bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reflex Lynch syndrome screening by example: A review of existing programs.
Authors: Daly Corinne , Rotenberg Carolyn , Facey Marcia , Baker Natalie A. , Baxter Nancy N. 
Published: February 2017

543 Background: Reflex screening for Lynch Syndrome (LS) has been recommended, however occurs in few jurisdictions worldwide. We aimed to explore program structure, pathology testing, implementation challenges and future directions of existing reflex LS screening programs in various jurisdictions to develop best practices for future programs. Methods: We identified existing reflex LS screening programs through a literature search and expert opinion. Information on program implementation, patient population, family care involvement, monitoring and improvements was collected through semi-structured interviews with program leaders, pathologists, technical staff, and family physicians. Pattern, thematic and content analysis were used to analyze and extract program features, sequence of pathological testing and best practices. Results: 26 participants across 7 programs completed interviews. There were 3 government-funded, population-based programs (Manitoba, Western Australia, and New South Wales), 2 private health management organization programs implemented across affiliated healthcare centers (Pennsylvania and Southern California); and 2 hospital-based programs (Ohio and Utah). Five programs screened all patients with CRC for LS while 2 programs designated an upper age limit for screening. The majority of programs tested tumor samples for LS using a combination of immunohistochemistry and BRAF mutation analysis. In jurisdictions relying on surgeons' referral to genetic counseling without navigation, uptake of genetic testing was lower than expected. Programs implementing early education of surgeons and pathologists in reflex screening procedures reported confidence in skills, collaboration and communication. Communication materials for family members of affected individuals were recommended to increase family engagement in genetic counselling. Conclusions: There are a variety of reflex LS screening programs with varying standards and protocols. Program design influences uptake of genetic testing; programs with an imbedded navigation plan for those who need genetic counseling enhance rates of adherence. This should be an important consideration when planning future reflex screening programs.
Genomic profiling of esophagogastric (EG) tumors in clinical practice.
Authors: Riches Jamie Cathleen , Schultz Nikolaus , Ku Geoffrey Yuyat , Imtiaz Tooba , Kelsen David Paul , Ilson David H. , Solit David B. , Berger Michael F. , Ladanyi Marc , Arcila Maria E. , Vakiani Efsevia , Janjigian Yelena Yuriy 
Published: February 2017

57 Background: Esophagogastric (EG) cancer is a phenotypically heterogeneous disease. The Cancer Genome Atlas (TCGA) identified four distinct subsets: 1) Epstein Barr Virus (EBV) tumors with PIK3CA mutations, PD-L1/2 amplification (amp), 2) Tumors with Microsatellite instability (MSI-H), 3) chromosomally unstable (CIN) tumors with frequent amplifications, 4) chromosomally stable/diffuse type tumors with RHOA mutations. We explore the utility/feasibility of genomic profiling of EG tumors in routine clinical practice. Methods: Patients (pts) with metastatic EG adenocarcinoma undergoing treatment at MSKCC were consented for molecular testing under institutional protocol. Archival formalin fixed paraffin embedded (FFPE) samples were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. Results: Of 70 analyzed EG tumors, 66 (94%) harbored at least one genomic alteration, the most frequent being TP53 mutations (77%), HER2 amp (30%) and EGFR amp (10%). Alterations in PI3K/AKT/mTOR (9%) and G1-S1 cell cycle regulators (CDK12 (11%), CDKN2A (10%)) were also observed. A comparison with the TCGA results revealed an over-representation of the CIN subtype (65% vs 50% in TCGA). We found very few EBV or MSI tumors (3% each), with the remaining 29% being chromosomally stable. Data is reported in the clinical medical record and maintained in the MSKCC-internal cBioPortal for Cancer Genomics ( http://cbioportal.org ) (Gao, et al.). The portal is a web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data and when available, to link these data to therapeutic interventions and clinical outcomes. Conclusions: CIN tumors with frequent amplifications represent majority of metastatic EG cancer at our institution. Optimal development of target-specific therapy for EG tumors will require genomic characterization. Comprehensive molecular profiling is feasible in routine clinical practice and has created a roadmap for pt stratification and genome-guided trial development.
Full report of the TROG 03.01, NCIC CTG ES2 multinational phase III study in advanced esophageal cancer comparing palliation of dysphagia and quality of life in patients treated with radiotherapy or chemoradiotherapy.
Authors: Penniment Michael Gordon 
Published: February 2017

