Open Access

ARTICLE

Comprehensive molecular analysis to predict the efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer

SUNG HEE LIM^1,#, HEE JIN CHO^1,2,3,#, KYOUNG-MEE KIM⁴, HO YEONG LIM¹, WON KI KANG¹, JEEYUN LEE¹, YOUNG SUK PARK¹, HEE CHEOL KIM^5,*, SEUNG TAE KIM^1,*

1 Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, 06351, Korea
2 Precision Medicine Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, 06351, Korea
3 Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, 41566, Korea
4 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
5 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, 06351, Korea

* Corresponding Authors: HEE CHEOL KIM. Email: ; SEUNG TAE KIM. Email:
# These authors contributed equally to this work

Oncology Research 2023, 31(6), 855-866. https://doi.org/10.32604/or.2023.030374

Received 03 April 2023; Accepted 24 July 2023; Issue published 15 September 2023

Abstract

Background: Although bevacizumab is an important treatment for metastatic colorectal cancer (CRC), not all patients with CRC benefit from it; in unselected patient populations, only modest survival benefits have been reported. Methods: We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identify biomarkers for a response to bevacizumab-containing treatment. The molecular analysis comprised whole-exome sequencing, ribonucleic acid sequencing, and a methylation array on patient tissues. Results: Genomic and molecular characterization was successfully conducted in 103 patients. Six of 103 CRC samples were hypermutated, and none of the non-hypermutant tumors were microsatellite unstable. Among those 103 patients, 89 had adenocarcinoma (ADC), 15 were diagnosed with mucinous ADC, and six had signet-ring cell carcinoma (SRCC). Consensus molecular subtype (CMS) 2 was unique to ADC. Of the four SRCCs, two were CMS1, one was CMS4, and the other was CMS3. APC mutation status was a significantly enriched factor in responders to bevacizumab treatment. Fibroblast growth factor receptor (FGFR) 1/2 signaling was upregulated in non-responders, whereas cell cycle, transfer ribonucleic acid processing, nucleotide excision repair, and oxidative phosphorylation pathways were enriched in responders. In addition, IGF1 was differentially expressed in non-responders (log2 fold change = −1.43, p = 4.11 × 10⁻⁵, false discovery rate = 0.098), and FLT1 was highly methylated in non-responders (p = 7.55 × 10⁻³). When the molecular pathways were reanalyzed separately according to the backbone chemotherapy (FOLFOX vs. FOLFIRI), the significance of the molecular pathways varied according to the backbone chemotherapy. Conclusions: This study sought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab. Our results need to be validated in a large group of homogenous patient cohort and examined according to the different chemotherapy backbones to create personalized therapeutic opportunities in CRC.

---

Keywords

---

Supplementary Material

Supplementary Material File

---