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

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?

SUBMITTER: Suenaga M

PROVIDER: S-EPMC6151284 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Suenaga Mitsukuni M Schirripa Marta M Cao Shu S Zhang Wu W Yang Dongyun D Cremolini Chiara C Lonardi Sara S Bergamo Francesca F Ning Yang Y Yamamoto Noriko N Okazaki Satoshi S Berger Martin D MD Miyamoto Yuji Y Gopez Roel R Barzi Afsaneh A Yamaguchi Toshiharu T Stintzing Sebastian S Heinemann Volker V Loupakis Fotios F Falcone Alfredo A Lenz Heinz-Josef HJ

The pharmacogenomics journal 20180621 5

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 c ...[more]

PMID: 29925895

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Project description:BackgroundThe randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC.Materials and methodsDNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG).ResultsPatient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS).ConclusionChromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC.Implications for practiceBevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

Dataset Information

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

Publications

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

Similar Datasets

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