Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI plus.

Slides:

Advertisements

Similar presentations

Miles DW et al. SABCS 2009;Abstract 41.

Advertisements

Part 2 Colorectal Cancer Thursday, July 26, :30 PM – 8:30 PM ET RTP TV: Emerging Treatment Strategies in Colorectal Cancer.

Mario Scartozzi Clinica di Oncologia Medica Ancona HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE.

FOLFOXIRI plus bevacizumab (bev) vs FOLFIRI plus bev

Highligths in management of gastrointestinal cancer April 11, 2008 CONTROVERSIES IN THE CONTROVERSIES IN THE ADJUVANT THERAPY ADJUVANT THERAPY OF GASTRIC.

Abbreviations: RECIST, Response Evaluation Criteria In Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease;

Mizutomo Azuma 1, Michael M. Shi 2, Christian J. Jacques 2, Carl Barrett 2, Kathleen D. Danenberg 3, Syma Iqbal 1, Anthony El-Khoueiry 1, Dongyun Yang.

ECCO ESMO 2011 GI Cancer Updates “ VELOUR” Study Author: J Tabernero et al Reviewed by: Dr. Scott Berry Date posted: October.

Introduction Materials and Methods Results Conclusions CD133 Polymorphisms are associated with clinical outcome in metastatic colorectal cancer (mCRC)

Introduction Patients and Methods Results Conclusion Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. Colorectal.

C. Lieu, H. Tran, Z. Jiang, M. Mao, M. Overman, C. Eng, J. Morris, L. Ellis, J. Heymach, and S. Kopetz Departments of Gastrointestinal Medical Oncology,

results from the phase III TRIBE trial

Fabio Puglisi Dipartimento di Oncologia Azienda Ospedaliero Universitaria di Udine Antiangiogenic Treatment Mediterranean School of Oncology.

A Meta Analysis of Risk of Cardiovascular Events in Patients with Metastatic Breast Cancer (MBC) Treated with Anti Vascular Endothelial Growth Factor (VEGF)

Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single agent (s/a) BEV as maintenance therapy in.

INT Translational research in head and neck cancer: preoperative chemotherapy in oral cavity cancer based on disease molecular profiling. Paolo Bossi MSO.

ASCO Annual Meeting 2012 PHASE II STUDY OF PANITUMUMAB (P) IN COMBINATION WITH FOLFOXIRI AS FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER (MCRC):

A Micro RNA Polymorphism (MiRSNP) in 3’UTR of K-ras gene was associated with clinical outcome in mCRC patients treated with either single agent cetuximab.

Mizutomo Azuma 1, Dongyun Yang 2, Marinella Carpanu 3, Ellen Hollywood 3, Michael Lue-Yat 3, Wu Zhang 1, Kathleen D. Danenberg 4, Peter V. Danenberg 5,

Prospective study of EGFR intron 1 CA tandem repeats as predictive factor of benefit from cetuximab and irinotecan Antoniotti C 1, 2, Loupakis F 3, Cremolini.

*University Hospital Gasthuisberg, Leuven, Belgium

ICAM-1, GRP-78 and NFkB gene polymorphisms associated with clinical outcome in patients with metastatic colorectal cancer treated with first line 5-FU.

Introduction Results Material and Methods Conclusions Genetic variants predict clinical outcome clinical outcome in patients (pts) with metastatic colorectal.

Cancer Stem Cell SNPs Have Opposite Prognostic Outcome in Patients with Gastric Cancer Among Asian and Western Countries Melissa J. LaBonte 1, Takeru Wakatsuki.

Impact of age and comorbidities on treatment effect, tolerance and toxicity in metastatic colorectal cancer (mCRC) patients (pts) treated on CALGB

2013 ASCO Annual Meeting Chicago, 31 May – 4 Jun 2013

ASCO 2008 Annual Meeting Chicago (IL), May 30 – June 3, 2008 FOLFOXIRI (irinotecan, oxaliplatin and infusional 5FU/LV) in combination with bevacizumab.

Risk Stratified Analysis Improves Prediction of Treatment Benefit Over Subgroup Analysis: Findings from Intergroup N9741 HK Sanoff, ME Campbell, HC Pitot,

Intratumoral mRNA expression of genes involved in angiogenesis and HIF-1 pathway to predict outcome to VEGFR tyrosine kinase inhibitor (TKI) in patients.

ASCO - Gastrointestinal Cancers Symposium Orlando (FL), January 2008 First-line Irinotecan, Oxaliplatin and Infusional 5FU/LV (FOLFOXIRI) in combination.

