Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy

Corine de Jong; Gerarda J M Herder; Simone W A van Haarlem; Femke S van der Meer; Anne S R van Lindert; Alexandra Ten Heuvel; Jan Brouwer; Toine C G Egberts; Vera H M Deneer

doi:10.3390/genes14010170

Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy

Genes (Basel). 2023 Jan 7;14(1):170. doi: 10.3390/genes14010170.

Authors

Affiliations

¹ Department of Clinical Pharmacy, Division of Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
² Department of Clinical Pharmacy, St. Antonius Hospital, 3430 EM Nieuwegein, The Netherlands.
³ Department of Pulmonology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands.
⁴ Department of Pulmonology, St Antonius Hospital, 3430 EM Nieuwegein, The Netherlands.
⁵ Department of Pulmonology, Diakonessenhuis, 3582 KE Utrecht, The Netherlands.
⁶ Department of Pulmonology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
⁷ Department of Pulmonology, Groene Hart Hospital, 2803 HH Gouda, The Netherlands.
⁸ Department of Pulmonology, Rivierenland Hospital, 4002 WP Tiel, The Netherlands.
⁹ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.

Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1−12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8−12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5−21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice.

Keywords: chemotherapy-induced peripheral neuropathy (CIPN); chemotherapy-induced toxicity; neurotoxicity; non-small cell lung cancer (NSCLC); platinum-based chemotherapy.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Follow-Up Studies
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / genetics
Platinum / adverse effects
Prospective Studies

Substances

Platinum

Associated data

NTR/NL5373610015

Grants and funding

The PGxLUNG study was funded by the St. Antonius Onderzoeksfonds and patient funding. Financial support for the genotyping was provided by Roche Nederland. The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the report.