J. Maurel

Pharmacogenetic predictors of severe peripheral neuropathy in colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy: a GEMCAD group study

BACKGROUND Oxaliplatin-based chemotherapy (CT), widely used as adjuvant therapy for stage III and selected high-risk stage II colon cancer (CC) patients, is often associated with cumulative peripheral neuropathy. Our aim is to identify single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, DNA repair mechanisms, cell cycle control, detoxification or excretion pathways to predict severe (grade 2-3) oxaliplatin-induced peripheral neuropathy (OXPN) among CC patients treated with oxaliplatin and fluoropyrimidine-based adjuvant CT. PATIENTS AND METHODS Genomic DNA was extracted from formalin-fixed-paraffin-embedded peritumoral samples from 206 high-risk stage II and stage III CC patients receiving oxaliplatin-based adjuvant CT from January 2004 to December 2009. Genotyping was carried out for 34 SNPs in 15 genes using MassARRAY (SEQUENOM) technology. A total of 181 stage II-III CC patients treated with the same CT regimens were enrolled as a validation set. RESULTS The rs2230641 cyclin H (CCNH) rs2230641 C/C [odd ratio (OR)=5.03, 95% confidence interval (CI) 1.061-2.41, P=0.042] and the ATP-binding cassette subfamily G, member 2 (ABCG2) rs3114018 A/A genotypes (OR=2.67; 95% CI 0.95-4.41; P=0.059) were associated with a higher risk of severe OXPN. In addition, patients harboring the combination of CCNH C/C and/or the ABCG2 rs3114018 A/A genotypes had a higher risk of grade 2-3 OXPN than those with the CCNH any T and ABCG2 any C genotypes (37.73% versus 19.42%; OR=2.46; 95% CI 1.19-5.07; P=0.014) in the logistic regression analysis using age, gender, adjuvant CT regimen and cumulative dose of oxaliplatin as covariates. The ability to predict severe OXPN of this combined analysis was independently validated in the second cohort (58% versus 33.33%; OR=2.99; 95% CI 1.45-6.13; P=0.002). CONCLUSIONS Our results suggest that SNPs in CCNH and ABCG2 can modulate the development of severe OXPN among stage II-III CC patients who received oxaliplatin-based CT, thus enabling the individualization of adjuvant treatment.

First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study

Background:Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC.Methods:Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg−1 and oxaliplatin 130 mg m−2 on day 1, plus capecitabine 1000 mg m−2 bid orally on days 1–14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP).Results:The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%).Conclusions:Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor–ligand inhibition should be investigated.

Phase II Trial of Doxorubicin Plus Escalated High-Dose Ifosfamide in Patients With Advanced Soft Tissue Sarcomas of the Adult: A Study of the Spanish Group for Research on Sarcomas (GEIS)

Background. To explore the tolerance and the activity of high-dose ifosfamide (IFOS) combined with doxorubicin (DXR) at 50 mg/m2 every 4 weeks in patients with soft tissue sarcomas. Methods. DXR was given IV bolus and IFOS by continuous infusion at 2 g/m2/day. Initial IFOS dose (12 g/m2) was adjusted to 10, 13, or 14 g/m2 according to toxicity. Results. Seventy patients received 277 cycles (median 3 cycles, range 1–10), 34% with IFOS dose increased, 30% decreased, and 48% delivered at 12 g/m2. Toxicity grade 4 occurred on granulocytes (67% of patients) or platelets (19%), 54% had febrile neutropenia, 31% grade 3/4 asthenia, and 26% abandoned the study due to toxicity. Three toxic deaths occurred. In 57 non-GIST patients objective activity was 45.6% (95% CI, 32 to 58%). Conclusion. At least 4 cycles were tolerated by 71% of patients, most receiving DXR 50 mg/m2 plus IFOS 10–12 g/m2, with substantial toxicity.

599PA VALIDATION OF CURRENT PROGNOSTIC SCORES IN METASTATIC COLORECTAL CANCER (MCRC) AND A NEW PROGNOSTIC SCORE (A GEMCAD STUDY)

Aim: Background: The two main prognostic scores for mCRC (Kohne and GERCOR) do not account for resectability of liver-only metastasis (LiM) and thus are limited as treatment guidance. We propose a classification of patients based on LiM resectability, performance status (PS) and lactate dehydrogenase (LDH) levels and compare its discrimination capacity against Kohne and GERCOR scores. Methods: We analyzed 395 patients treated with first-line oxaliplatin-based regimes with or without monoclonal antibodies. Patients were classified as stage 1 if LiM were considered resectable ( 4 and 5 cm diameter), PS 0-1 and LDH 1.5 ULN. This score, Kohne, and GERCOR scores were tested for discrimination using Harrel’s C index (HCI, higher is better) and calibration using Akaike information criterion (AIC, smaller is better) of progression-free survival (PFS) and overall survival (OS). Results:

