review to obtain data regarding the costs and utilities of toxicities. All costs are in 2015 US dollars. The model was constructed using a 1-month cycle length and 3-year time horizon, discounted at an annual rate of 3%. The model used quality-adjusted life-year (QALY) to measure the health outcomes for each treatment option. Results: P produced 9.8 months life-years gain and 0.56 QALYs at the cost of $74,827 per patient. C produced a 9.2 months life-years gain and 0.53 QALYs, at the cost of $79,916 per patient. The incremental net monetary benefit of P is $10,168 when compared to C under a societal willingness-to-pay threshold of $150,000 per QALY. The model showed robustness to the one-way sensitivity analysis and various alternative scenarios, and was found to be most sensitive to the cost of C. P and C are equivalent when cost of C drops from $1,038 to $782 per 100mL vial. Conclusions: In the US, effectiveness and toxicities are the main variables for choice of treatment regimen. The rising cost of care is forcing providers and policy makers to consider other data points in treatment selection. Our results indicate that P has a cost advantage over C and provide a strong argument to use P in lieu of C in mCRC.
Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: Early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors.
Authors: Hurwitz Herbert , Hainsworth John D. , Swanton Charles , Perez Edith A. , Sweeney Christopher , Burris Howard A. , Spigel David , Meric-Bernstam Funda , Strickland Donald K , Leon Larry , Brammer Melissa , Beattie Mary Stanley , Bose Ron 
Published: February 2017

653 Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]
Prognostic value of primary tumor resection in synchronous metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of first-line randomized trials from the ARCAD database.
Authors: Koopman Miriam , Shi Qian , Goey Kaitlyn K.H. , Green Erin , Heinemann Volker , Diaz-Rubio Eduardo , Aranda Enrique , Falcone Alfredo , De Gramont Aimery , Sargent Daniel J. , Punt Cornelis J. A. 
Published: February 2017

658 Background: In patients (pts) with mCRC with an asymptomatic primary tumor, there is limited evidence regarding the indication for primary tumor resection. The primary objective was to evaluate the prognostic value of primary tumor resection in synchronous mCRC pts. Methods: In this IPD analysis, a total of 3,423 pts from 8 first-line randomized trials (RCTs) with systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Five RCTs included targeted (anti-VEGF and/or anti-EGFR) agents. Synchronous mCRC was defined as distant metastases occurring ≤ 6 months of the initial CRC diagnosis. Overall survival (OS) and progression-free survival (PFS) were compared by stratified multivariate Cox models. Results: There were 710 (21%), 1,705 (50%) and 1,008 (29%) pts with non-resected and resected synchronous mCRC and metachronous mCRC, respectively. Compared to the non-resection group, pts in the synchronous resection group were associated with female gender, colon tumor, isolated liver/lung involvement, single metastatic site, and lower LDH (all p<.001). Adjusted for age, gender, performance status and prior chemotherapy, the non-resection group had a significantly worse median OS (16.4m) compared to the resection (22.2m; HR 1.60, 95% CI 1.43-1.78) and metachronous (22.4m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, PFS was significantly worse for the non-resection group (7.9m) compared to the resection (9.7m; HR 1.31, 95% CI 1.19-1.44) and metachronous group (8.9m; HR 1.47, 95% CI 1.30-1.66). Similar trends were observed in pts treated with non-targeted vs targeted agents, and anti-VEGF vs anti-EGFR therapy. In a subset analysis (n= 526), the observed associations remained after additional adjustment for primary tumor location, liver/lung involvement, number of metastatic sites, BMI and LDH. Conclusions: In this largest IPD analysis of mCRC trials to date, primary tumor resection is associated with better OS and PFS in synchronous mCRC pts. These results may be subject to bias since reasons for (non)resection were not available. Prospective RCTs on this topic are ongoing.
Chasing the proverbial unicorn of relative value units (RVU) and block time.
Authors: Rajeev Rahul , Johnston Fabian McCartney , Gamblin T. Clark , Turaga Kiran 
Published: February 2017

660 Background: Competitive market forces on healthcare have led to increasing demands on work effort of academic surgical oncologists. This has to be balanced against resource constraints of limited operating room space and block time availability. We hypothesized that current work RVU (wRVU) requirements pose an unrealistic expectation of practicing surgical oncologists. Methods: University HealthSystem Consortium (UHC) median wRVUs were utilized to determine the effort expected of a surgical oncologist. Surgical oncology subspecialties were divided into breast, colorectal, melanoma, sarcoma, liver and pancreas. Representative procedures from each specialty were determined using Healthcare Common Procedure Coding System and median wRVUs were obtained per procedure including a single consultation cost without incorporating modifiers and adjustments for multiple procedures. A work year was assumed to include 48 weeks of work time to account for CME, and vacation. Night and weekend call was excluded from the analysis. Results: The median UHC wRVU for a surgical oncologist is 7800 wRVU, which corresponds to a theoretical reimbursement of $383,387-493,459 in a pure Medicare population. In order to meet the work RVU requirements, the number of annual major procedures performed varied from 124-1625 procedures (breast 365-701, colorectal 192- 324, melanoma 677-1625, sarcoma 234-334, liver 124-571, pancreas 139-264). The number of major procedures performed per day varied from 3 procedures/day for a 4 day block time to 12 procedures/day for a single day block time. Conclusions: Current wRVU expectations and block time schedules need to be better aligned to account for increasing demands on surgical oncologists. Society driven surveys as recently conducted by ASBS might be effective ways to truly understand workforce demands in the nation.
Patterns in KRAS testing and EGFRi therapy across lines of treatment for metastatic colorectal cancer in Canada: A retrospective analysis.
Authors: Kennecke Hagen F. , Maroun Jean Alfred , Kavan Petr , Aucoin Nathalie , Couture Felix , Poulin-Costello Melanie , Gillesby Brad , Berry Scott R. 
Published: February 2017

