Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912

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4535 Background: JCOG9912 (randomized phase III trial) showed a significant non-inferiority of S-1 to 5-FU (P<0.001); however, either S-1 or irinotecan plus cisplatin (IP) failed to show superiority to 5-FU (P=0.034 and 0.055, respectively) in overall survival. Excision repair cross-complementing group 1 (ERCC1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are reportedly related to outcome of advanced gastric cancer (AGC) patients (pts) treated with IP or 5-FU. Efficacy analyses are performed to evaluate the status of ERCC1, TS, DPD and 5 biomarkers related to anticancer drug sensitivity in first-line pts treated with IP, S-1, or 5-FU monotherapy under controlled conditions. Methods: Blocks from endoscopic biopsy specimens of primary lesions before chemotherapy were available from 365 of 704 pts in JCOG9912. Using laser-captured microdissection and real-time RT-PCR, we analyzed mRNA expression of ERCC1, TS, DPD in paraffin-embedded specimens. Expression levels of each gene were categorized into low and high values at each median. Results: The subjects with available tissue for analysis were representative of all randomized pts; 232 samples were assessable for TS, 168 for DPD, and 235 for ERCC1. There were no statistical differences in patient numbers between 3 arms. Pts with high TS showed worse progression-free survival (PFS) compared with those with low TS (hazard ratio (HR):1.26 [95%CI: 0.97–1.63]) in all pts; there was no difference in PFS between DPD and ERCC1 expression level. IP showed better PFS than S-1 in low DPD (HR: 0.57 [95%CI: 0.32–1.01]) but not in high DPD (HR: 1.24 [95%CI: 0.76–2.04]); there was no clear difference in PFS between pts treated with IP and S-1 regardless of TS and ERCC1 expression status. S-1 showed almost consistently better PFS than 5-FU regardless of mRNA expression status. Conclusions: This large analysis showed the prognostic value of TS status in AGC pts and the predictive value of DPD status for IP and S-1 as first-line treatment. Studies of DPD as a predictive marker for IP activity in AGC are warranted in future personalized phase III. [Table: see text]