Associação entre o polimorfismo do gene UGT1A1*28 e a neutropenia severa decorrente do tratamento do câncer colorretal com irinotecano: evidências baseadas em meta-análise

Santos, Tayná Aparecida de Oliveira; Leão-Cordeiro, Jacqueline Andréia Bernardes; Cunha, Daiane de Oliveira; Vilanova-Costa, Cesar Augusto Sam Tiago; Passos, Xisto Sena; Silva, Antonio Márcio Teodoro Cordeiro

doi:10.1055/s-0041-1725047

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Journal of Coloproctology (Rio de Janeiro)

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Sumário

Review Article • J. Coloproctol. (Rio J.) 41 (02) • Apr-Jun 2021 • https://doi.org/10.1055/s-0041-1725047 copiar

Associação entre o polimorfismo do gene UGT1A1*28 e a neutropenia severa decorrente do tratamento do câncer colorretal com irinotecano: evidências baseadas em meta-análise

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo

Avaliar a relação do polimorfismo do gene UGT1A1*28 com a prevalência de neutropenia em pacientes com câncer colorretal submetidos a tratamento com o irinotecano.

Método

Foram incluídos 13 estudos sobre o tema proposto, selecionados nas bases de dados da Biblioteca Virtual de Saúde, Scientific Electronic Library Online, International Health Sciences Literature e PubMed.Os dados foramcoletados dos artigos científicos selecionados e avaliados com o auxílio do software BioEstat 5.3 (BioEstat, Belém, PA, Brasil).

Resultados

Osgenótipos analisados foram6/6 (tipo selvagem), 6/7 e 7/7. Foramincluídos 2.146 pacientes. Destes, 55,6% (n=1.193) apresentaram genótipo 6/6, 37,3% (n=801) eramheterozigotos (6/7) e 7,1%(n=152) tinhamo genótipo 7/7.Umtotal de 1.672 (77,9%) pacientes apresentou neutropenia leve e 474 (22,1%) neutropenia severa. Ao contrastar os genótipos 6/7 e 7/7 como 6/6, percebeu-se, coma execução dos testes estatísticos demetaanálise, que os pacientes como alelo 7, emhomozigose ou heterozigose, tinhammaior risco de desenvolver neutropenia severa que pacientes com o genótipo 6/6 (razão de chances =1,559; intervalo de confiança de 95%=1,163-2,090; p=0,003).

Conclusão

A análise do polimorfismo do gene UGT1A1*28 pode auxiliar na escolha do tratamento do paciente comcâncer colorretal, no contexto da medicina personalizada, ampliando, assim, as chances de sucesso terapêutico.

Palavras-chave:
neutropenia; câncer colorretal; polimorfismos

Authors	6/6			6/7			7/7
Authors	n	SN	f (%)	n	SN	f (%)	n	SN	f (%)
McLeod et al.⁹9 McLeodHL, Sargent DJ, Marsh S, et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 2010;28(20):3227-3233	44	3	6.8	54	6	11.1	11	2	18.2
Glimelius et al.¹⁰10 Glimelius B, Garmo H, Berglund A, et al. Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J 2011;11(01): 61-71	72	15	20.8	51	13	25.5	13	7	53.8
Shulman et al.⁶6 Shulman K, Cohen I, Barnett-Griness O, et al. Colorectal Cancer Patients. 2012;117(14):3156-3162	91	5	5.5	98	8	8.2	25	6	24.0
Braun et al.¹¹11 Braun MS, Richman SD, Thompson L, et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009;27(33):5519-5528	79	57	72.2	68	44	64.7	20	15	75.0
Toffoli et al.¹²12 Toffoli G, Cecchin E, Corona G, et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006;24(19):3061-3068	114	12	10.5	114	21	18.4	22	4	18.2
Kweekel et al.¹³13 Kweekel DM, GelderblomH, Van der Straaten T, Antonini NF, Punt CJA, Guchelaar HJDutch Colorectal Cancer Group study. UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer 2008;99(02):275-282	46	1	2.2	31	6	19.4	3	0	0.0
Ruzzo et al.¹⁴14 Ruzzo A, Graziano F, Loupakis F, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with firstline FOLFIRI chemotherapy. Pharmacogenomics J 2008;8(04):278-288	59	9	15.3	72	13	18.1	15	12	80.0
Liu et al.¹⁵15 Liu D, Li J, Gao J, Li Y, Yang R, Shen L. Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis. BMC Cancer 2017;17(01):437	501	90	18.0	152	42	27.6	8	4	50.0
Rouits et al.¹⁶16 Rouits E, Boisdron-CelleM,Dumont A, Guérin O, Morel A, Gamelin E. Relevance of different UGT1A1 polymorphisms in irinotecaninduced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004;10(15):5151-5159	31	3	9.7	35	9	25.7	7	2	28.6
Carlini et al.¹⁷17 Carlini LE, Meropol NJ, Bever J, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 2005;11(03):1226-1236	28	10	35.7	29	11	37.9	5	0	0.0
Marcuello et al.¹⁸18 Marcuello E, Altés A,Menoyo A, Del Rio E, Gómez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004;91(04):678-682	40	6	15.0	45	12	26.7	10	4	40.0
Stewart et al.¹⁹19 Stewart CF, Panetta JC, O'ShaughnessyMA, et al. UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan. J Clin Oncol 2007;25(18):2594-2600	27	5	18.5	36	3	8.3	9	0	0.0
Bai et al.²⁰20 Bai Y, Wu HW, Ma X, Liu Y, Zhang YH. Relationship between UGT1A16/28 gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy. OncoTargets Ther 2017; 10:3071-3081	61	11	18.0	16	2	12.5	4	1	25.0
Combined values	1,193	227	19.0	801	190	23.7	152	57	37.5