665 Background: Selection and sequencing of treatment regimens for individual metastatic colorectal cancer (mCRC) patients is governed by the goals of maintaining reasonable quality of life while extending survival. The timing of KRAS testing and its effect on EGFRi therapy is poorly described. The goals of this analysis wereto describe rates and timing of KRAS testing relative to EGFRi therapy for Canadian patients diagnosed with mCRC. Methods: A retrospective chart review conducted at 6 Canadian centres included patients diagnosed with mCRC from Jan 1, 2009 onwards, who commenced 1st-line systemic treatment for mCRC between Jan 1–Dec 31, 2009. Information on the proportion of patients who received 2nd, 3rd, or subsequent lines of systemic therapy for mCRC was determined and the rates and timing of KRAS testing was ascertained. Results: 200 patients commenced 1st-line therapy and the median age was 62 yr; 78% had mCRC at the time of diagnosis. The proportions of patients who started 2nd, 3rd, and 4th lines of systemic therapy were 70%, 30%, and 15%, respectively. 103 (52%) patients had KRAS testing; 6%, 18%, 57%, 16%, 2%, and 1% of patients were tested at diagnosis or before the 2nd, 3rd, 4th, 5th and 6th lines of therapy, respectively. Median time from testing to EGFRi treatment was 105 (range, 7–1192) days, and varied by site. The frequency of KRAS testing for patients ranged from 30%–70% across study sites; across provinces, the frequency of testing ranged from 46%–60%. 38/68 (56%) of patients with wt KRAS tumors received EGFRi; 31 (46%) patients received EGFRi therapy as next therapy following KRAS testing. 19 (28%) died and 4 were lost to follow-up within 120 days of KRAS testing with no other therapy. 2 additional patients with unknown KRAS status received EGFRi (1 without KRAS testing; 1 undetermined). Conclusions: KRAS testing occurred after starting 2nd line in 76% of cases and varied by site and province. About half of patients underwent KRAS testing and 56% of those patients with wt KRAS tumors received an EGFRi. The short time interval between (K)RAS testing and EGFRi therapy may point to the need for earlier testing if EGFRi therapy is to be used in earlier lines of therapy.
Predictive factor for toxicities and treatment termination in adjuvant S-1 therapy for stage III colorectal cancer using data from JCOG0910.
Authors: Yamazaki Kentaro , Yoshida Yukio , Mizusawa Junki , Kanemitsu Yukihide , Kinugasa Yusuke , Komori Koji , Ohue Masayuki , Ota Mitsuyoshi , Takiguchi Nobuhiro , Nishizawa Yusuke , Ojima Hitoshi , Takii Yasumasa , Yamagami Hideki , Tanada Minoru , Sekimoto Mistugu , Yamaguchi Takashi , Bandou HIroyuki , Katayama Hiroshi , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: February 2017

669 Background: S-1 has demonstrated antitumor effects in various cancers. Gastrointestinal (GI) toxicities associated with S-1 sometimes cause treatment interruption or termination, and previous reports suggested that low creatinine clearance (Ccr) was associated with the dose reduction and schedule modification during adjuvant S-1 therapy for gastric cancer. However, there are few reports evaluating these associations in colorectal cancer (CRC). Methods: We used the data of patients (pts) allocated to S-1 arm in JCOG0910 trial which evaluated the non-inferiority of S-1 to capecitabine as adjuvant therapy for stage III CRC. The association between pts’ background factors including age, gender, BSA, BMI, surgical procedures, Ccr, AST, ALT, and T-bil, versus treatment termination due to toxicity, and ≥ Grade 2 (G2) diarrhea, ≥ G2 anorexia, and ≥ G2 nausea were evaluated by using logistic regression. Results: Between Mar. 2010 and Aug. 2013, 1564 pts were enrolled, 782 pts were randomized to S-1 arm and 766 pts were analyzed. Pts’ background factors were as follows: ≥ 70 years, 34%; male, 49%; BSA higher, 28%; BMI ≥ 25 kg/m2, 17%; low anterior resection (LAR) or abdominoperineal resection (APR), 19%; Ccr < 50 ml/min, 7%; AST or ALT ≥ upper limit of normal, 16%; T-bil ≥ 1.0 mg/dL, 7%. Among them, 139 pts (18%) terminated treatment due to toxicity or death. The incidence of ≥ G2 diarrhea, anorexia, and nausea were observed in 18, 14 and 10%. The multivariate analysis revealed that some pts’ background factors were significantly associated with the incidence of treatment termination, or ≥ G2 GI toxicities (see table). Conclusions: Low Ccr, female, higher age or lower BMI might be risk factors of treatment termination due to toxicity or > G2 GI toxicities for pts treated with S-1. Clinical trial information: UMIN000003272. [Table: see text]
Effect of vorinostat (VOR) and hydroxychloroquine (HCQ) on immunity and autophagy in metastatic colorectal cancer (mCRC).
Authors: Patel Sukeshi R. , Hurez Vincent , Nawrocki Steffan T , Goros Martin , Michalek Joel , Sarantopoulos John , Curiel Tyler J. , Mahalingam Devalingam 
Published: February 2017

