ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pa...

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Authors: Barba Joaquin, Andrés|||0000-0003-2500-0253, López Vilaró, Laura|||0000-0002-5428-8017, Ferre, Malena, Majem Tarruella, Margarita|||0000-0002-9919-7485, Martínez-Recio, Sergio|||0000-0001-8056-7100, Bell, Olga|||0009-0000-2858-6187, Arranz, María Jesús|||0000-0002-6757-9198, Salazar, Juliana|||0000-0002-3581-4499, Sullivan, Ivana|||0000-0002-0434-3436
Format: article
Publication Date:2024
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:308585
Online Access:https://ddd.uab.cat/record/308585
https://dx.doi.org/urn:doi:10.3390/pharmaceutics16091121
Access Level:Open access
Keyword:ERCC1
ERCC2
Pharmacogenomics
Platinum-based chemotherapy
Small cell lung cancer
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spelling ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung CancerBarba Joaquin, Andrés|||0000-0003-2500-0253López Vilaró, Laura|||0000-0002-5428-8017Ferre, MalenaMajem Tarruella, Margarita|||0000-0002-9919-7485Martínez-Recio, Sergio|||0000-0001-8056-7100Bell, Olga|||0009-0000-2858-6187Arranz, María Jesús|||0000-0002-6757-9198Salazar, Juliana|||0000-0002-3581-4499Sullivan, Ivana|||0000-0002-0434-3436ERCC1ERCC2PharmacogenomicsPlatinum-based chemotherapySmall cell lung cancerStandard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.Universitat Autònoma de Barcelona 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/308585https://dx.doi.org/urn:doi:10.3390/pharmaceutics16091121reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3085852026-06-06T12:50:31Z
dc.title.none.fl_str_mv ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
title ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
spellingShingle ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
Barba Joaquin, Andrés|||0000-0003-2500-0253
ERCC1
ERCC2
Pharmacogenomics
Platinum-based chemotherapy
Small cell lung cancer
title_short ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
title_full ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
title_fullStr ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
title_full_unstemmed ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
title_sort ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer
dc.creator.none.fl_str_mv Barba Joaquin, Andrés|||0000-0003-2500-0253
López Vilaró, Laura|||0000-0002-5428-8017
Ferre, Malena
Majem Tarruella, Margarita|||0000-0002-9919-7485
Martínez-Recio, Sergio|||0000-0001-8056-7100
Bell, Olga|||0009-0000-2858-6187
Arranz, María Jesús|||0000-0002-6757-9198
Salazar, Juliana|||0000-0002-3581-4499
Sullivan, Ivana|||0000-0002-0434-3436
author Barba Joaquin, Andrés|||0000-0003-2500-0253
author_facet Barba Joaquin, Andrés|||0000-0003-2500-0253
López Vilaró, Laura|||0000-0002-5428-8017
Ferre, Malena
Majem Tarruella, Margarita|||0000-0002-9919-7485
Martínez-Recio, Sergio|||0000-0001-8056-7100
Bell, Olga|||0009-0000-2858-6187
Arranz, María Jesús|||0000-0002-6757-9198
Salazar, Juliana|||0000-0002-3581-4499
Sullivan, Ivana|||0000-0002-0434-3436
author_role author
author2 López Vilaró, Laura|||0000-0002-5428-8017
Ferre, Malena
Majem Tarruella, Margarita|||0000-0002-9919-7485
Martínez-Recio, Sergio|||0000-0001-8056-7100
Bell, Olga|||0009-0000-2858-6187
Arranz, María Jesús|||0000-0002-6757-9198
Salazar, Juliana|||0000-0002-3581-4499
Sullivan, Ivana|||0000-0002-0434-3436
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv ERCC1
ERCC2
Pharmacogenomics
Platinum-based chemotherapy
Small cell lung cancer
topic ERCC1
ERCC2
Pharmacogenomics
Platinum-based chemotherapy
Small cell lung cancer
description Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.
publishDate 2024
dc.date.none.fl_str_mv 2
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/308585
https://dx.doi.org/urn:doi:10.3390/pharmaceutics16091121
url https://ddd.uab.cat/record/308585
https://dx.doi.org/urn:doi:10.3390/pharmaceutics16091121
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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