bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relevance of sex and PER2 SNPs for predicting irinotecan tolerability in cancer patients.
Authors: Pirovano M. , Fornasari D. , Nasisi A. , Caronno A. , Innominato P. F. , Garufi C. , Moroni M. , Scaglione F. , Levi F. ,   TEMPO consortium
Published: February 2017

416 Background: Advances in understanding the mechanisms underlying diseases and drug responses are creating increasing opportunities to offer safer and more effective treatments to individual patients (pts). Biomarkers are needed for predicting likelihood of therapeutic safety and efficacy in each individual pt. Down-regulation of core clock gene PER2 in tumors predicted for poor survival in pts with metastatic colorectal cancer (Jacobelli. J Clin Oncol. 26: 2008 May 20 suppl; abstr 11032). Methods: A clinical data base and tissue bank involving primary tumor (T) and healthy adjacent colon mucosa (C) from 139 pts treated with circadian-shaped or standard infusion of (A)-single-agent irinotecan (63 pts) or (B) in combination with oxaliplatin and 5FU (76 pts) for previously-treated metastatic colorectal cancer was established and tissues were collected. Clinical relevance of constitutive or acquired single nucleotide polymorphisms (SNPs) for 5 metabolism (ABCB1, ABCB2, CES2, TOP1, UGT1A1) and for two PER2 SNP's (A4572G and C3968T). Results: No acquired mutation in the genes analysed was found (100% T and C concordance). The incidence of grade 3-4 toxic event of any kind was significantly lower in women as compared to men in A population(39% vs 76%, p=0.007) and in A+B population (p=0.05), independently from other factors (p=0.02) this difference is lost if you consider only B population where oxaliplatin is added (p=0.5). No SNP in metabolism genes predicted for toxicity in this cohort. Conversely, SNPs in core clock gene PER2 (1 pt with A4572G and 4 pts C3968T) were significantly associated with higher incidence of G3-4 toxicity (100% in polymorphic pts. vs 17.2% in wild type pts, p=0.01). Conclusions: Irinotecan tolerability is sex dependent and woman has significative low incidence of toxic effects. We demonstrated for the first time an association between constitutive SNPs in a core clock gene and toxicity, further supporting the relevance of the circadian timing system in chemotherapy tolerability. Moreover, our findings are in good agreement with data in mice, supporting the hypothesis that sex determines two chronotoxicity classes in patients with metastatic colorectal cancer. No significant financial relationships to disclose.
Folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) plus chemoradiation (CRT) with 5-fluorouracil (5FU) as adjuvant treatment for patients with operable gastric cancer (OGC): A feasibility study with pharmacogenetic analysis.
Authors: Athanasiadis A. , Boukovinas I. , Sfakianaki M. , Saridaki Z. , Papadaki C. , Tzardi M. , Androulakis N. E. , Polyzos A. , Georgoulias V. , Sougklakos I. 
Published: February 2017

44 Background: To evaluate the efficacy and safety of FOLFIRI plus CRT with 5FU as adjuvant treatment for patients with OGC. Methods: Patients received treatment with FOLFIRI (irinotrecan 150 mg/m2, d1, LV 200 mg/m2, d1+2 and 5FU [400 mg/m2/d bolus and 600 mg/m2/d, 22 h infusion, d1+2]) for 2 15-day cycles followed by RT (45Gy) with 5FU continuous infusion (325 mg/m2/d in the 1st and 5th week) administration. Eight additional cycles of FOLFIRI were administered after the completion of CRT. BRCA1, ERCC1, XPD, TOPO-I, TOPO-IIA and B and TS mRNA expression was determined in the primary tumor where available. Results: The median age of the 171 enrolled patients was 62 years, 114 (66%) were males, 136 (79%) had R0 resections and 152 (89%) had at least a D1 resection. Treatment was completed as per protocol in 107 (63%) of the patients. CRT was completed in all but 5 (3%) patients. The median rate of drug exposure was 93% for irinotecan, 87% for 5FU and 91% for LV. The most common grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (3.5%) and diarrhea (7%). After a median follow-up of 45.7 months 84 had relapsed and 70 were deceased. The median disease-free survival (DFS) was 30 months (95% CI: 18-41 months), while the projected median overall survival (mOS) was 53.7 months (95% CI: 30-77 months). The recurrence free probability at 5 years was 44% while the probability of survival at 5 years was 46%. From the studied pharmacogenetic markers only TS low expression was correlated with a trend towards improved DFS and OS in patients with R0 resections. Conclusions: These results show that the administration of FOLFIRI plus CRT with 5FU as adjuvant treatment in OGC is a feasible approach with acceptable toxicity and challenging efficacy which merits further evaluation in a randomized trial. No significant financial relationships to disclose.
Human epidermal growth factor receptor-2 (HER2) Ile655Val single nucleotide polymorphism (SNP) is associated with gender-specific outcome in patients with metastatic colorectal cancer (mCRC) treated with cetuximab in a phase II study (IMCL-0144).
Authors: Gerger A. , Bohanes P. O. , Yang D. , Winder T. , Ning Y. , Labonte M. J. , Mauro D. J. , Langer C. , Rowinsky E. K. , Lenz H. 
Published: February 2017