6 Background: RT relieves dysphagia of advanced oesophageal cancer, without data from randomised phase III trials determining response, toxicity, or role of palliative CRT. Aims (1) to establish effective and least toxic treatment for symptom relief (2) determine effects of common cancer treatments on QoL (3) establish an evidence base for patient decision making. Methods: 220 patients were randomised to receive a course of palliative RT [35 Gy in 15 fractions, (n=115) or 30 Gy in 10 fractions (n=105) in Canada and UK], or concomitant CRT with Cisplatin and 5FU (D1-4) (n=111). Dysphagia measured using the Mellow score, toxicity using CTCAE v2, and QoL using EORTC QLQ30, oesophagus module (OES-18). The primary end point was proportion of patients with improved dysphagia measured at week 9 maintained until week 13. Results: Radiotherapy alone showed a dysphagia response (at any point) of 68% compared to CMT 74%, not a significant difference (p=0.343). the primary endpoint of maintained swallowing improvement was achieved in 41% with RT, 47% CMT again not statistically significant(p=0.4163).There was increased toxicity in patients receiving CRT, (nausea (p=0.0019) and vomiting (p=0.0072)). Median survival was 210 days for CRT, 203 days for RT. Although the results of the trial showed equally poor survival prognosis in both arms, there were some patients (n=21) still alive at 2 years post treatment.Quality of life analysis showed no statistical difference between arms. 17 patients in the RT alone arm ultimately received chemotherapy for specific palliative endpoints, thus 92 patients did not require chemotherapy. Conclusions: Although the CRT group had slightly better dysphagia response and median survival, the bowel toxicity was worse. Nearly 10% of patients were alive at 2 years indicating this is a group of patients who should not be denied active cancer treatment, but it should be tailored to offer maximum symptom relief minimising treatment toxicity. This multicentre trial, conducted in the UK, Canada, Australia, and New Zealand reflects practice in several countries. Clinical trial information: ACTRN12606000526572.
Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer.
Authors: Yaeger Rona D. , Cercek Andrea , O'Reilly Eileen Mary , Reidy Diane Lauren , Kemeny Nancy E. , Wolinsky Tamar , Gollub Marc J. , Lacouture Mario E. , Rosen Neal , Vakiani Efsevia , Saltz Leonard 
Published: February 2017

611 Background: BRAF mutant metastatic colorectal cancer (mCRC) is an aggressive subset of colorectal cancer that exhibits minimal response to selective RAF inhibitors. Preclinical data suggest that epidermal growth factor receptor (EGFR) reactivation with RAF inhibition attenuates the efficacy of RAF inhibitors in mCRC and that combined EGFR and RAF inhibition may be a promising therapeutic strategy. Methods: We undertook a pilot trial to assess the response rate and safety of the combination of the selective RAF inhibitior vemurafenib and anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received panitumumab 6 mg/kg IV every 14 days starting on day 1 and vemurafenib 960 mg orally twice daily continuously starting on day 8, with treatment staggered for planned correlative studies. Results: Fifteen patients received treatment. Median age was 62 years (range 22-83 years), seven patients (47%) were male, and 11 patients (73%) had a right-sided primary tumor. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight patients (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Acneiform rash (all grade 1 or 2) (53%), fatigue (53%), and arthralgias (40%) were the most frequently observed treatment-related adverse events. Treatment response was assessed in 12 patients because two patients died from disease progression before the first scan and one patient withdrew consent soon after starting treatment. Two patients (13%) had confirmed partial responses (100% and 64% regression) lasting 40 and 24 weeks, respectively. Eight patients (53%) had stable disease (SD) with tumor regression of >15% by RECIST measurement in six of these patients, including two of whom achieved stable disease lasting over six months. Conclusions: Combined RAF and EGFR inhibition is well tolerated and leads to tumor regression in a subset of patients with BRAF mutant mCRC. Planned correlative studies will evaluate degree of pathway inhibition and reactivation of other upsteam pathways with vemurafenib and panitumumab treatment. Clinical trial information: NCT01791309.
Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab.
Authors: Janjigian Yelena Yuriy , Riches Jamie Cathleen , Ku Geoffrey Yuyat , Imtiaz Tooba , Capanu Marinela , Chou Joanne F. , Kelsen David Paul , Ilson David H. , Berger Michael F. , Vakiani Efsevia 
Published: February 2017