1416PDINTEGRATING GENOTYPE IN RISK CLASSIFICATION FOR GIST RECURRENCE. A SPANISH GROUP FOR SARCOMA RESEARCH (GEIS) STUDY

ABSTRACT Aim: Relevant prognostic factors for relapse free survival (RFS) in GIST relies on clinical and pathologic variables as size, mitoses, location or tumor rupture. However, being GIST a solid tumor model for molecular research and targeted therapies, it seems legitimate to explore the integration of relevant molecular prognostic factors into the risk classification. Several authors have pointed out the detrimental prognostic role of deletion type mutations involving 557/558 (DEL-5758) codons of exon 11 in KIT gene. On the other hand, mutations of PDGFR (MUT-PDGFR) gene have been associated with lower risk of recurrence. We will analyze the influence of these genotype factors for each Miettinen risk category (MRC). Methods: Clinical data, therapeutic and follow-up procedures stemmed from the GIST Registry of GEIS. Main inclusion criteria were: localized GIST, adequate surgery, size>2 cm, complete genotype for KIT and PDGFR genes, no adjuvant imatinib and minimum follow-up of 3 years. RFS was measured by Kaplan-Meier method. For each MRC, RFS was estimated for those harboring DEL-5758 or MUT-PDGFR. Univariate and multivariate analysis were performed using log-rank test and Cox regression. Results: 429 patients were identified according to the inclusion criteria, 35 of them had insufficient data, thus 394 patients entered into the analysis. Median size was 7 cm and with a median follow-up of 84 months there were 137 recurrences (37%). DEL-5758 and MUT-PDGFR were present in 65 and 25 cases respectively. The 7-year RFS for low MRC were 93% in MUT-PDGFR, 76% in DEL-5758 and 90% in the remainder (p=0.35), for Intermediate MRC were 80%, 26% and 64% (p=0-009) respectively and for high MRC were 40%, 21% and 28% (p=0.79) respectively. On univariate analysis: mitoses, size, location (gastric vs non gastric) and genotype were found to be significantly correlated with RFS. Multivariate analyses revealed that size (HR 1.75; CI 1.04-2.90), location (HR 1.79; CI 1.24-2.60), mitoses (RR 3.4; CI 2.31-5.05) and DEL-5758 (RR 1.5; CI 1.02-2.32) were independent prognostic factors for RFS. Conclusions: Genotype significantly affects prognosis in localized GIST and therefore should be integrated into the risk classification especially in intermediate MCR. Disclosure: All authors have declared no conflicts of interest.

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study

The aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60 mg m−2 by i.v. bolus on day 1 followed by gemcitabine at 800 mg m−2 over 80 min on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2′,2′-difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8 h after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3–4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9–35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration.

Association between genotypes, clinical scores and survival outcome in metastatic colorectal cancer.

3553Background: Several prognostic clinical scores for metastatic colorectal cancer (mCRC) GEMCAD (Ann Oncol 25 (Supp 4)), 2014; GERCOR (Oncologist 16, 2011); Kohne (Ann Oncol 13, 2002) are useful ...

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

Background:First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients.Methods:This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734).Results:Forty-three patients were enroled, median age 17 years (range, 3–40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41–74%) with an EFS of 50.0% (95% CI, 36–68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57–100%) and 71.0% (CI, 54–94%); for HR 36.0% (CI, 20–65%) and 29.0% (CI, 15–56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56–97%) and 31.0% for >18 years (95% CI, 15–66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively).Conclusions:Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.

227PPROGNOSIS OF PHOSPHORYLATED-INSULIN GROWTH FACTOR RECEPTOR (P-IGF-1R) AND METALLOPROTEINASE-3 (MMP3) EXPRESSION IN ADVANCED GASTROINTESTINAL STROMAL TUMORS (GIST) PATIENTS TREATED WITH IMATINIB. A GEIS STUDY

ABSTRACT Aim: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, with PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated expression of p-IGF-1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS) Methods: Ninety-six advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF-1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF-1R system, we have used an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9,11,13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirecctional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p Results: MMP3 was overexpressed in 10% of cases and p-IGF-1R in only 2% of cases. 68% of patients had KIT mutations, 4% had PDGFRA mutations and 28% were WT for KIT and PDGFRA. At univariate analysis KIT exon 11/13 vs rest (WT/WT, KIT exon 9 mutations and PDGFRA mutations) had better PFS (p = 0.038; HR: 0.58; 95%CI (0.35-0.96). Less than 24 months disease free-interval (HR 24.2, 95% CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95% CI 2.5-15.9), extension of disease; > 1 organ (HR 1.89; 95% CI 1.03-3.4) and positive expression of p-IGF-1R or MMP3 (HR 2.1; 95% CI 1.01-4,2) but not mutational analysis (HR 1.02; 95%CI 0.53-1.96) were the strongest prognostic factors for PFS in the multivariate analysis. For OS only PS, disease free-interval and number of metastatic sites remain significant. Conclusions: Our findings suggest that p-IGF-1R (Y1316) and MMP3 expression have major prognostic significance for PFS in advanced GIST treated with imatinib therapy. Disclosure: All authors have declared no conflicts of interest.