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. 2018 Apr 27;18(1):479.
doi: 10.1186/s12885-018-4298-5.

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients

Zhu Mei  1   2 , Yang W Shao  3   4 , Peinan Lin  1 , Xiaomin Cai  1 , Biao Wang  1 , Yan Ding  3 , Xiangyuan Ma  3 , Xue Wu  3 , Yewei Xia  5 , Dongqin Zhu  5 , Yongqian Shu  6 , Zan Fu  7 , Yanhong Gu  8
Affiliations

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients

Zhu Mei et al. BMC Cancer. .

Abstract

Background: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit.

Methods: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed.

Results: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients.

Conclusions: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

Keywords: Cetuximab; Metastatic colorectal cancer; NF1; Next-generation sequencing; Prognosis; SMAD4.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the ethic committee of the First Affiliated Hospital with Nanjing Medical University. All the patients enrolled in this study have provided written informed consents for specimen collection, genetic testing, and participation in the research anonymously.

Consent for publication

Not applicable.

Competing interests

Yang W. Shao, Yan Ding, Xiangyuan Ma, and Xue Wu are the shareholders or employees of Geneseeq Technology Inc.; Yewei Xia, and Dongqin Zhu are the employee of Nanjing Geneseeq Technology Inc..

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Genetic alterations detected from 33 Chinese mCRC patients using targeted NGS with a 416 cancer-related gene panel. Twenty one genes with at least 4 recurrences are shown in the figure. PFS upon receiving cetuximab are shown on the top. Different mutation types are colour coded: cyan represents single nucleotide variant (SNV), orange represents copy number variation (CNV), and red represents insert/deletion (Indel). Patients received previous chemotherapy are labeled differently as indicated in their PFS
Fig. 2
Fig. 2
Comparison of PFS curves according to the mutation status of a defined gene or gene combination upon receiving cetuximab-based therapy. a. Comparison of PFS curves of the SMAD4mut group and the SMAD4wt group. b. Comparison of PFS curves of the NF1mut group and the NF1wt group. c. Comparison of PFS curves of the SMAD4mut or NF1mut group comparing with the SMAD4wt and NF1wt group. The P value is calculated according to Gehan-Breslow-Wilcoxon test. Figures are made using GraphPad Prism 5
See this image and copyright information in PMC

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