E2100 A Randomized Phase III Trial of Paclitaxel versus Paclitaxel plus Bevacizumab as First- Line Therapy for Locally Recurrent or Metastatic Breast Cancer.

Tumor clock protein PER2 as a determinant of survival in patients (pts) receiving oxaliplatin-5-FU- leucovorin as 1st line chemotherapy for metastatic.

Transcription Factor 7-like 2 (TCF7L2) Polymorphism Was Associated with Worse Survival in Three Independent Cohorts from the USA, Austria, and Japan Rita.

KRAS status and efficacy in the first- line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience Carsten.

Cmab might have therapeutic benefit in Japanese patients with KRAS p.G13D mutant colorectal cancer. Limitations of this study are its retrospective design.

ECCO ESMO 2011 GI Cancer Updates TAS102 and BSC vs. Placebo and BSC Reviewer: Dr. Scott Berry Date posted: October 2011.

Preliminary Results from a Phase II study of FOLFIRI and Bevacizumab as First Line Treatment for Metastatic Colorectal Cancer (Abstract #3579) S. Kopetz,

Introduction Patients and Methods Results Conclusion Pericytes are a key component in the maturation of the VEGF driven tumor angiogenic process 1. Bevacizumab.

Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer: the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL.

1 CONFIDENTIAL – DO NOT DISTRIBUTE ARIES mCRC: Effectiveness and Safety of 1st- and 2nd-line Bevacizumab Treatment in Elderly Patients Mark Kozloff, MD.

Figure 1. Hazard ratios for progression-free survival analyzed with fixed effect model. Table 1: Relevant trials Table 2. Methodological quality Conclusions.

Introduction Patients and Methods Results Conclusion Table 1. Baseline characteristics of the 108 patients included in the biomarker analysis. Objectives.

IntroductionPatient baseline characteristics Conclusion The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer.

Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer ? N. Perez-Staub, B. Chibaudel, A. Figer, A. Cervantes,

1 A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib.

Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients treated with second-line irinotecan (IR)+/- cetuximab (CB): The EPIC experience.

Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs FOLFIRI in the G.O.N.O. randomized phase III.

COMPARING DISEASE OUTCOME OF WOMEN WITH HORMONE RECEPTOR NEGATIVE/HER2 POSITIVE (HR-/HER2+) OR TRIPLE NEGATIVE (TN) METASTATIC BREAST CANCER (MBC) RECEIVING.

ECCO ESMO 2011 GI Cancer Updates “VELOUR” Study

Higher Vitamin D Levels Associated With Improved Survival in Metastatic Colorectal Cancer CCO Independent Conference Highlights of the 2015 ASCO Annual.

CCO Independent Conference Coverage

Alessandra Gennari, MD PhD

in locally advanced rectal carcinoma (LARC): The phase II TRUST trial

Prognostic Factors for First-line Chemotherapy + Bevacizumab or Cetuximab in Metastatic Colorectal Cancer CCO Independent Conference Highlights* of the.

VEGF and VEGFR1 Gene expression levels predict tumor recurrence in adjuvant colon cancer Yan Ning1, Georg Lurje1, Kathleen Danenberg2, Janine Cooc2, Dongyun.

BRAF mutant mCRC patients – What would you recommend? FOLFIRINOX/Bev

Ospedale Misericordia, Grosseto

Genetic variants of kinases suppressors of Ras (KSR)in KRAS-BRAF

A subgroup analysis of a large multicenter study

The DISTINCTIVE study: a biologically enriched phase II study of seconD-line folfiri/aflIbercept in proSpecTIvely stratified, anti-EGFR resistaNt, metastatic.

44th ASCO Annual Meeting May 30-June 3, 2008

Published online September 20, 2017 by JAMA Surgery

Cetuximab with chemotherapy as 1st-line treatment for metastatic colorectal cancer: a meta-analysis of the CRYSTAL and OPUS studies according to KRAS.

Primary side of origin affects the outcome of mCRC patients treated with first-line FOLFIRI plus bevacizumab independently of BRAF status and mucinous.

Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials E Mitry, A Fields,

10th World Congress on Gastrointestinal Cancer, June 25-28, 2008

Treated with Neoadjuvant Therapy

KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab Marta Schirripa1, Fotios Loupakis1, Chiara Cremolini1, Dongyun.

