Purpose: UGT1A1^★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI). Patients and Methods: In addition to UGT1A1^★28, UGT1A1^★60, UGT1A1^★93, UGT1A7^★3, and UGT1A9^★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available. Results: UGT1A7^★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9^★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1^★28, haplotype II (all the variant alleles but UGT1A9^★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1^★28 was the only marker associated with TTP. Conclusion: We propose that UGT1A variants additional to UGT1A1^★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.

Purpose: We aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan. Patients and Methods: Patients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m² for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained. Results: The dose of irinotecan was escalated to 370 mg/m² in patients with the *1/*28 genotype and to 420 mg/m² in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m² and in two of three of *1/*1 patients at 420 mg/m². No DLTs were observed in 10 *1/*28 patients at 310 mg/m² and in 10 *1/*1 patients at 370 mg/m²; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics. Conclusion: The recommended dose of 180 mg/m² for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

The tyrosine kinase inhibitor (TKI) sorafenib continues to be the anchor drug in the treatment of advanced stage hepatocellular carcinoma (HCC). Other TKIs as well as immune checkpoint inhibitors (ICIs) have also been approved, however the response rates remain poor and heterogeneous among HCC patients, largely due to antitumor drug resistance. Studies aimed at identifying novel biomarkers and developing new strategies to improve the response to current treatment and to overcome drug resistance, are urgently needed. Germline or somatic mutations, neoantigens, and an immunotolerogenic state against constant inflammatory stimuli in the liver, are crucial for the anti-tumor response. A pharmacogenetic approach has been attempted considering germline polymorphisms in genes encoding for proteins involved in drug-targeted pathways. Single gene and comprehensive multi-gene somatic profiling approaches have been adopted in HCC to identify tumor sensitivity scores and immunogenic profiles that can be exploited for new biomarkers and innovative therapeutic approaches. However, the high genomic heterogeneity of tumors and lack of molecularly targeted agents, hamper the discovery of specific molecular markers of resistance to therapy. Adoptive cell therapy with chimeric antigen receptor redirected T (CAR-T) cells targeting specific tumor-associated antigens (TAAs) was proposed recently. The specificity of the chosen TAA, an efficient homing of CAR-T cells to the tumor site, and the ability of CAR-T cells to survive in the tumor microenvironment are central factors in the success of CAR-T therapy. The current review describes the principal systemic treatments for HCC and the molecular evidence regarding potential predictive host and somatic genetic markers, as well as the emerging strategy of liquid biopsy for disease monitoring. Novel immunotherapeutic approaches for HCC treatment, including the use of ICIs and CAR-T, as well as strategies to overcome drug resistance, are discussed.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.