63 Background: Trastuzumab-based therapy is the standard therapeutic approach for patients with metastatic HER2+ esophagogastric (EG) tumors. While trastuzumab prolongs survival in this population, responses are rarely complete and resistance invariably develops. Loss of HER2 and presence of co-occurring molecular alterations may impact the efficacy of HER2 targeted agents in second line setting. Methods: We reviewed clinical and pathologic data of patients (pts) with metastatic HER2+ (IHC 3+ or FISH >2.0) EG adenocarcinoma undergoing trastuzumab/chemotherapy treatment at MSKCC. Samples with ample tissue were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. When available, biopsy at the time of disease progression on trastuzumab was tested for HER2 by IHC and FISH. Results: Eighty four pts with Stage IV HER2+ EG adenocarcinoma (57 IHC 3+, 27 IHC2+/FISH+) treated with trastuzumab with chemotherapy. Median progression free survival on 1stline trastuzumab therapy 9.4 months (mos) [95%CI: 6.9-13.3 mos]. Median overall survival 20.3 mos [95%CI: 14.7-22.4 mos]. Post-trastuzumab biopsy available in 23 of 84 (27%) pts, of those 35% (8 of 23) lost HER2 positivity (4-IHC 0, 4 FISH negative). NGS performed on 24 of 84 (28%) samples. Alterations were observed in EGFR (13%), TP53 mut (92%), cell cycle mediators such as cyclin dependent kinases (42%) and the phosphoinositide 3-kinase/AKT/mTOR axis (21%). Conclusions: Loss of HER2 expression occurs in patients with HER2+ EG cancer treated with trastuzumab and presents a possible mechanism for trastuzumab resistance. Our data suggest the need for repeat biopsies to accurately determine appropriate use of second-line HER2 directed therapy.
FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group.
Authors: Cremolini Chiara , Loupakis Fotios , Masi Gianluca , Zagonel Vittorina , Bergamo Francesca , Salvatore Lisa , Cortesi Enrico , Tomasello Gianluca , Ronzoni Monica , Pinta Francesco , Zaniboni Alberto , Tonini Giuseppe , Buonadonna Angela , Amoroso Domenico , Sonaglio Claudia , De Stefano Alfonso , Boni Corrado , Allegrini Giacomo , Boni Luca , Falcone Alfredo 
Published: February 2017

657 Background: The phase III TRIBE trial met its primary endpoint, by demonstrating that first-line FOLFOXIRI plus bev significantly prolongs PFS, as compared to FOLFIRI plus bev. Also RECIST response rate, early response rate and deepness of response were significantly increased. At the first statistical analysis, with a median follow-up of 32.2 months, OS results were considered preliminary. Methods: Between July 2008 and May 2011, 508 patients were randomized to either FOLFIRI plus bev (arm A, n=256) or FOLFOXIRI plus bev (arm B, n=252). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Results: At a median follow-up of 48.1 months, 374 deaths were recorded (Arm A=200 vs. Arm B=174). Median OS for Arm B vs. Arm A was 29.8 vs. 25.8 months (HR=0.80, 95% CI, 0.65-0.98, p=0.030). Long-term survival rates are reported in Table 1. Treatment effect was consistent across all analyzed subgroups. Among clinical variables, ECOG performance status of 1 or 2, right-sided primary tumor, synchronous metastases, disease not confined to the liver, unresected primary tumor, high Kohne score negatively affected prognosis at univariate analyses. At an exploratory model accounting for these variables, adjusted HR for treatment effect on OS was 0.77 (95% CI, 0.61-0.96, p=0.020). Conclusions: FOLFOXIRI plus bev improves survival of mCRC patients, as compared to FOLFIRI plus bev. The estimated 5-years OS rate of patients treated with FOLFOXIRI plus bev was equal to 24.9%, with an absolute benefit of 12.5% compared to controls. FOLFOXIRI plus bev represents a valuable option for the upfront treatment of mCRC. Clinical trial information: NCT00719797. [Table: see text]
Trial-level association between response-based endpoints (RBEs) and progression-free (PFS)/overall survival (OS) in first-line therapy for metastatic colorectal cancer (mCRC) in the ARCAD database.
Authors: Coart Elisabeth , Saad Everardo D. , Shi Qian , Sommeijer Dirkje Willemien , Zalcberg John Raymond , Maughan Tim , Goldberg Richard M. , Schmoll Hans-Joachim , Punt Cornelis J. A. , Van Cutsem Eric , Douillard Jean-Yves , Hoff Paulo Marcelo , Tebbutt Niall C. , Fuchs Charles S. , Falcone Alfredo , Tournigand Christophe , De Gramont Aimery , Sargent Daniel J. , Burzykowski Tomasz , Buyse Marc E. ,   ARCAD Group
Published: February 2017

