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

ABSTRACT: 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.

SUBMITTER: Okazaki S

PROVIDER: S-EPMC5528002 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Okazaki Satoshi S Stintzing Sebastian S Sunakawa Yu Y Cao Shu S Zhang Wu W Yang Dongyun D Ning Yan Y Matsusaka Satoshi S Berger Martin D MD Miyamoto Yuji Y Suenaga Mitsukuni M Schirripa Marta M West Jordan D JD Gopez Roel R Akihito Tsuji T Ichikawa Wataru W Heinemann Volker V DePaolo R William RW Lenz Heinz-Josef HJ

International journal of cancer 20170621 6

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 nu ...[more]

PMID: 28569041

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Project description:BackgroundThe efficacy of neoadjuvant chemotherapy is closely related to the long-term prognosis of colorectal cancer (CRC) patients. Apparent diffusion coefficient (ADC) is an index in dynamic enhanced magnetic resonance imaging (MRI), reflecting the density of tumor cells. ADC has been shown to be related to the efficacy of neoadjuvant chemotherapy in other malignant tumors, but there is still a lack of relevant research in CRC patients.MethodsA total of 128 patients with CRC treated with neoadjuvant chemotherapy in The First Affiliated Hospital of Xiamen University from January 2016 to January 2017 were retrospectively collected. According to the response after neoadjuvant chemotherapy, the patients were divided into an objective response group (n=80) and a control group (n=48). The clinical characteristics and ADC levels of the two groups were compared, and the predictive value of ADC on the efficacy of neoadjuvant chemotherapy was analyzed. The patients were followed up for 5 years to observe the difference of survival rate between the two groups, and further analyzed the correlation between ADC and survival rate.ResultsCompared with the control group, the tumor size in the objective response group was significantly reduced (3.32±1.60 vs. 5.07±2.19 cm, P=0.000); ADC significantly increased (1.23±0.18 vs. 0.98±0.18 ×10-3 mm2/s, P=0.000); albumin significantly increased (39.32±4.14 vs. 37.46±4.18 g/L, P=0.016); the proportion of patients with poorly differentiated or undifferentiated tumor cells was significantly lower (51.25% vs. 72.92%, P=0.016); and the 5-year mortality decreased significantly (40.00% vs. 58.33%, P=0.044). ADC had the highest predictive value of objective response for locally advanced CRC patients after neoadjuvant chemotherapy, and the area under the curve (AUC) was 0.834 [95% confidence interval (CI): 0.765-0.903, P=0.000]; ADC had certain predictive value for the 5-year survival of locally advanced CRC patients, and the AUC was 0.778 (95% CI: 0.696-0.861, P=0.000). ADC >1.055×10-3 mm2/s, tumor size <4.1 cm, and moderately or well differentiated tumors were favorable factors for patients with locally advanced CRC to obtain objective response after neoadjuvant chemotherapy (P<0.05).ConclusionsADC could be used as a predictor of the efficacy of neoadjuvant chemotherapy in locally advanced CRC patients.

Dataset Information

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

Publications

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

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