KDR Mutation as a Novel Predictive Biomarker of Exceptional Response to Regorafenib in Metastatic Colorectal Cancer

Abstract

This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma (CRC) metastatic to the liver, retroperitoneum, anastomotic site, and distal rectal sigmoid colon. She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab, as well as disease progression. Next generation sequencing of her tumor was ordered, and further discussion of her malignancy’s genomic information took place at a multidisciplinary molecular tumor board. The patient had mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) which made her ineligible for epidermal growth factor receptor (EGFR) inhibitors; however, a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance (VUS). KDR (kinase insert domain receptor) is the human gene encoding for vascular endothelial growth factor receptor 2 (VEGFR-2). She was then considered a suitable candidate for regorafenib, which she could only tolerate at a low dose of 40 mg daily, with the intent of prolonging her survival and to optimize her quality of life. We report her excellent tolerance and exceptional response to low dose regorafenib, including symptomatic, tumor marker, and sustained partial metabolic radiological improvement. In the largest Phase III trial of regorafenib in CRC, only five patients (1%) of 760 experienced a partial response (versus one patient, 0.4%, receiving placebo). KDR R961W mutation has been described but no functional data has been reported. This mutation occurs in the tyrosine kinase domain of the VEGFR-2. Regorafenib targets VEGFR-2 (KDR). Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer. To our knowledge, this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC, leading to what is considered an exceptional response. Further studies based on this preliminary data are warranted.

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

“…This difference might be present due to different cancer groups and the small number of patients studied. Furthermore, in a recently reported case study [15], KDR mutation, KRAS mutation and APC mutation were found together in a patient of colon cancer although no clinical significance was reported for their correlation. This case study collectively with our results indicates that KRAS and KDR mutation can together play a role in proliferation of tumor cells when VEGF signaling pathway proceeds via MAPK signaling route.…”

KDR gene as a Predictive Biomarker of Response to Regorafenib in Patients with Metastatic Colorectal Cancer (mCRC)

“…Because of small sample of Indian patients, response rates cannot be compared with African patients (2 patient's vs. 6 patients). KDR gene mutation occurs in tyrosine kinase domain of VEGFR2 making it a potential target for regoarfenib [2]. Failure of regorafenib in the present study may be due to absence of KDR mutation.…”

“…It accounts for over 9% of all cancer incidences [1,2]. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world, and its burden is expected to increase by 60% to more than 2.2 million new cases and 1.1 million cancer deaths by 2030 [3].…”

“…This study is based on published case report by Bonilla et al [2], which reported exceptional response to regorafenib in KDR mutated MCRC.…”

A Systematic Review and Meta-analysis of Retrospective Series of Regorafenib for Treatment of Metastatic Colorectal Cancer

“…This would allow other patients, who are less likely to respond, to avoid the adverse effects of the drug. In this respect, an exceptional response to regorafenib was reported in a patient with metastatic colorectal cancer and a mutation in the KDR gene encoding for VEGFR2 (32). This patient had an ongoing PR for over 9 months at the time of the report, despite being able to tolerate only a reduced dose of 40 mg. Another prolonged PR of 15 months as well as SD for over 20 months were observed in two patients participating in a phase I trial of the combination of regorafenib with cetuximab (33).…”