666 Background: Early tumor shrinkage (ETS; ≥20% decrease from baseline) and early objective tumor response (EOTR; CR/PR by RECIST) are associated with improved PFS/OS to a similar extent than best overall response (BOR), confirmed response (ConfR) and non-progression rate (NPR; CR/PR/SD by RECIST) at the individual level in first-line mCRC (ASCO 2014, abstr 3538/3578). We assessed these RBEs at the trial level. Methods: Data were available on 12,185 pts enrolled in a total of 17 randomized trials of chemotherapy (CT) alone or with targeted agents (TAs). ETS, EOTR and NPR were assessed at 6/8/9 and 12 weeks (wks), whereas BOR and ConfR were ascertained within 26 wks from randomization. Association between treatment effects on RBEs and on PFS/OS was assessed by coefficients of determination (R2, adjusted for estimation errors) using a copula model). Results: None of the RBEs had consistently strong correlations with PFS or OS (Table). The number of trials was insufficient to obtain reliable estimates for antiangiogenics and anti-EGFR separately. Conclusions: Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in first-line mCRC, given their poor predictive ability. [Table: see text]
A post-hoc health-related quality of life (HRQoL) analysis of patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial.
Authors: Chang Jane , Odom Dawn , Radder Christina , Kappeler Christian , Xu Rui-hua , Qin Shukui , Kim Tae Won , Li Jin 
Published: February 2017

667 Background: CONCUR (NCT01584830) showed that regorafenib (REG) significantly improves overall survival (OS) and progression-free survival (PFS) vs. placebo (PBO) in Asian patients with mCRC who progressed after standard therapy (J Li, et al. WCGI 2014). Post hoc exploratory analyses were conducted to assess the effect of treatment on HRQoL. Methods: Patients were randomly assigned 2:1 to treatment with either REG (n=136) or PBO (n=68). The HRQoL analyses included all 204 patients and were selected a priori based on clinical relevance; the global health status/QoL (QL) and the physical functioning (PF) scales of the EORTC QLQ-C30 questionnaire were used. A linear mixed-effects model (LMM) was used to examine the treatment effect on HRQoL and trends over time, assuming that data were missing at random. A pattern-mixture model (PMM) was applied to assess the treatment effect while accounting for potentially informative missing data. Time-to-deterioration (TTD) of HRQoL and responder analyses were conducted to determine the treatment effect based on timing and proportion of patients reaching a minimal important difference (MID) change in QL/PF (≥10 points). Results: The QL and PF changes over time were numerically similar between REG and PBO based on the LMM. The PMM grouped patients based on timing of last HRQoL assessment (<3 or ≥3 cycles) and had results similar to the LMM, demonstrating little impact of informative missing data. For the TTD analysis, when an event was defined as the earliest MID decrease in QL/PF, disease progression, or death, REG showed significantly different TTD curves from PBO (QL: median 8.0 vs. 7.0 weeks, hazard ratio (HR)=0.54; PF: median 7.9 vs. 7.0 weeks, HR=0.59, respectively; all p<0.01). Median TTD was comparable between treatments after removing progression/death from the definition. The responder analyses showed that a similar proportion of patients achieved an improvement in MID in REG vs. PBO (QL: 27.2% vs. 29.4%; PF: 14.0% vs.16.2%, respectively). Conclusions: The findings of this exploratory analysis demonstrate that HRQoL is similar for the REG and PBO groups, indicating that REG prolongs OS and PFS vs. PBO while maintaining a comparable HRQoL. Clinical trial information: NCT01584830.
Preoperative infusional 5-FU and sorafenib with external radiation therapy in locally advanced rectal cancer: Results of a phase I study.
Authors: Prithviraj Gopi Kesaria , Jiang Kun , Zhao Xiuhua , Chen Dung-Tsa , Campos Tiffany , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Shibata David , Kim Richard D. 
Published: February 2017

