A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Miguel Cordova-Delgado; María Loreto Bravo; Elisa Cumsille; Charlotte N. Hill; Matías Muñoz-Medel; Mauricio P. Pinto; Ignacio N. Retamal; María A. Lavanderos; Juan Francisco Miquel; Maria Rodriguez-Fernandez; Yuwei Liao; Zhiguang Li; Alejandro H. Corvalán; Ricardo Armisén; Marcelo Garrido; Luis A. Quiñones; Gareth I. Owen

doi:10.1186/s12885-021-08745-0

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Miguel Cordova-Delgado, María Loreto Bravo, Elisa Cumsille, Charlotte N. Hill, Matías Muñoz-Medel, Mauricio P. Pinto, Ignacio N. Retamal, María A. Lavanderos, Juan Francisco Miquel, Maria Rodriguez-Fernandez, Yuwei Liao, Zhiguang Li, Alejandro H. Corvalán, Ricardo Armisén, Marcelo Garrido, Luis A. Quiñones^*, Gareth I. Owen^*

^*Corresponding author for this work

Facultad de Odontología

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Original language	English
Article number	1030
Pages (from-to)	1-18
Journal	BMC Cancer
Volume	21
Issue number	1
Early online date	16 Sep 2021
DOIs	https://doi.org/10.1186/s12885-021-08745-0
State	Published - Dec 2021

Bibliographical note

Funding Information:
MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers’ bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors have no conflicts of interest to declare.

Funding Information:
This study was funded by the grants issued by the Government of Chile: CONICYT FONDAP-15130011 (GIO), BMRC CTU06 (GIO), Millennium Institute on Immunology & Immunotherapy IMII P09/016-F (GIO), FONDECYT 1180241 (GIO), FONDECYT 1180173 (MG) and FONDECYT 1191928 (AHC). The first author (MCD) is a CONICYT doctoral scholarship recipient (#21150695).

Funding Information:
We would like to thank the patients and their families for participating in this study, to the RED UC Christus and the department of pathology at the ?Hospital Cl?nico UC? for the access to patient data and paraffin embedded samples and to the Biomedical Research Consortium of Chile for the initial support in this project.

Publisher Copyright:
© 2021, The Author(s).

Keywords

Chemotherapy toxicity
Fluoropyrimidines
Platinums
Predictive models
Single nucleotide polymorphism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cordova-Delgado, M., Bravo, M. L., Cumsille, E., Hill, C. N., Muñoz-Medel, M., Pinto, M. P., Retamal, I. N., Lavanderos, M. A., Miquel, J. F., Rodriguez-Fernandez, M., Liao, Y., Li, Z., Corvalán, A. H., Armisén, R., Garrido, M., Quiñones, L. A., & Owen, G. I. (2021). A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer. BMC Cancer, 21(1), 1-18. Article 1030. https://doi.org/10.1186/s12885-021-08745-0

@article{843e607c16c34558822fceca3f187e0d,

title = "A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer",

abstract = "Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.",

keywords = "Chemotherapy toxicity, Fluoropyrimidines, Platinums, Predictive models, Single nucleotide polymorphism, Chemotherapy toxicity, Fluoropyrimidines, Platinums, Predictive models, Single nucleotide polymorphism",

author = "Miguel Cordova-Delgado and Bravo, {Mar{\'i}a Loreto} and Elisa Cumsille and Hill, {Charlotte N.} and Mat{\'i}as Mu{\~n}oz-Medel and Pinto, {Mauricio P.} and Retamal, {Ignacio N.} and Lavanderos, {Mar{\'i}a A.} and Miquel, {Juan Francisco} and Maria Rodriguez-Fernandez and Yuwei Liao and Zhiguang Li and Corval{\'a}n, {Alejandro H.} and Ricardo Armis{\'e}n and Marcelo Garrido and Qui{\~n}ones, {Luis A.} and Owen, {Gareth I.}",

