British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellu... more The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy. Forty patients infected with hepatitis C virus (HCV) genotype 1 and starting anti-HCV therapy with telaprevir in combination with pegylated-IFN/ribavirin were prospectively evaluated for SNPs at the SLC29A1 gene and inosine triphosphatase (ITPA) genes using a real-time PCR system. 40% of patients developed severe anaemia with a haemoglobin (Hb) decline ≥5 g/dL from the pretreatment value. The SLC29A1 rs760370 GG genotype was associated with the severity of Hb ...
British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, h... more Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs.
ABSTRACT Reduced activity of DPD leads to severe toxicity in cancer patients receiving standard d... more ABSTRACT Reduced activity of DPD leads to severe toxicity in cancer patients receiving standard doses of fluoropyrimidines, particularly in the case of combination regimens. We describe a 38-year-old man with a resectable metastasis from hereditary nonpolyposis colorectal cancer, with indication of neoadjuvant chemotherapy and a family history of fluoropyrimidine-associated toxicity. We tested our patient for functional DPYD variants, before any choice of the neoadjuvant regimen, including for the c.496A>G, already described in his mother, and a deep intronic variant c.1129-5923C>G recently reported associated to severe toxicity. Our patient was found to be heterozygous for both c.469A>G and c.1129-5923C>G DPYD variants. We thus offered the most active perioperative regimen, capecitabine, oxaliplatin, irinotecan plus bevacizumab by which we reduced the dosing of capecitabine to 50%. Treatment was well tolerated, with grade 2 diarrhea as the most significant adverse event, and led to a complete pathological response after liver resection. We provide a rationale approach to improve the safety of fluoropirimidine-based therapy in a patient with family history of fluoropyrimidine-associated toxicity.
British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recog... more Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recognise a range of molecular structures in pathogens. One of the most studied members of this family is the TLR4, which is essential for the signalling of lipopolysaccharide. The gene encoding for TLR4 is highly polymorphic and this genetic variability may explain in part the interindividual variability observed in several clinical setting, including the response to vaccination. Herein, we review and systematise the available scientific evidence about the effect of TLR4 polymorphisms on vaccine response, including approved prophylactic, new therapeutic cancer vaccines and recently approved vaccine adjuvants. Data reviewed in this analysis indicate that TLR4 polymorphisms significantly affect vaccine response. If these results are confirmed by further analyses, the use of these genetic biomarkers may become a useful tool to tailor vaccination in specific subsets of patients.The Pharmacogenom...
The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellu... more The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy. Forty patients infected with hepatitis C virus (HCV) genotype 1 and starting anti-HCV therapy with telaprevir in combination with pegylated-IFN/ribavirin were prospectively evaluated for SNPs at the SLC29A1 gene and inosine triphosphatase (ITPA) genes using a real-time PCR system. 40% of patients developed severe anaemia with a haemoglobin (Hb) decline ≥5 g/dL from the pretreatment value. The SLC29A1 rs760370 GG genotype was associated with the severity of Hb ...
Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, h... more Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs.
Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccin... more Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccines has been ascribed to unpredictable stochastic processes. Recent advances in pharmacogenomics indicate that some features of host response to immunisation are influenced by genetic traits, henceforth predictable. The ability to predict the adverse reaction to vaccination would represent an important step towards the development of personalised vaccinology and could enhance public confidence in the safety of vaccines. Herein, we have reviewed all the available information on the association between genetic variants and the risk for healthy subjects to develop adverse reactions.The Pharmacogenomics Journal advance online publication, advance online publication, 7 October 2014; doi:10.1038/tpj.2014.57.
Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part... more Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%-30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients' homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences i...
British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellu... more The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy. Forty patients infected with hepatitis C virus (HCV) genotype 1 and starting anti-HCV therapy with telaprevir in combination with pegylated-IFN/ribavirin were prospectively evaluated for SNPs at the SLC29A1 gene and inosine triphosphatase (ITPA) genes using a real-time PCR system. 40% of patients developed severe anaemia with a haemoglobin (Hb) decline ≥5 g/dL from the pretreatment value. The SLC29A1 rs760370 GG genotype was associated with the severity of Hb ...
British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, h... more Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs.
ABSTRACT Reduced activity of DPD leads to severe toxicity in cancer patients receiving standard d... more ABSTRACT Reduced activity of DPD leads to severe toxicity in cancer patients receiving standard doses of fluoropyrimidines, particularly in the case of combination regimens. We describe a 38-year-old man with a resectable metastasis from hereditary nonpolyposis colorectal cancer, with indication of neoadjuvant chemotherapy and a family history of fluoropyrimidine-associated toxicity. We tested our patient for functional DPYD variants, before any choice of the neoadjuvant regimen, including for the c.496A>G, already described in his mother, and a deep intronic variant c.1129-5923C>G recently reported associated to severe toxicity. Our patient was found to be heterozygous for both c.469A>G and c.1129-5923C>G DPYD variants. We thus offered the most active perioperative regimen, capecitabine, oxaliplatin, irinotecan plus bevacizumab by which we reduced the dosing of capecitabine to 50%. Treatment was well tolerated, with grade 2 diarrhea as the most significant adverse event, and led to a complete pathological response after liver resection. We provide a rationale approach to improve the safety of fluoropirimidine-based therapy in a patient with family history of fluoropyrimidine-associated toxicity.
British journal of clinical pharmacology, Jan 17, 2015
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for... more Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated, more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not; rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G,...
Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recog... more Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recognise a range of molecular structures in pathogens. One of the most studied members of this family is the TLR4, which is essential for the signalling of lipopolysaccharide. The gene encoding for TLR4 is highly polymorphic and this genetic variability may explain in part the interindividual variability observed in several clinical setting, including the response to vaccination. Herein, we review and systematise the available scientific evidence about the effect of TLR4 polymorphisms on vaccine response, including approved prophylactic, new therapeutic cancer vaccines and recently approved vaccine adjuvants. Data reviewed in this analysis indicate that TLR4 polymorphisms significantly affect vaccine response. If these results are confirmed by further analyses, the use of these genetic biomarkers may become a useful tool to tailor vaccination in specific subsets of patients.The Pharmacogenom...
The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellu... more The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy. Forty patients infected with hepatitis C virus (HCV) genotype 1 and starting anti-HCV therapy with telaprevir in combination with pegylated-IFN/ribavirin were prospectively evaluated for SNPs at the SLC29A1 gene and inosine triphosphatase (ITPA) genes using a real-time PCR system. 40% of patients developed severe anaemia with a haemoglobin (Hb) decline ≥5 g/dL from the pretreatment value. The SLC29A1 rs760370 GG genotype was associated with the severity of Hb ...
Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, h... more Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs.
Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccin... more Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccines has been ascribed to unpredictable stochastic processes. Recent advances in pharmacogenomics indicate that some features of host response to immunisation are influenced by genetic traits, henceforth predictable. The ability to predict the adverse reaction to vaccination would represent an important step towards the development of personalised vaccinology and could enhance public confidence in the safety of vaccines. Herein, we have reviewed all the available information on the association between genetic variants and the risk for healthy subjects to develop adverse reactions.The Pharmacogenomics Journal advance online publication, advance online publication, 7 October 2014; doi:10.1038/tpj.2014.57.
Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part... more Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%-30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients' homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences i...
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