441 Background: HER2 pathway is an important growth-regulatory pathway in many malignancies. In-vitro data from various cell lines suggest that activation of HER family members predicts resistance to cetuximab. HER2 also interacts with hormone receptors and estrogen, promoting tumor proliferation in breast cancer models. We previously demonstrated that polymorphisms in HER1 and ER-β were associated with gender-specific survival in colorectal cancer patients. HER2 Ile655Val (rs1136201) SNP's functionality was shown in breast cell lines with Val-expressing cells exhibiting increase growth capacity. We tested whether this SNP may predict gender-specific clinical outcome in mCRC treated with cetuximab. Methods: Tissue samples of 130 patients, 64 males and 66 females, with mCRC, enrolled in a phase II trial of cetuximab monotherapy were analyzed. Genomic DNA was extracted from FFPE tumor tissue. K-Ras mutation status and HER2 Ile655Val (rs1136201) SNP were analyzed using direct DNA-sequencing and PCR-RFLP. 23 out of 130 patients were still alive at the time of data analysis with a median follow-up of 12.3 months. Results: Females with the low activity HER2 Ile/Ile (n = 41) genotype had better progression-free survival (PFS) when compared to Ile/Val or Val/Val (n = 21) genotypes (median PFS = 2.4 vs. 1.2 months; HR = 2.06 (95% CI: 1.08-3.92), p = 0.0281) based on the multivariable Cox regression model adjusting for KRAS, performance status and severity of skin rash and stratified by race. In KRAS wild-type females, 15 patients out of 20 (75%) with HER2 Ile/Ile genotype responded or had stable disease when compared to 4 out of 12 (33%) Ile/Val or Val/Val genotypes (exact conditional test p = 0.143). In males, HER2 Ile655Val SNP is not associated with outcome. HER2 Ile655Val SNP is not associated with gender-specific overall survival. Conclusions: Our data suggest that HER2 Ile655Val SNP may identify females with mCRC likely to experience better outcome when treated with cetuximab. Prospective biomarker-embedded clinical trials are needed to validate our results. [Table: see text]
Chemotherapy-induced neutropenia association with survival in metastatic colorectal cancer (MCC): Schedule dependency.
Authors: Innominato P. F. , Giacchetti S. , Smaaland R. , Focan C. N. , Garufi C. , Bjarnason G. A. , Iacobelli S. , Tumolo S. , Karaboué A. , Levi F. ,   ARTBC International Chronotherapy group
Published: February 2017

454 Background: Circadian clocks control cellular proliferation and drug metabolism over 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronoFLO4) offered no survival benefit as compared to the non-time stipulated FOLFOX2 in an international randomized trial involving patients (pts) with previously untreated MCC (EORTC05963). We hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Methods: Pts with available data (N=556) were categorized into three subgroups according to the worst grade of neutropenia experienced during treatment. Distinct multivariate models were constructed for each treatment schedule. Results: Neutropenia (all grades) occurred in 39% of the pts on chronoFLO4 as compared to 67% of those on FOLFOX2 (p< 0.0001), with G3-4 being encountered in 7% and 25%, respectively (p< 0.0001). In both schedules, neutropenia was more frequent and more severe in women than in men (p<0.04).The occurrence (but not the severity) of neutropenia was significantly associated with improved objective response rate, progression-free and overall survival in pts on FOLFOX2 (p< 0.0001), confirming previous results by others. In pts on chronoFLO4, the occurrence of neutropenia was not associated with any efficacy advantage (p=0.36), and worst survival was observed in pts developing severe neutropenia. Conclusions: Neutropenia was more frequent and severe in women than in men, and on FOLFOX2 than on chronoFLO4. Neutropenia was positively correlated with survival in pts on FOLFOX2 supporting intra-patient dose escalation to achieve toxicity for conventional chemotherapy. No survival prolongation was found in pts with neutropenia on chronoFLO4. Thus, reaching maximum tolerated dose was unnecessary to achieve optimal effectiveness of circadian-timed therapy, and should even be avoided. [Table: see text] No significant financial relationships to disclose.
Relationship between methylation status of PTEN and point mutation of the EGFR L2 domain and efficacy of cetuximab in metastatic colorectal cancer.
Authors: Ito Y. , Yamada Y. , Asada K. , Ushijima T. , Iwasa S. , Kato K. , Hamaguchi T. , Shimada Y. 
Published: February 2017

