Published online Mar 15, 2020. doi: 10.4251/wjgo.v12.i3.301
Peer-review started: November 14, 2019
First decision: November 18, 2019
Revised: February 7, 2020
Accepted: February 17, 2020
Article in press: February 17, 2020
Published online: March 15, 2020
Processing time: 119 Days and 0.8 Hours
Colorectal cancer is one of the leading causes of cancer-related death and the third most commonly diagnosed cancer in humans in the world. For many years 5-fluorouracil was the only active drug for treatment of metastatic colorectal cancer (mCRC). The addition of irinotecan and oxaliplatin to 5-fluorouracil increased the median progression free survival (PFS), which further improved with the later addition of target therapies. Regorafenib is a multi-kinase inhibitor targeting VEGFR1-3, TIE2, fibroblast growth factor receptors 1 and platelet-derived growth factor receptors β, c-KIT, RET, c-RAF/RAF-1, BRAF V600E mutant. It can be used after failure of conventional treatment options.
In previous studies, regorafenib monotherapy showed the ability to improve PFS and overall survival in a subset of mCRC patients. However, no appropriate biomarkers are currently available. We analyzed the levels of many cytokines involved in angiogenesis and CRC pathogenesis, in plasma of mCRC patients before treatment with regorafenib. Our purpose was to identify potential biomarkers to select patients most likely to respond to regorafenib.
The aim of our study is to identify biomarkers useful to select mCRC patients for treatment with regorafenib and, possibly, an immune profile potentially correlated with the clinical outcome.
We collected blood samples of mCRC patients before starting regorafenib therapy for the evaluation of circulating TNF-α, TGF-β, VEGF, CCL-2, CCL-4, and CCL-5. The cytokines were measured at baseline using ELISA tests and the clinical outcome of each patient was correlated to the cytokines profile. We also analyzed the same cytokines levels in six healthy volunteers.
We found higher basal levels of TNF-α, TGF-β, VEGF, CCL-2 and CCL-5 in non-responders (NR; patients showing progression of disease, n = 12) compared to those who respond to therapy (complete response CR, n = 1, partial response PR, n = 1, Stable Disease SD, n = 3), and a reversed trend for CCL-4. Moreover, we found that CCL-2 and VEGF basal levels were significantly higher in NR patients compared to healthy individuals. Furthermore, high values of TGF-β and TNF-α negatively correlated with PFS. We further investigated the possible association between basal cytokine levels and PFS and we found that TNF-α and TGF-β negatively correlated with PFS in the patient cohort. Both these basal cytokines positively correlated between them.
We realized a cytokine signature which could potentially discriminate between responder and non-responder patients to Regorafenib therapy. If our data is confirmed, it will be possible to drive treatment with regorafenib to patients most likely respond to the drug.
Our data should be verified on larger and independent series of patients. It might also be of interest to extend analysis to other cytokines and cells population not determined in our study.