Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer

Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Chiara Cremolini, Sara Lonardi, Francesca Bergamo, Yang Ning, Noriko Yamamoto, Satoshi Okazaki, Martin D Berger, Yuji Miyamoto, Roel Gopez, Afsaneh Barzi, Toshiharu Yamaguchi, Sebastian Stintzing, Volker Heinemann, Fotios Loupakis, Alfredo FalconeHeinz-Josef Lenz

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Abstract

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P < 0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P = 0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45-0.91, P = 0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47-0.78, P < 0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62-1.02, P = 0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

Original languageEnglish
Pages (from-to)623-632
Number of pages10
JournalPharmacogenomics Journal
Volume18
Issue number5
DOIs
Publication statusPublished - Sep 2018

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Suenaga, M., Schirripa, M., Cao, S., Zhang, W., Yang, D., Cremolini, C., Lonardi, S., Bergamo, F., Ning, Y., Yamamoto, N., Okazaki, S., Berger, M. D., Miyamoto, Y., Gopez, R., Barzi, A., Yamaguchi, T., Stintzing, S., Heinemann, V., Loupakis, F., ... Lenz, H-J. (2018). Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer. Pharmacogenomics Journal, 18(5), 623-632. https://doi.org/10.1038/s41397-018-0030-8