670 Background:HCQ enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR in pre-clinical CRC models. Our phase 1 dose escalation trial found that patients (pts) with mCRC obtained prolonged clinical benefit from VOR + HCQ. Thus, a single arm expansion cohort in refractory mCRC was done. Methods: Pts with refractory mCRC received VOR 600 mg by mouth (PO) + HCQ 400 mg PO daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS), adverse events (AE) (NCI-CTCAEv3.0), flow cytometry (FACS) of peripheral blood mononuclear cells (PBMCs), tumor biopsies. Results: 20 pts were enrolled (19 evaluable for survival): mean age 61 (44-74). Female 7/male 23, 9 Caucasian/10 Hispanic/1 Black, 11 KRAS mutated. ECOG 0-1 (18 pts). 3+ prior lines (13), previous regorafenib (4). Dose level reduction on study (7). mPFS 2.8 months (95% CI: 1.63-8.16). mOS 6.7 months (95% CI: 4.63-NR). Treatment-related grade 3 AEs: nausea/vomiting (3), anemia (3). Grade 4 thrombocytopenia (3). Grade 4 INR elevation (1 pt on Coumadin). No grade 5 AEs. Five pts (26%) had stable disease ≥12 weeks. Treatment significantly reduced regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and increased CD45RO+CD62L-CD4+ (effector) T cells, consistent with improved anti-tumor immunity. On-study biopsies (3) showed increased lysosomal protease CTSD and LC3-II consistent with autophagy inhibition. Conclusions: VOR/HCQ is active, safe and tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity (decreased exhausted and regulatory T cells and increased effector phenotype T cells) and reduced tumor autophagy. A randomized phase II trial of VOR/HCQ versus regorafenib is now open. Clinical trial information: NCT01023737.
Induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery in locally advanced rectal carcinoma (LARC): The phase II TRUST trial.
Authors: Vivaldi Caterina , Sainato Aldo , Lonardi Sara , Buccianti Piero , Marcucci Lorenzo , Di Clemente Francesco , Musettini Gianna , Montrone Sabrina , Bergamo Francesca , Franceschi Matteo , Ginocchi Laura , Martignetti Angelo , Laliscia Concetta , Battaglin Francesca , Urbani Lucio , Manfredi Bruno , Rumano' Laura , Sidoti Francesco , Falcone Alfredo , Masi Gianluca 
Published: February 2017

673 Background: Induction chemotherapy (CT) is a promising option in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. Methods: Patients (pts) with LARC at < 12 cm from the anal verge, N+ or cT4 or high risk cT3 (MRI criteria) underwent 6 cycles of FOLFOXIRI + BV followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 800 mg/m2/bid 5 days/week + BV 5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint is 2-year disease-free survival (DFS). Results: From April 2012 to April 2015 48 pts were enrolled. At now, 46 pts completed induction CT, 43 completed CRT and 39 underwent surgery (5 pts ongoing). Pts characteristics were: median age, 53 years (range 30-74); cT2/cT3/cT4, 4%/60%/36%; cN0/N+, 4%/96%. Main grade (G) 3/4 toxicities during induction were neutropenia (42%), febrile neutropenia (4.2%), diarrhea (12.5. Two pts did not complete induction: one died due to bowel perforation and sepsis and one discontinued CT after acute kidney injury. Response rate (RR) after induction was 77%. Forty-five pts started CRT (1 pts underwent surgery after induction because of SAE). After the first 13 patients, protocol was amended and schedule of capecitabine modified due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%). After amendment all pts completed CRT with acceptable toxicity: G3 proctitis 6.7% and proctalgia 3.3%. One pts died due to early progressive disease (PD) after CRT. RR after CRT was 88%. Surgery was low anterior resection 87%, abdomino-perineal resection 8%, other 5%. Radical resection was achieved in 95% of pts. Early post-surgical complication rate was 31%. Pathologic complete response was reached in 33% and pathological downstaging in 44% of pts. At a median follow up of 17 months, 8 pts had PD and estimated 2y-DFS is 72%. Conclusions: Induction CT with FOLFOXIRI + BV is feasible and highly active. A protocol amendment was needed due to toxicities during CRT. The rate of early post-surgical complications is not negligible. A longer follow up is needed for DFS. Clinical trial information: 2011-003340-45.