Correlation of UGT1A1 and ERCC1 gene polymorphisms with the outcome of combined irinotecan plus cisplatin treatment in recurrent ovarian cancer

Abstract

ABSTRACT. The aim of this study was to define the genotypes of UGT1A1 and ERCC1 and to examine their relationship with the efficacy and toxicity of a combination therapy of irinotecan and cisplatin in patients with advanced ovarian cancer. The allelic frequencies of the UGT1A1 and ERCC1 variants in a group of 89 patients with advanced ovarian cancer were determined. The relationship between the adverse events of irinotecan-based chemotherapy and the efficacy of cisplatin in patients with advanced ovarian cancer were analyzed. For patients who carried the UGT1A1*28 wild-type (WW) or the UGT1A1*28 heterozygous and homozygous mutant (WM+MM) genotypes, the incidences of grade 2 or 3 tardive diarrhea were 52.2 and 72.7% respectively, and the difference was statistically significant (P = 0.031, OR = 2.1, 95%CI = 1.6-9.2). For grade 3 or 4 tardive diarrhea, the incidence rates were 7.5 and 36.4% respectively; this difference was also statistically significant (P = 0.000, OR = 4.9, 95%CI = 3.3-15.8). The response rates of ERCC1 WW and ERCC1 WM+MM carriers were 30.3 and 20.2% respectively; this difference was significant (P = 0.032, OR = 3.2, 95%CI = 1.4-9.1). Together, the results from this study suggest that UGT1A1 is a target gene for tardive diarrhea, and that the UGT1A1*28 gene mutation might increase the risk of diarrhea with irinotecan-based chemotherapy. Furthermore, the results suggest that ERCC1 WW carriers might obtain a better rate of clinical response from a combined irinotecan and cisplatin regimen than ERCC1 WM+MM carriers.

Study of polymorphisms of UGT1A1 and DPYD genes in chemotherapy for colorectal cancer

“…В схемах химиотерапии рака толстой кишки (распространенного рака желудка, рака яичников, рака легких и других) наиболее часто используются препараты на основе фторпиримидинов (5-фторурацил и капецитабин), а также иринотекан [3][4][5][6]. Дефицит фермента дигидропиримидин дегидрогеназы (DPYD), наследуемый по аутосомнорецессивному типу, является основной причиной тяжелой и даже летальной токсичности лекарственных препаратов на основе 5-фторурацила (5-ФУ).…”

Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

“…Among these studies, 16 studies investigated the associations in Caucasians 11-15, 18, 25-35, 40 in Asians 3, 9, 16, 17, 36-62, and two in mixed population or not reported 63, 64. All studies were retrospective or prospective studies, including 29 metastatic colorectal cancer (mCRC) studies, five metastatic non-small cell lung cancer (mNSCLC), three advanced gastric cancer (GC) studies, two SCLC studies, and two advanced esophageal cancer studies and others.…”

“…Several methods such as surgery, radiotherapy, and chemotherapy are widely applied for the clinical treatment of cancer. Irinotecan-based chemotherapy is one of the most used chemotherapies for patients with advanced gastric cancer, ovarian cancer, metastatic colorectal cancer, and other cancers 3-5. Irinotecan, a camptothecin derivative, is mainly transported into liver by solute carriers and metabolized into ametabolite, SN-38, by a carboxylesterase 6.…”

Short-term prognosis of childhood hepatoblastoma in relation to ERCC1 C118T single nucleotide polymorphism and VEGF expression

“…Patients with the T allele may also be more sensitive to PDs [31,32]. Globally, many studies in non-small cell lung cancer [8], ovarian cancer [9], gastric cancer [10], esophageal cancer [11], pancreatic cancer [12], and colorectal cancer [13] have shown patients with the CT or TT genotypes in ERCC1 C118T mutation to be more sensitive to PDs when compared to patients with the CC genotype.…”

“…ERCC1 single nucleotide polymorphisms (SNPs), particularly the C-T mutation at the 118 th codon in exon 4, can affect gene expression level and change gene copy number, thus affecting the resistance to PDs [8]. Many studies have reported that the ERCC1 C118T mutation exhibits a predictive value for PD efficacy and disease prognosis in different types of cancers, such as non-small cell lung cancer [8], ovarian cancer [9], gastric cancer [10], esophageal cancer [11], pancreatic cancer [12], and colorectal cancer [13]. Therefore, screening ERCC1 mutation before chemotherapy may have important guiding significance and prognostic value for chemotherapy.…”