Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer.

Okazaki, Satoshi; Stintzing, Sebastian; Sunakawa, Yu; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Matsusaka, Satoshi; Berger, Martin Dave; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; West, Jordan D; Gopez, Roel; Akihito, Tsuji; Ichikawa, Wataru; Heinemann, Volker; DePaolo, R William; Lenz, Heinz-Josef (2017). Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer. International journal of cancer, 141(6), pp. 1222-1230. Wiley-Blackwell 10.1002/ijc.30810

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The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n = 244) or a control set (FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Nicole Corminboeuf

Date Deposited:

08 Mar 2018 09:07

Last Modified:

08 Mar 2018 09:07

Publisher DOI:

10.1002/ijc.30810

PubMed ID:

28569041

Uncontrolled Keywords:

TLR7 cetuximab metastatic colorectal cancer polymorphism predictive marker

BORIS DOI:

10.7892/boris.111371

URI:

https://boris.unibe.ch/id/eprint/111371

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