Authors	6/6					6/7 + 7/7					OR	CI 95%		Weight
Authors	n	MN	f (%)	SN	f (%)	n	MN	f (%)	SN	f (%)	OR	Lower value	Upper value	Weight
McLeod et al.⁹9 McLeodHL, Sargent DJ, Marsh S, et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 2010;28(20):3227-3233	44	41	93.2	3	6.8	65	57	87.7	8	12.3	1.753	0.474	6.478	2.25
Glimelius et al.¹⁰10 Glimelius B, Garmo H, Berglund A, et al. Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J 2011;11(01): 61-71	72	57	79.2	15	20.8	64	44	68.8	20	31.3	1.709	0.794	3.680	6.53
Shulman et al.⁶6 Shulman K, Cohen I, Barnett-Griness O, et al. Colorectal Cancer Patients. 2012;117(14):3156-3162	91	86	94.5	5	5.5	123	109	88.6	14	11.4	2.083	0.750	5.783	3.68
Braun et al.¹¹11 Braun MS, Richman SD, Thompson L, et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009;27(33):5519-5528	79	22	27.8	57	72.2	88	29	33.0	59	67.0	0.789	0.409	1.523	8.89
Toffoli et al.¹²12 Toffoli G, Cecchin E, Corona G, et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006;24(19):3061-3068	114	102	89.5	12	10.5	136	111	81.6	25	18.4	1.875	0.906	3.884	7.25
Kweekel et al.¹³13 Kweekel DM, GelderblomH, Van der Straaten T, Antonini NF, Punt CJA, Guchelaar HJDutch Colorectal Cancer Group study. UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer 2008;99(02):275-282	46	45	97.8	1	2.2	34	28	82.4	6	17.6	6.918	1.103	43.391	1.14
Ruzzo et al.¹⁴14 Ruzzo A, Graziano F, Loupakis F, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with firstline FOLFIRI chemotherapy. Pharmacogenomics J 2008;8(04):278-288	59	50	84.7	9	15.3	87	62	71.3	25	28.7	2.169	0.944	4.985	5.55
Liu et al.¹⁵15 Liu D, Li J, Gao J, Li Y, Yang R, Shen L. Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis. BMC Cancer 2017;17(01):437	501	411	82.0	90	18.0	160	114	71.3	46	28.8	1.847	1.226	2.782	22.87
Rouits et al.¹⁶16 Rouits E, Boisdron-CelleM,Dumont A, Guérin O, Morel A, Gamelin E. Relevance of different UGT1A1 polymorphisms in irinotecaninduced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004;10(15):5151-5159	31	28	90.3	3	9.7	42	31	73.8	11	26.2	2.973	0.811	10.901	2.28
Carlini et al.¹⁷17 Carlini LE, Meropol NJ, Bever J, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 2005;11(03):1226-1236	28	18	64.3	10	35.7	34	23	67.6	11	32.4	0.862	0.306	2.427	3.59
Marcuello et al.¹⁸18 Marcuello E, Altés A,Menoyo A, Del Rio E, Gómez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004;91(04):678-682	40	34	85.0	6	15.0	55	39	70.9	16	29.1	2.217	0.803	6.125	3.72
Stewart et al.¹⁹19 Stewart CF, Panetta JC, O'ShaughnessyMA, et al. UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan. J Clin Oncol 2007;25(18):2594-2600	27	22	81.5	5	18.5	45	42	93.3	3	6.7	0.337	0.080	1.414	1.87
Bai et al.²⁰20 Bai Y, Wu HW, Ma X, Liu Y, Zhang YH. Relationship between UGT1A16/28 gene polymorphisms and the efficacy and toxicity of irinotecan-based chemotherapy. OncoTargets Ther 2017; 10:3071-3081	61	50	82.0	11	18.0	20	17	85.0	3	15.0	0.878	0.236	3.269	2.22
Combined values	1193	966	81.0	227	19.0	953	706	74.1	247	25.9	1.559	1.163	2.090	p = 0.0030

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[1] Address for correspondence Antonio Márcio Teodoro Cordeiro Silva, D.Sc., Medicine Course, Escola de Ciências Médicas, Farmacêuticas e Biomédicas. Pontifícia Universidade Católica de Goiás (PUC Goiás), Avenida Universitária 1.440, Setor Universitário, Campus 1, Área 4, Goiânia, Goiás, 74605-010, Brazil (e-mail: marciocmed@gmail.com).