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ABCB1 and ERCC1 gene polymorphisms are associated with nephro- and hepatotoxicity to carboplatin/paclitaxel-based chemotherapy in patients with gynecologic cancers

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in ERCC1, ABCB1, CYP2C8, and CYP3A5 genes on the incidence of severe toxicities, including nephro- and hepatotoxicity.

Methods

A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin was recruited at the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consultations or from electronic medical records. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR.

Results

ABCB1 c.1236C>T was associated with moderate-to-severe (grades 2–4) nephrotoxicity (ORadjusted 2.40; 95% CI 1.39–4.15), even after adjustment for age (≥ 65) and diabetes. The risk association between ABCB1 c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (ORadjusted 2.16; 95% CI 1.22–3.82). ERCC1 c.118C>T was the only individual variable associated with an increased risk for moderate-to-severe (grades 2–4) hepatotoxicity (OR 3.71; 95% CI 1.08–12.77), severe nausea (OR 4.18; 95% CI 1.59–10.95), and severe myalgia (OR 1.95; 95% CI 1.12–3.40).

Conclusions

ABCB1 c.1236C>T and ERCC1 c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers.

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Acknowledgments

We thank the patients who volunteered to participate in the study, the Instituto Nacional de Câncer, Research Coordination (Dr. Guilherme Suarez-Kurtz), Hospital do Câncer II, for the authorization and use of laboratory facilities, and the members of the groups of the Department of Pharmacology of EPM-Unifesp.

Funding

We thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp, São Paulo, Brazil) – Proc. 2013/09295-3 and Fundação Carlos Chagas Filho de Amparo à Pesquisa no Rio de Janeiro (FAPERJ, Rio de Janeiro, Brazil) – Proc. 26/010.002644/2014 and E-26/210.784/2015. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance Code 001 (LC Costa-Junior is a recipient of a fellowship from CAPES, Brazil) by Programa de Pós-Graduação em Farmacologia (EPM-Unifesp).

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Author notes

  1. Rosane Vianna-Jorge and Paulo Caleb Junior Lima Santos contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (Unifesp), Rua Três de Maio, nº 100, 4° andar, Infar, Vila Clementino, São Paulo, SP, 04044-020, Brazil

    Luiz Carlos da Costa Junior & Paulo Caleb Júnior Lima Santos

  2. Hospital do Câncer II (HCII), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil

    Clarissa Lourenço de Castro

  3. Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública (ENSP), Fundação Osvaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil

    Clarissa Lourenço de Castro, Daniely Regina Freitas-Alves & Rosane Vianna-Jorge

  4. Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas, nº 373, Bl.J, 1° andar, sala 27, Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil

    Daniely Regina Freitas-Alves & Rosane Vianna-Jorge

  5. Coordenação de Pesquisa (CPQ), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil

    Rosane Vianna-Jorge

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Contributions

LCCJ: data curation, formal analysis, investigation, methodology, project administration, software, visualization, writing—original draft and review.

CLC: data curation, formal analysis, investigation, methodology, project administration, software, visualization, and writing review.

DRFA: formal analysis, investigation, methodology, software, visualization, writing—original draft and review.

RV-J and PCJLS: conceptualization, funding acquisition, methodology (selection and development); project administration; resources; supervision; validation; visualization; and writing (review and editing).

Corresponding authors

Correspondence to Rosane Vianna-Jorge or Paulo Caleb Júnior Lima Santos.

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The study protocol was approved by the Ethics Committees of Instituto Nacional de Câncer (20406413.6.0000.5274) and Escola Paulista de Medicina, Universidade Federal de São Paulo (84775518.3.0000.5505).

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da Costa Junior, L.C., de Castro, C.L., Freitas-Alves, D.R. et al. ABCB1 and ERCC1 gene polymorphisms are associated with nephro- and hepatotoxicity to carboplatin/paclitaxel-based chemotherapy in patients with gynecologic cancers. Eur J Clin Pharmacol 76, 1401–1408 (2020). https://doi.org/10.1007/s00228-020-02934-9

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