683 Background: The standard of care in locally advanced rectal cancer (T3, T4, or N1) is preoperative treatment with fluoropyrimidine-based chemotherapy. Sorafenib works synergistically with radiation (RT), and inhibits ras/raf, PDFGR and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45 Gy) day 1-5 at all dose levels. 6-10 weeks following neoadjuvant therapy, patients underwent surgery. Results: 17 patients were enrolled at Moffitt Cancer Center, including 10 females and 7 maleswith a median age of 54years (range: 31-72).After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily.Following this, the primary G3 toxicity was hypertension, in 2 patients at 200 mg adjusted DL (day 1-5) and 1 patient at the 400 mg PO BID DL. 1 patient had G3 ALT elevation at the 400 mg PO BID DL, and no grade IV toxicities were observed. G1 and G2 toxicities included diarrhea, mucositis, nausea, fatigue, proctitis, and thrombocytopenia. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery.The pCR rate was 35.7% and downstaging was observed in 85.7% of patients.KRAS status was available for 12 patients. The pCR was 40% in those with KRASmutant tumors (2/5 pts). Median NAR (neoadjuvant rectal cancer) score was 8.4. Conclusions: This regimen was very well tolerated after changing the dosing schedule. The pCR and downstaging rate is encouraging, and supports further clinical investigation of this regimen. Clinical trial information: NCT01376453. [Table: see text]
Effects of regorafenib therapy on health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial.
Authors: Qin Shukui , Kim Tae Won , Yau Thomas Cheung , Ma Brigette , Pan Hongming , Xu Jian-Ming , Bai Yuxian , Wang Liwei , Yeh Kun-Huei , Bi Feng , Cheng Ying , Le Tuan Anh , Lin Jen-Kou , Liu Tianshu , Dong Ma , Kappeler Christian , Chang Jane , Xu Rui-hua , Li Jin ,   on behalf of CONCUR Investigators
Published: February 2017

697 Background: The CONCUR trial (NCT01584830) showed that the multikinase inhibitor regorafenib (REG) significantly improved overall survival and progression-free survival vsplacebo (PBO) in Asian patients with mCRC who had progressed on approved standard therapies. HRQoL was an exploratory endpoint. Methods: In this international multicenter trial conducted in Asia, patients were randomized 2:1 to receive REG 160 mg (n=136) or PBO (n=68) once daily for the first 3 weeks of each 4-week cycle. Prespecified QoL analyses were conducted on all 204 patients using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol-five dimension questionnaire (EQ-5D). HRQoL outcomes were expressed as time-adjusted area under the curve (AUC) to allow descriptive evaluations of QoL in the REG and PBO groups across the entire treatment period. Individual domains were also compared using descriptive statistics. Results: Overall, changes in HRQoL were similar in the REG and PBO groups. Difference in least-squares (LS) mean time-adjusted AUC of the EORTC QLQ-C30 global health status/QoL (GH) score: −0.40 (95% CI: −3.53 to 2.72); differences in LS mean time-adjusted AUC for EQ-5D index and visual analog scale (VAS) scores: −0.03 (95% CI: −0.08 to 0.01) and −1.18 (95% CI: −4.01 to 1.66), respectively. The PBO group had <5 patients after cycle 3, so results should be interpreted with caution. Changes from baseline scores in cycles 2 and 3 did not appear to differ between REG and PBO on the 15 domains of the EORTC QLQ-C30, the EQ-5D index, and the VAS. Conclusions: No substantial differences in overall changes in HRQoL were seen between patients treated with REG and PBO in the CONCUR trial. Clinical trial information: NCT01584830. [Table: see text]