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Impact of gene polymorphisms on the systemic toxicity to paclitaxel/carboplatin chemotherapy for treatment of gynecologic cancers

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Gynecologic malignancies are often detected in advanced stages, requiring chemotherapy with taxane/platinum combinations, which may cause severe toxicities, such as neutropenia and peripheral neuropathy. Gene polymorphisms are suspected as possible causes for the interindividual variability on chemotherapy toxicities.

Objective

To evaluate the role of ABCB1 1236C>T, 3435C>T; CYP2C8*3; CYP3A5*3C variants on paclitaxel/carboplatin toxicities.

Methods

A cohort of 503 gynecologic cancer patients treated with paclitaxel/carboplatin at the Brazilian National Cancer Institute (INCA-Brazil) was recruited (2013–2017). Polymorphisms were genotyped by real-time PCR, and toxicities were evaluated by patients’ interviews at each chemotherapy cycle and by data collection from electronic records. The association of clinical features and genotypes with severe toxicities was estimated using Pearson’s Chi square tests and multiple regression analyses, with calculation of adjusted odds ratios (ORadjusted), and respective 95% confidence intervals (95% CI).

Results

CYP2C8*3 was significantly associated with increased risks of severe (grades 3–4) neutropenia (ORadjusted 2.11; 95% CI 1.24–3.6; dominant model) and severe thrombocytopenia (ORadjusted 4.93; 95% CI 1.69–14.35; recessive model), whereas ABCB1 variant genotypes (ORadjusted 2.13; 95% CI 1.32–3.42), in association with CYP2C8*3 wild type (GG) (ORadjusted 1.93; 95% CI 1.17–3.19), were predictive of severe fatigue.

Conclusions

The present study suggests that CYP2C8*3 is a potential predictor of hematological toxicities related to paclitaxel/carboplatin treatment. Since hematological toxicities, especially neutropenia, may lead to dose delay or treatment interruption, such prognostic evaluation may contribute to clinical management of selected patients with paclitaxel-based chemotherapy.

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Acknowledgements

The authors thank Dr Guilherme Suarez-Kurtz for the use of laboratory facilities and the personnel from the Instituto Nacional de Câncer (HC2-INCA) for logistic support in sample and data collection. The authors are grateful to Dr. Richard Koch, who kindly revised the manuscript for style and grammatical editing.

Funding

The study was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa no Rio de Janeiro (Grants E-26/010.002644/2014 and E-26/210.784/2015), and by Coordenação de Apoio ao Pessoal de Nível Superior (CAPES) via Programa de Pós-Graduação em Saúde Pública e Meio Ambiente (ENSP-FIOCRUZ). KSS and TSLS received scholarships from CAPES.

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Authors and Affiliations

  1. Hospital do Câncer II, Instituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil

    Clarissa Lourenço de Castro

  2. Coordenação de Pesquisa, Instituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil

    Clarissa Lourenço de Castro, Luiz Carlos da Costa Junior, Taiana Sousa Lopes da Silva & Rosane Vianna-Jorge

  3. Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública, FIOCRUZ, Rio de Janeiro, RJ, Brazil

    Clarissa Lourenço de Castro, Karine Souza Seba & Rosane Vianna-Jorge

  4. Programa de Pós-Graduação em Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Luiz Carlos da Costa Junior

  5. Escola de Enfermagem Anna Nery, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Letícia Vieira Lourenço

  6. Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Karine Souza Seba & Taiana Sousa Lopes da Silva

  7. Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Bl.J, 1º andar, sala 27, Centro de Ciências da Saúde, Cidade Universitária, Ilha Do Fundão, Rio de Janeiro, RJ, CEP 21941-902, Brazil

    Rosane Vianna-Jorge

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Contributions

CLC: data curation, formal analysis, investigation, methodology, project administration, software, visualization, writing—original draft and review. LCCJ: data curation, investigation, methodology, and visualization. LVL: data curation, investigation, methodology, and visualization. KSS: data curation, software, and visualization. TSLS: data curation and visualization. RV-J: conceptualization, funding acquisition, methodology (selection and development); project administration; resources; supervision; validation; visualization; and writing (review and editing).

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Correspondence to Rosane Vianna-Jorge.

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The authors declare no conflicts of interest.

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The study was conducted following the international precepts of ethics in research, including the 1964 Helsinki Declaration and its later amendments, and of good clinical practice. The authors complied with the Brazilian regulation of clinical research. The study protocol was approved by the Ethics Committees of the Brazilian National Cancer Institute (INCA 20406413.6.0000.5274) and of the National School of Public Health (FIOCRUZ/CAAE 58944216.0.0000.5240), and all participants gave written consent to participate.

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de Castro, C.L., da Costa Junior, L.C., Lourenço, L.V. et al. Impact of gene polymorphisms on the systemic toxicity to paclitaxel/carboplatin chemotherapy for treatment of gynecologic cancers. Arch Gynecol Obstet 300, 395–407 (2019). https://doi.org/10.1007/s00404-019-05197-7

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