Evaluation of the Association of Perioperative UGT1A1 Genotype–Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma

Abstract

IMPORTANCE Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ՆT3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value. OBJECTIVE To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. INTERVENTIONS Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m 2 over 46 hours; oxaliplatin, 85 mg/m 2 ; irinotecan, 180 mg/m 2 for UGT1A1 genotype 6/6, 135 mg/m 2 for UGT1A1 genotype 6/7, or 90 mg/m 2 for UGT1A1 genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). MAIN OUTCOMES AND MEASURES Margin-negative resection rate and PRG. RESULTS A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10

DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence and Considerations for Clinical Implementation

“…Implementation of UGT1A1 genotyping has been slow partly due to this lack of consensus in correlating optimal dosage adjustments with doses used in current clinical practice. Given that applicable genotype‐adjusted irinotecan doses may improve tumor response as recently evidenced by Catenacci and colleagues, it is anticipated that the results from additional and ongoing studies (ClinicalTrials.gov identifier NCT02138617, NCT01643499, and NCT01639326) will help accelerate UGT1A1 testing uptake into routine practice 54 …”

“…Given that applicable genotype-adjusted irinotecan doses may improve tumor response as recently evidenced by Catenacci and colleagues, it is anticipated that the results from additional and ongoing studies (ClinicalTrials.gov identifier NCT02138617, NCT01643499, and NCT01639326) will help accelerate UGT1A1 testing uptake into routine practice. 54…”

Implementation of pharmacogenomic testing in oncology care (PhOCus): study protocol of a pragmatic, randomized clinical trial

“…Innocenti et al 33 Shirasu et al 42 CPIC 44 Catenacci et al 47 Sharma et al 60 Toffoli et al 61 Tsai et al 62 Páez et al 63 Poor metabolizer Innocenti et al 33 Shirasu et al 42 CPIC 44 Sharma et al 60 Tsai et al 62 time of enrollment. In addition, anticancer treatment details, including disease setting and treatment modalities, will be recorded.…”

Bringing Personalized Medicine to Precision Medicine in Gastroesophageal Cancer

“…Patients with homozygous germline polymorphisms (ie, genotype 7/7) exhibit a more severe phenotype, susceptible to increased toxic effects from irinotecan. Building on their work in the metastatic setting, Catenacci et al 3 pursued an up-front dose reduction of irinotecan for patients with genotyping results associated with diminished activity of the UGT1A1 enzyme. In enrolling patients at 2 US centers, it is not surprising that 31 of 38 patients were white individuals, with 3 patients exhibiting the higher risk of toxic effects of the 7/7 genotype.…”

“…Regarding their observed efficacy outcomes, Catenacci et al 3 used the feasible and clinically relevant coprimary end points of margin-negative resection rate and pathologic response grade (PRG, also commonly referred to as tumor regression grade [TRG]) to power their single-group statistical analysis of 36 evaluable patients. For their intention-to-treat population, 33 of 36 patients (92%) met the investigators' goal of at least 30 patients achieving a margin-negative resection, although 3 patients (8%) achieving a complete pathologic response (ie, PRG 1a) fell short of their target of 4 patients to reject the null hypothesis.…”