TY - JOUR
T1 - Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy
AU - de Jong, Corine
AU - Herder, Gerarda J M
AU - van Haarlem, Simone W A
AU - van der Meer, Femke S
AU - van Lindert, Anne S R
AU - Ten Heuvel, Alexandra
AU - Brouwer, Jan
AU - Egberts, Toine C G
AU - Deneer, Vera H M
N1 - Funding Information:
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.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/1/7
Y1 - 2023/1/7
N2 - 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.
AB - 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.
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Follow-Up Studies
KW - Humans
KW - Lung Neoplasms/drug therapy
KW - Peripheral Nervous System Diseases/chemically induced
KW - Platinum/adverse effects
KW - Prospective Studies
KW - chemotherapy-induced peripheral neuropathy (CIPN)
KW - chemotherapy-induced toxicity
KW - platinum-based chemotherapy
KW - neurotoxicity
KW - non-small cell lung cancer (NSCLC)
UR - http://www.scopus.com/inward/record.url?scp=85146767849&partnerID=8YFLogxK
U2 - 10.3390/genes14010170
DO - 10.3390/genes14010170
M3 - Article
C2 - 36672910
SN - 2073-4425
VL - 14
JO - Genes
JF - Genes
IS - 1
M1 - 170
ER -