Polymorphisms correlated with the clinical outcome of locally advanced or metastatic colorectal cancer patients treated with ALIRI vs. FOLFIRI

Pteridines

Giovannetti Elisa¹  Peters Godefridus J.¹  Maftouh Mina¹  Barcelos Ana¹  Griffioen Pieter²  de Jonge Robert²  Hanauske Axel R.³ 

[1] Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands;Department of Clinical Chemistry, University Medical Center Rotterdam, Rotterdam, The Netherlands;Eli Lilly and Company, Indianapolis, IN, USA;

关键词: 5-fluorouracil;    clinical outcome;    colorectal cancer;    pemetrexed;    polymorphisms;   

DOI  :  10.1515/pterid-2013-0021

来源: DOAJ

【 摘 要 】

Leucovorin-modulated 5-fluorouracil (5-FU) plus irinotecan (FOLFIRI) is the most common treatment of metastatic colorectal cancer (CRC). 5-FU inhibits thymidylate synthase (TS) and irinotecan topoisomerase I, leading to inhibition of DNA replication and repair. FOLFIRI efficacy suggested that other TS inhibitors might synergize with irinotecan, and Phase I/II studies for second-line treatment showed promising results of combinations with the multitargeted antifolate pemetrexed (PMX), which exerts its effects primarily via TS inhibition. However, a randomized Phase II trial of PMX + irinotecan (ALIRI) showed similar efficacy and safety, but significantly shorter progression-free survival (PFS) compared with FOLFIRI in locally advanced or metastatic CRC. In our previous aCGH study, we evaluated genome-wide copy number variations, whereas in the current study we evaluated relationships between functional polymorphisms and PFS. Candidate polymorphisms were studied by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) (TSER-2R/3R) or Taqman-PCR (MTHFR-1958G>A, MTR-2756A>G, MTHFR-1298A>C, SHMT1-1420C>T, ATIC-347C>G, AMPD-134C>T, MTRR-66A>G and SLC-19A180G>A) in 84 patients (40 FOLFIRI, 44 ALIRI). The Kaplan-Meier method was used to plot PFS, and the log-rank test to compare curves. At univariate analysis the homozygous variants of both MTR-2756A>G and SHMT1-1420C>T were associated with significantly shorter PFS. Conversely, a significantly longer PFS (7.3 months) was observed when ATIC-347C>G CC+CG genotypes were grouped vs. GG. At multivariate analysis the genotypes MTR-2756A>G AA+AG, SHMT1-1420C>T TT+CT and ATIC-347C>G CC+CG emerged as significant predictors for PFS. Because MTR, SHMT1 and ATIC are all involved in folate pathways, we further explored the effect of a combination of their risk genotypes on PFS, showing that patients carrying two risk genotypes had a significantly shorter PFS (3.9 months, p<0.001). The correlations of polymorphisms in genes with clinical outcome underscore the importance of a candidate gene-based approach. Ultimately, the validation of the role of these polymorphisms in prospective multicenter trials might optimize currently available treatments in selected CRC patients (e.g., FOLFIRI) or PMX-based treatments in other tumor types.

【 授权许可】

Unknown