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Prospective study of EGFR intron 1 CA tandem repeats as predictive factor of benefit from cetuximab and irinotecan - PowerPoint PPT Presentation
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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 C 1, 2, Zhang W 3, Yang D 3,Wakatsuki T 3, Schirripa M 1, 2, Salvatore L 1, 2, Ricci V 4, Graziano F 5, Masi G 1 ,2, Ruzzo A 6, LaBonte MJ 3, Ning Y 3, El-Khoueiry R 3, Falcone A1, 2, Lenz HJ 3
1. U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy; 2. Istituto Toscano Tumori (ITT), Italy; 3. Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA;
4. Unità di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy; 5. Medical Oncology Unit, Hospital of Pesaro, Pesaro, Italy; 6. Section of Biochemistry and Molecular Biology, Department of Biomolecular Sciences, University of Urbino, Urbino, Italy Abstract ID: 3540
Preclinical data suggest that the number of CA tandem repeats in EGFR intron 1 might affect gene transcription.
Different retrospective studies have investigated the impact of the number of EGFR intron 1 CA repeats on the efficacy of cetuximab in mCRC patients, providing contrasting results.
As reported below, different cut-off values were adopted to define polymorphic variants and patients with heterogeneous clinical and molecular characteristics were included.
Results
At a median f-up of 21.9 mos, mPFS and mOS were 5.2 and 13.4 mos, respectively. EGFR (CA)n genotype was L- and SS in 45 (40%) and 68( 60%) pts respectively. Ten (22%) out of 45 L- pts achieved response compared to 22 (33%) out of 67 SS pts (Fisher’s Exact test: p=0.617).No differences in PFS or OS were observed between L- and SS genotypes mPFS: 4.4 versus 5.3 mos, HR: 1.00 [95%CI: 0.67-1.51], p=0.991; mOS: 11.3 versus 14.2 mos, HR: 1.30 [95%CI: 0.80-2.22], p=0.261.
Conclusions
This prospective study, including a clinically homogenous and molecularly selected population, does not confirm any predictive or prognostic effect for EGFR (CA)n repeat allelic variants with respect to the efficacy of cetuximab and irinotecan in advanced lines of treatment.
The present experience strengthens the need of prospectively challenging retrospective findings, to validate apparently promising biomarkers.
Background
N Setting Definition of allelic variants Finding
Lurje et al, Clin Can Res 2008
117 Advanced linesShort : <20 CA repeatsLong: ≥ 20 CA repeats
No association with clinical outcome.
Graziano et al, J Clin Oncol 2008
110 Advanced linesShort: <17 CA repeats Long: ≥17 CA repeats
SS variant is associated with longer OS
Pander et al, Eur J Cancer 2010
123 First-lineShort: <20 CA repeatsLong: ≥ 20 CA repeats
L- variants are associated with shorter PFS
Dahan et al, BMC Cancer 2011
56First and
subsequent linesShort:sum of CA repeats ≤35Long:sum of CA repeats >35
No association with clinical outcome.
Park et al, Canc Chem Pharm
201165
First and subsequent lines
Short:sum of CA repeats ≤36Long:sum of CA repeats ≥37
No association with clinical outcome.
Patients and Methods
We designed a prospective confirmatory study in KRAS and BRAF wild-type irinotecan-resistant mCRC patients treated with biweekly cetuximab and irinotecan in advanced lines. We defined S and L allelic variants those presenting < and ≥ 20 CA repeats, respectively.
To detect a HR for PFS of 1.75 for L- compared to SS genotypes, estimating a prevalence of 60% of SS variant and setting a two-sided alfa=0.05 with a power of 80%, 104 events were required .
MAIN PATIENTS’ CHARACTERISTICS
Other exploratory analyses adopting different cut-off values reported in literature led to similar results.
Characteristics N=113 %
Sex Females 36 32
Males 77 68
Age ≤65 years 56 50
>65 years 57 50
ECOG PS 0 65 57
1-2 48 43
N.metastatic sites 1 27 24
>1 86 76
Liver-only mets Yes 21 19
No 92 81