458 Background: The KRAS mutation has been associated with resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in metastatic colorectal cancer (mCRC). However, the predictive biomarkers of cetuximab resistance in KRAS wild-type mCRC remain unknown. We explored the possible roles of PTEN methylation and mutation of the EGFR L2 domain, which is the site of binding to cetuximab, in cetuximab resistance in KRAS wild-type mCRC. Methods: The subjects were 247 mCRC patients screened for KRAS status at the National Cancer Center Hospital between September 2008 and April 2010. Genomic DNA was extracted from formalin- fixed paraffin-embedded colorectal cancer tissue samples. Mutation analysis of KRAS and the EGFR L2 domain was performed by direct sequencing. Methylation analysis of PTEN was performed by quantitative real-time methylation-specific PCR with a set of primers specific to the methylated and unmethylated sequences, using sodium bisulfate-modified DNA. Results: Of the 247 mCRC patients, 136 patients had wild-type KRAS (55%). In 9 of these patients, the quality of the DNA was sufficient for analysis of PTEN methylation levels. Eight of the 9 patients received a cetuximab-based regimen (with irinotecan: 4, monotherapy: 4). The best response was PR in 4 patients (25%), SD in 2 (12.5%), and PD in 2 (12.5%). The best response of the one patient with methylated PTEN treated with cetuximab and irinotecan was SD. Mutation analysis of the EGFR L2 domain was performed in 65 of the 136 patients with wild-type KRAS. All of them received a cetuximab-based regimen (with irinotecan: 50, monotherapy: 15). The best response was PR in 13 patients (20%), SD in 26 (40%), PD in 20 (31%). The one patient who had a mutation at exon 9 showed a partial response to cetuximab and irinotecan. Conclusions: Methylation of PTEN and mutation of the EGFR L2 domain were analyzed in Japanese mCRC patients. Our findings do not provide sufficient evidence that EGFR L2 domain mutation and methylation of PTEN are correlated with resistance to cetuximab. No significant financial relationships to disclose.
The effect of tumor response on quality of life (QoL) in patients with KRAS wild-type metastatic colorectal cancer (mCRC): Analysis from the CRYSTAL study.
Authors: Griebsch I. , Lang I. , Sartorius U. , Van Cutsem E. 
Published: February 2017

476 Background: In the CRYSTAL study cetuximab (cet) added to first-line chemotherapy (CT) significantly improved tumor response compared with CT alone in patients (pts) with KRAS wild-type (wt) mCRC, confirming existing data in this setting. Response to CT has been reported to lead to a corresponding increase in QoL, and QoL scores to predict overall survival in mCRC. In this exploratory analysis tumor response and QoL was investigated in pts from the CRYSTAL study. Methods: Pts were classified as responders (Rs) or nonresponders (NRs) according to best overall response. QoL was assessed using single-item symptoms questions from the EORTC QLQ-C30 (q8-10, q12-18). Pts at baseline were considered symptomatic if they answered “quite a bit” or “very much” and asymptomatic if they answered “not at all” or “a little” to either one of the symptoms questions. Analysis was performed in all treatment groups (gps) on the change in symptoms in pts considered symptomatic or asymptomatic at baseline. Results: 471 of 627 KRAS wt pts assessed for QoL had baseline data showing they were symptomatic or asymptomatic. In pts asymptomatic at baseline (n=278) there were more Rs (58%) than NRs (42%). In pts symptomatic at baseline (n=193), there were less Rs (40%) than NRs (60%). At week 8 in all treatment gps, in pts symptomatic at baseline more Rs than NRs became asymptomatic (Table). In pts asymptomatic at baseline, in the CT + cet gp at week 8, 61% of Rs remained asymptomatic compared with 50% of NRs. Data from week 16 and 24 also showed trends in favor of Rs in symptomatic or asymptomatic pts at baseline and will be presented. Conclusions: Rs who are symptomatic at baseline experience higher symptom relief than NRs. Furthermore Rs who are asymptomatic at baseline are more likely to remain asymptomatic post baseline than NRs. These findings are independent of treatment. [Table: see text] [Table: see text]
A randomized phase II study comparing mFOLFOX-6 combined with axitinib or bevacizumab or both in patients with metastatic colorectal cancer (mCRC).
Authors: Infante J. R. , Cohn A. L. , Reid T. R. , Edenfield W. J. , Cescon T. , Hamm J. T. , Tarazi J. C. , Kim S. , Rosbrook B. , Cartwright T. H. 
Published: February 2017