GOCS GRUPO ONCOLÓGICO COOPERATIVO DEL SUR

Presentation transcript:

Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI plus bevacizumab (BV). C. Cremolini 1, F. Loupakis 1,2, D. Yang 2, L. Salvatore 1, W. Zhang 2, T. Wakatsuki 2, M. Schirripa 1, S. Lonardi 3, C. Antoniotti 1, G. Aprile 4, G. Masi 1, F. Graziano 5, A. Ruzzo 6, S. Lucchesi 7, M. Ronzoni 8, M.K.H. Maus 9, G. Bocci 10, G. Tonini 11, A. Falcone 1 and HJ Lenz 2 1.U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 2. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; 3. Istituto Oncologico Veneto, IRCCS, Padova, Italy; 4.Azienda Ospedaliero-Universitaria di Udine, Udine, Italy; 5. UOC Oncologia, A. O., Pesaro, Italy; 6. Section of Biochemistry and Molecular Biology, Department of Biomolecular Sciences, University of Urbino, Urbino, Italy; 7. U.O. Oncologia Medica, Ospedale, Pontedera, Italy; 8. Dipartimento di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy; 9. Response Genetics Inc., Los Angeles, CA; 10. Division of Chemotherapy and Pharmacology Department of Internal Medicine, University of Pisa, Pisa, Italy; 11. Università Campus Bio-Medico, Rome, Italy; University of Pisa, Pisa, Italy No predictors of benefit from BV have been so far identified The association of the T/T variant of VEGF rs C/T SNP with worse PFS and OS was retrospectively reported by our group in a cohort of 111 pts treated with first-line FOLFIRI plus BV but not in a historical cohort of pts treated with first-line FOLFIRI Loupakis et al, BMC 2011 A potential prognostic or predictive role of other VEGF, VEGFR1 and 2 and EPAS1 SNPs was suggested by other retrospective series and by the post-hoc analysis of phase III randomized trials as reported below Background Geners numberFindingReference VEGF-Ars699947Predictive Schneider et al. JCO ‘08 VEGF-Ars699946Predictive Lambrechts et al. ESMO ‘11 VEGFR-1rs Predictive Lambrechts et al. ECCO ‘09 VEGFR-1rs Predictive Claes et al. AACR ‘12 VEGFR-2rs Predictive Lambrechts et al. ESMO ‘11 VEGFR-2rs Prognostic Lambrechts et al. ESMO ‘11 VEGFR-2rs Predictive Gerger et al. CCR ‘11 EPAS-1rs Prognostic Lambrechts et al. ESMO ‘11 Based on our retrospective findings, we planned a prospective validation trial in mCRC patients treated with first-line FOLFIRI+BV To detect an HR for PFS of 1.7 for VEGF rs T/T variant compared to C-, with α and β errors of 0.05 and 0.20 respectively, 199 events were required. As secondary endpoint, we planned a confirmatory analysis of the following candidate SNPs. Germ-line DNA was extracted by peripheral blood and candidate SNPs were analyzed by PCR and sequencing No association of VEGF rs C/T variants with PFS was found TT (N= 147) median PFS: 10.2 mos C- (N= 276) median PFS: 10 mos HR: 1.17 ( ) Log-rank test p=0.218 At the univariate analysis, no association of other candidate SNPs with PFS was found, except for VEGFR C/T variants CC (N= 11) median PFS: 10.7 mos CT (N= 107) median PFS: 9.5 mos TT (N= 306) median PFS: 10.9 mos Log-rank test p=0.047 Conclusions N=424% Sex M/F252/17259/41 Age (median)62 ECOG PS 0/1/2357/63/484/15/1 Primary site Right/Left/Rectum110/187/12726/44/30 Liver-only disease Yes/No136/28832/68 Number of mts sites 1/>1194/23046/54 MAIN PATIENTS’ CHARACTERISTICS This prospective trial does not confirm the predictive impact of VEGF rs C/T SNP suggested by our retrospective experience. Also previous findings on other candidate SNPs are not confirmed. The prospective validation is an essential step on biomarkers’ way toward clinical practice. Future studies on predictors of benefit from BV should provide a comprehensive overlook on the complexity of tumoral angiogenesis not only from the genetic perspective. Patients and MethodsResults C- (N= 118) median PFS: 9.5 mos TT (N= 306) median PFS: 10.9 mos HR: 1.40 ( ) Log-rank test p=0.015 At the multivariate analysis, including Kohne score, mucinous histology, ECOG PS, LDH levels and primary tumor site as covariates, the association of VEGFR C- variants with shorter PFS was still significant (HR: [ ], p=0.012).Significance was lost when applying multiple testing correction.