UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI

Abstract

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer—A Case Series Study Target Therapy of BRAF-Mutated mCRC

“…Another compelling question is whether primary tumor location affects the outcome in BRAF-mutated mCRC treated with triplet therapy. Although the role of tumor location in the prognosis of BRAF-mutated mCRC remains controversial [16,21], it may have some impact with the concomitant use of target therapy such as bevacizumab or cetuximab [22]. Several studies have demonstrated that first-line bevacizumab plus chemotherapy resulted in a superior prognosis for right-sided BRAF-mutated mCRC [16,[23][24][25].…”

“…Although the role of tumor location in the prognosis of BRAF-mutated mCRC remains controversial [16,21], it may have some impact with the concomitant use of target therapy such as bevacizumab or cetuximab [22]. Several studies have demonstrated that first-line bevacizumab plus chemotherapy resulted in a superior prognosis for right-sided BRAF-mutated mCRC [16,[23][24][25]. Conversely, leftsided mCRC had more favorable outcomes when treated with anti-EGFR agents than did right-sided tumors [22,26], which was consistent with our observation.…”

“…BRAF V600E mutation analysis was performed using direct deoxyribonucleic acid (DNA) sequencing from formalin-fixed, paraffin-embedded CRC tissue samples according to our previous study [16]. After deparaffinization and air-drying, DNA was isolated using the proteinase K and QIAamp DNA Micro Kit (QIAGEN).…”

Oncological Outcomes of Patients with Peritoneal Metastasis–only Colorectal Cancer Treated with First-line Bevacizumab and FOLFIRI through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis–only, and Lung Metastasis–only

“…Recently, our prospective, randomized study also suggested that if patients with mCRC, regardless of their KRAS gene status, receive UGT1A1 genotyping, they can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without signi cantly increased toxicity [9,12]. Furthermore, the oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a rst-line therapy are acceptable with tolerable adverse events; this approach may be a feasible treatment option for such patients [10]. In the current retrospective study, we investigated the clinical outcomes of patients with PC-only mCRC who received rst-line bevacizumab and FOLFIRI with irinotecan dose escalation according to UGT1A1 polymorphism.…”

“…Finally, this study was a retrospective review of 206 patients with mCRC, and written informed consent was obtained from all patients (KMUHIRB-E(I)-20200036). The responses were classi ed by a radiologist according to RECIST Version 1.1 [10]. DNA extraction for direct sequencing of KRAS/NRAS and immunohistochemical (IHC) analysis of epidermal growth factor receptor (EGFR) expression were performed using the methods described in our previous study [9].…”