485 Background: Vascular endothelial growth factor receptor inhibitors, including axitinib (AG-013736), may be useful in treating patients with mCRC. The goals of this study were to estimate the objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety in patients with mCRC treated with mFOLFOX-6 combined with axitinib or bevacizumab or both. Methods: Patients with mCRC untreated with any systemic chemotherapy >12 months prior to enrollment, ECOG PS 0/1, adequate organ function, and controlled hypertension were eligible for this randomized, open-label, phase II study. Patients receiving prior treatment with antiangiogenic agents or those who were pregnant were ineligible. All patients received standard mFOLFOX-6 treatment and were randomized to receive either axitinib 5 mg (Arm A), or bevacizumab 5 mg/kg (Arm B), or axitinib 5 mg + bevacizumab 2 mg/kg (Arm C). Axitinib was administered orally twice daily. Efficacy was determined by RECIST criteria. Results: A total of 42, 43, and 41 patients were enrolled in Arms A, B, and C, respectively. The ORR was 29%, 49%, and 39% for Arms A, B, and C, respectively. Median PFS was 315 days, 350 days, and 377 days, with 1-year survival of 72%, 79%, and 80% for Arms A, B, and C, respectively. Discontinuations due to adverse events (AEs) were more common in Arm A (36%), than in Arms B (19%) or C (32%). More patients withdrew from Arm A (18%) than from Arms B (5%) or C 12%). The rates of grade 3 AEs were similar across arms, except for hypertension and fatigue which were more common in Arms A (15% and 12%) and C (21% and 29%) compared with Arm B (2% and 12%). Serious AEs were reported by 41%, 40%, and 56% of patients in Arms A, B, and C, respectively; the most common were gastrointestinal disorders (21%, 16%, 15%, respectively). Conclusions: In combination with mFOLFOX-6 chemotherapy, treatment with axitinib resulted in a lower ORR but comparable survival to bevacizumab and this did not appear to improve significantly in the presence of both agents. This result may have been affected by the higher numbers of discontinuations and withdrawals in Arm A compared with the other 2 arms. [Table: see text]
Use of a multigene prognostic assay for selection of adjuvant chemotherapy in patients with stage II colon cancer: Impact on quality-adjusted life expectancy and costs.
Authors: Meropol N. J. , Lyman G. H. , Chien R. , Hornberger J. C. 
Published: February 2017

491 Background: Uncertainty exists regarding the use of adjuvant therapy in patients with stage II colon cancer. To assist decision making, we compared quality-adjusted life expectancy and costs associated with using a multigene recurrence score (RS) assay with the use of clinicopathological factors currently recommended in clinical guidelines. Methods: A state-transition (Markov) model was developed to assess outcomes associated with the use of the RS (Oncotype Dx gene expression assay) in adjuvant therapy decisions in stage II colon cancer (excluding T4 tumors and those with deficient DNA mismatch repair). RS test characteristics were based on results reported from a randomized controlled trial (QUASAR, Kerr et al. ASCO, 2009). Current rates of administering adjuvant chemotherapy (aCTX) as a function of age, lymphatic invasion, tumor stage, and number of lymph nodes examined was derived from the NCCN Colon/Rectum Cancer Outcomes study (Earle et al, J Surg Oncol, 2009). Effects of aCTX on recurrence risk were based on published data. Medicare fee schedules were used to estimate cost; toxicities, recurrence, and quality-of-life adjustments were obtained from published studies. Results: Treatment decisions based on RS and a patient's years of life remaining without cancer recurrence would reduce aCTX use by 17% compared with current treatment patterns, and increase quality-adjusted life expectancy by an average of 0.035 years. With lower use of aCTX, direct medical costs are expected to decrease by an average of $2,971 per patient. One-way sensitivity analysis predicts overall QALY improvement with the RS through a range of variables, with the results most sensitive to the disutility associated with aCTX use. Sensitivity analyses also show the assay to be cost-saving under a variety of conditions. Conclusions: Clinical use of a multigene RS to assess risk of recurrence in T3 stage II colon cancers with intact mismatch repair is likely to improve quality-adjusted life expectancy and be cost-saving from a societal perspective. Patient age and disutility associated with chemotherapy are important considerations in adjuvant treatment decisions. [Table: see text]
Comparative clinical efficacy of adjuvant chemotherapy regimens in randomized controlled trials (RCTs) of early-stage colon cancer: Systematic review and meta-analysis.
Authors: Cassidy J. , Schmoll H. , Chu E. , Hawkins N. , Tatt I. , Saini J. P. , Urspruch A. 
Published: February 2017