note = "Funding Information: MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers{\textquoteright} bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors have no conflicts of interest to declare. Funding Information: This study was funded by the grants issued by the Government of Chile: CONICYT FONDAP-15130011 (GIO), BMRC CTU06 (GIO), Millennium Institute on Immunology & Immunotherapy IMII P09/016-F (GIO), FONDECYT 1180241 (GIO), FONDECYT 1180173 (MG) and FONDECYT 1191928 (AHC). The first author (MCD) is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: We would like to thank the patients and their families for participating in this study, to the RED UC Christus and the department of pathology at the ?Hospital Cl?nico UC? for the access to patient data and paraffin embedded samples and to the Biomedical Research Consortium of Chile for the initial support in this project. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s12885-021-08745-0",

language = "English",

volume = "21",

pages = "1--18",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central Ltd.",

number = "1",

}

Cordova-Delgado, M, Bravo, ML, Cumsille, E, Hill, CN, Muñoz-Medel, M, Pinto, MP, Retamal, IN, Lavanderos, MA, Miquel, JF, Rodriguez-Fernandez, M, Liao, Y, Li, Z, Corvalán, AH, Armisén, R, Garrido, M, Quiñones, LA & Owen, GI 2021, 'A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer', BMC Cancer, vol. 21, no. 1, 1030, pp. 1-18. https://doi.org/10.1186/s12885-021-08745-0

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer. / Cordova-Delgado, Miguel; Bravo, María Loreto; Cumsille, Elisa et al.
In: BMC Cancer, Vol. 21, No. 1, 1030, 12.2021, p. 1-18.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

AU - Cordova-Delgado, Miguel

AU - Bravo, María Loreto

AU - Cumsille, Elisa

AU - Hill, Charlotte N.

AU - Muñoz-Medel, Matías

AU - Pinto, Mauricio P.

AU - Retamal, Ignacio N.

AU - Lavanderos, María A.

AU - Miquel, Juan Francisco

AU - Rodriguez-Fernandez, Maria

AU - Liao, Yuwei

AU - Li, Zhiguang

AU - Corvalán, Alejandro H.

AU - Armisén, Ricardo

AU - Garrido, Marcelo

AU - Quiñones, Luis A.

AU - Owen, Gareth I.

N1 - Funding Information: MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers’ bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors have no conflicts of interest to declare. Funding Information: This study was funded by the grants issued by the Government of Chile: CONICYT FONDAP-15130011 (GIO), BMRC CTU06 (GIO), Millennium Institute on Immunology & Immunotherapy IMII P09/016-F (GIO), FONDECYT 1180241 (GIO), FONDECYT 1180173 (MG) and FONDECYT 1191928 (AHC). The first author (MCD) is a CONICYT doctoral scholarship recipient (#21150695). Funding Information: We would like to thank the patients and their families for participating in this study, to the RED UC Christus and the department of pathology at the ?Hospital Cl?nico UC? for the access to patient data and paraffin embedded samples and to the Biomedical Research Consortium of Chile for the initial support in this project. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

AB - Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

KW - Chemotherapy toxicity

KW - Fluoropyrimidines

KW - Platinums

KW - Predictive models

KW - Single nucleotide polymorphism

KW - Chemotherapy toxicity

KW - Fluoropyrimidines

KW - Platinums

KW - Predictive models

KW - Single nucleotide polymorphism

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U2 - 10.1186/s12885-021-08745-0

DO - 10.1186/s12885-021-08745-0

M3 - Article

C2 - 34525956

AN - SCOPUS:85115079952

SN - 1471-2407

VL - 21

SP - 1

EP - 18

JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 1030

ER -

Cordova-Delgado M, Bravo ML, Cumsille E, Hill CN, Muñoz-Medel M, Pinto MP et al. A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer. BMC Cancer. 2021 Dec;21(1):1-18. 1030. Epub 2021 Sep 16. doi: 10.1186/s12885-021-08745-0

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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