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Open AccessArticle

TP53 DNA Binding Domain Mutations Predict Progression-Free Survival of Bevacizumab Therapy in Metastatic Colorectal Cancer

1
Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan
2
College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan
3
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan
4
Chief Scientific Officer, ACT Genomics Co. Ltd., 3F., No.345, Xinhu 2nd Rd., Neihu Dist, Taipei City 114, Taiwan
5
Chief Executive Officer, ACT Genomics Co. Ltd., 3F., No.345, Xinhu 2nd Rd., Neihu Dist, Taipei City 114, Taiwan
6
Department of Medical Informatic, ACT Genomics Co. Ltd., 3F., No.345, Xinhu 2nd Rd., Neihu Dist, Taipei City 114, Taiwan
*
Authors to whom correspondence should be addressed.
These authors have contributed equally to this work as senior authors.
Cancers 2019, 11(8), 1079; https://doi.org/10.3390/cancers11081079
Received: 8 July 2019 / Revised: 22 July 2019 / Accepted: 26 July 2019 / Published: 30 July 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13–0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification. View Full-Text
Keywords: metastatic colorectal cancer; bevacizumab therapy; next-generation sequencing; progression-free survival; TP53 DNA binding domain mutation metastatic colorectal cancer; bevacizumab therapy; next-generation sequencing; progression-free survival; TP53 DNA binding domain mutation
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Hsu, H.-C.; You, J.-F.; Chen, S.-J.; Chen, H.-C.; Yeh, C.-Y.; Tsai, W.-S.; Hung, H.-Y.; Yang, T.-S.; Lapke, N.; Tan, K.T. TP53 DNA Binding Domain Mutations Predict Progression-Free Survival of Bevacizumab Therapy in Metastatic Colorectal Cancer. Cancers 2019, 11, 1079.

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