498 Background: A systematic review was conducted to identify RCTs of adjuvant chemotherapy regimens for early-stage colon cancer and a network meta-analysis performed to compare efficacy of oxaliplatin/fluoropyrimidine regimens. Methods: A systematic review identified RCTs recruiting adult patients with early-stage (adjuvant) stage II/III colon cancer. Outcome measures included hazard ratios for DFS and OS. Only publications in English were considered. Study quality was assessed using the Cochrane Collaboration “risk of bias” assessment tool. A single reviewer screened abstracts/titles using predefined selection criteria, with critical appraisal and data extraction conducted independently by two reviewers. A Bayesian network meta-analysis was used to estimate comparative efficacy of adjuvant chemotherapy across RCTs. Results: 56 articles describing 40 trials were selected, of which six reported data on regimens accepted as current standard of care (capecitabine/X-ACT, XELOX/NO16968, FOLFOX/MOSAIC, FLOX/C-07) or common comparators: bolus 5FU/LV and LV5FU2 (C-96-1, PETACC-2). Statistical assessment of heterogeneity was not possible due to the limited study network. Baseline characteristics were similar across trials with the exception of three trials recruiting only stage III patients; sub-group analysis on these trials was not possible due to lack of common comparators. There was no significant difference in DFS at a median follow-up of 3-years (or closest reported analysis) for XELOX vs. FLOX (HR=0.99, 95% CI 0.80–1.22) or FOLFOX (HR=1.00, 95% CI 0.72–1.41). There was also no significant difference in OS at a median follow-up of at least 5 years. Taken as a class, oxaliplatin-containing regimens (XELOX, FOLFOX, FLOX) improved DFS vs. non-oxaliplatin-containing regimens (HR=0.80, 95% CI 0.73–0.87). This result was confirmed for OS. Conclusions: Despite the limited number of available trials, the results of these analyses demonstrate a clear benefit of incorporating oxaliplatin into combination regimens for early-stage colon cancer. XELOX, FOLFOX and FLOX appear to be equivalent in terms of efficacy in this setting. [Table: see text]
Study on the deterioration of verbal memory in colon cancer patients after receiving adjuvant chemotherapy.
Authors: Martinez Marín V. , Lopez Santiago S. , De Castro J. , Cruzado J. A. , Belda-Iniesta C. , Cano J. , Barriuso Feijoo J. , Feliu M. , Smith J. , Feliu J. 
Published: February 2017

509 Background: Usually, patients treated with chemotherapy (CT) complain about memory loss. This was mainly studied on patients receiving adjuvant CT for breast cancer. However there are no data on adjuvant treatment of colon cancer (CC). The aim of this study is to investigate whether adjuvant CT induces in CC patients impaired memory, particularly the verbal one. Methods: 77 patients diagnosed with stage II-III CC who received adjuvant CT for 6 months with FOLFOX-4 were included between January 2008 and May 2010. Verbal memory was investigated pre-and post-treatment by the Test Barcelona. Peña-Casanova, (1990). Results: Data of 54 patients who completed the analysis pre-and post-treatment were collected. Population characteristics are: male (61%), mean age of 66, less than 5 years of education (58.3%), stage II/III (43/57%) treated with FOLFOX-4/Xeloda (85/15%). Analysis of verbal memory performance can be seen in the table. Conclusions: We found a clear verbal memory impairment after adjuvant CT in CC patients, although the number of words Learning decreases without reaching statistical significance. Remembering of stories is significantly deteriorated after the administration of QT, affecting the patient immediate recall of stories, even when given clues. So it is the delayed recall (after 5′). This can have a negative impact on the patient's life in tasks involving immediate or delayed recall of events. This interesting finding must be tested in larger series and placebo controlled randomized trials. [Table: see text] No significant financial relationships to disclose.