Transcript ASCO_2009_files/Yang PG EPIC ASCO 2009

Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients treated with second-line irinotecan (IR)+/- cetuximab (CB): The EPIC experience
Dongyun Yang1, Alexandra Pohl1, Wu Zhang1, Georg Lurje1, Yan Ning1, Anthony El-Khoueiry1,
Shirin Khambata-Ford2, Christiane Langer2, Syma Iqbal1 and Heinz-Josef Lenz1
1.USC/Norris Comprehensive Cancer Center, Los Angeles, CA 2. Bristol Myers Squibb Research and Development, Princeton, NJ
Introduction
EPIC, a multinational phase III clinical trial with
IR + CB vs IR alone in mCRC patients in the
second-line setting after failure of FOLFOX
demonstrated a benefit for IR+CB in
progression-free survival (PFS) and response
rate (RR). We evaluated functional germline
polymorphisms involved in the EGFR- (EGF,
EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) and drug-metabolism related genes (UGT1A1,
MTHFR) for their potential role as molecular
predictors for clinical outcome in patients
treated with CB/IR vs. IR alone.
Patients and method
Genomic DNA was extracted from formalinfixed paraffin-embedded tumor samples from
186 EPIC- trial participants (US sites only,
14% of total trial participants). 84 patients
were treated with IR/CB (arm A); 102 patients
received IR alone (arm B).
Genotyping was performed using PCR-RFLP
assays, direct sequencing or 5’ -end [ϒ-33P]
ATP’ labeled PCR-protocols.
Results
Patients baseline characteristics
PFS by EGFR-CA repeat for arm A
OS by MTHFR 677C>T for arm B
OS by MTHFR 1298A>C for arm B
In this patient cohort, 11/84 patients (13%), who received IR/CB, showed CR or
PR, whereas 73/84 (87%) patients had SD or PD. For arm B, 6/102 patients
(6%) showed CR or PR, whereas 96/102 patients (94%) had SD or PD. Median
PFS in arm A was 3.0 months (range 2.4- 4.1 months) vs 2.7 months (range
2.2-2.9 months) in arm B; median overall survival (OS) was 9.3 months (range
7.1-21.1 months) in arm A vs. 12.3 months (range 10.4- 17.9 months) in arm B.
Patients baseline characteristics were not representative for the whole study
population (table 1). K-ras mutation status was not significantly associated with
PFS or response to CB/IR in this patient cohort of 186 patients. We found an
EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, logrank test), whereas the EGFR-CA repeat in arm B was not significantly
associated with PFS (p=0.98, log-rank test).
In arm B, we found a significant association with RR (p=0.0103, Fisher’s exact
test) for MTHFR 1298A>C. Furthermore, MTHFR 677C>T (p =0.005, log-rank
test) and MTHFR 1298A>C (p=0.039, log-rank test) were also found to be
associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was
significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR
677C>T and MTHFR 1298A>C appeared to be prognostic factors for OS
(adjusted p=0.028 and 0.026, respectively, cox-proportional hazard models),
independent from K-ras mutation status, race and number of disease sites.
Conclusion
Our study demonstrates a prognostic and potentially predictive
value for polymorphisms in the EGFR- and MTHFR- gene in
patients with mCRC, treated in second-line setting with IR+/- CB.
To our knowledge, this is the first study to show a potential
influence of MTHFR with irinotecan-sensibility. However, the
underlying molecular mechanisms are unclear and need further in
vivo- and in vitro evaluation.