Author(s): Hye In Woo aff1 , Jung A Kim aff2 , Hyun Ae Jung aff3 , Ka-Kyung Kim aff4 , Ji Yean Lee aff5 , Jong-Mu Sun aff3 , Jin Seok Ahn aff3 , Keunchil Park aff3 , Soo-Youn Lee [*] aff1 aff6 , Myung-Ju Ahn aff3
ATIC; GGH; NSCLC; pharmacogenetics; prognosis; SNPs
Pemetrexed is an antifolate agent that has been approved as a first- and second-line chemotherapeutic agent in the treatment of advanced lung adenocarcinoma [1 ]. Although the clinical benefits along with diminished drug toxicity were demonstrated after introduction of pemetrexed [2-5 ], differences in the therapeutic response and clinical outcome according to each patient have been observed. Despite extensive work on pemetrexed predictive markers, no definitive biomarker for the prediction of therapeutic efficacy of pemetrexed in lung adenocarcinoma has been established [ 2,3,6 ].
Pemetrexed is a multitargeted folate analog like methotrexate (MTX) that enters the cell through SLC19A1 (Figure 1). Intracellular pemetrexed is activated by FPGS to become polyglutamate derivatives that inhibit multiple enzymes including TYMS, DHFR, GART, ATIC and PPAT. Reversely, GGH removes glutamyl residues from polyglutamate derivatives, resulting in the inactivation of pemetrexed [7-11 ]. TYMS is the primary target of polyglutamated pemetrexed, 30-200 times more potent to TYMS than ATIC and GART [7,12 ]. In addition, MTHFR and SHMT1 are involved in the folate pathway which is related to the process of metabolites produced by prior enzymes [13 ].
Previous studies have reported that non-small-cell lung cancer (NSCLC) cell lines with an overexpression of TYMS showed reduced sensitivity to pemetrexed [14 ]. It has been demonstrated that polymorphisms on SLC19A1, GGH, MTHFR and XPD genes are associated with the progression-free survival (PFS) and overall survival (OS) [2,3,15 ], and polymorphisms on SLC19A1, FPGS and GGH genes with drug toxicity in NSCLC patients treated with pemetrexed-based chemotherapy [2 ]. On the other hand, negative findings of these correlations have been also reported [6 ]. Until now, there have still been only a few reports about the relationship between genetic polymorphisms and the therapeutic efficacy of pemetrexed-based chemotherapy in NSCLC, especially in lung adenocarcinoma. Moreover, most studies are involved in patients treated with pemetrexed in combination with other various agents, and only a small number of polymorphisms. In this respect, we evaluated the association between the genetic polymorphisms in genes related to the metabolic pathway of pemetrexed and the therapeutic efficacy in a large number of advanced lung adenocarcinoma patients treated with pemetrexed as a single agent.
Materials & methods
Patients eligibility criteria, treatment & evaluation
Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC who had been treated with pemetrexed alone as second or more line of therapy at Samsung Medical Center between April 2007 and February 2010 were included. Other eligible criteria included: 18 years-of-age or older; a measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST); an ECOG performance status of 0-2; adequate function of the bone marrow (absolute neutrophil count [greater than]1.5 × 109 /l, platelet count [greater than]100 × 109 /l), kidney (serum creatinine...