Abstract
METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.
RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.
CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 1269-1277 |
| Number of pages | 9 |
| Journal | British Journal of Cancer |
| Volume | 117 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Oct 24 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. / Ruzzo, A.; Graziano, F.; Galli, Fabio; Galli, Francesca; Rulli, E.; Lonardi, S.; Ronzoni, M.; Massidda, B.; Zagonel, V.; Pella, N.; Mucciarini, C.; Labianca, R.; Ionta, M. T.; Bagaloni, I.; Veltri, E.; Sozzi, P.; Barni, S.; Ricci, V.; Foltran, L.; Nicolini, M.; Biondi, E.; Bramati, A.; Turci, D.; Lazzarelli, S.; Verusio, C.; Bergamo, F.; Sobrero, A.; Frontini, L.; Menghi, M.; Magnani, M.
In: British Journal of Cancer, Vol. 117, No. 9, 24.10.2017, p. 1269-1277.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
AU - Ruzzo, A.
AU - Graziano, F.
AU - Galli, Fabio
AU - Galli, Francesca
AU - Rulli, E.
AU - Lonardi, S.
AU - Ronzoni, M.
AU - Massidda, B.
AU - Zagonel, V.
AU - Pella, N.
AU - Mucciarini, C.
AU - Labianca, R.
AU - Ionta, M. T.
AU - Bagaloni, I.
AU - Veltri, E.
AU - Sozzi, P.
AU - Barni, S.
AU - Ricci, V.
AU - Foltran, L.
AU - Nicolini, M.
AU - Biondi, E.
AU - Bramati, A.
AU - Turci, D.
AU - Lazzarelli, S.
AU - Verusio, C.
AU - Bergamo, F.
AU - Sobrero, A.
AU - Frontini, L.
AU - Menghi, M.
AU - Magnani, M.
PY - 2017/10/24
Y1 - 2017/10/24
N2 - METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.
AB - METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.
UR - http://www.scopus.com/inward/record.url?scp=85033396342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033396342&partnerID=8YFLogxK
U2 - 10.1038/bjc.2017.289
DO - 10.1038/bjc.2017.289
M3 - Article
C2 - 29065426
AN - SCOPUS:85033396342
VL - 117
SP - 1269
EP - 1277
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 9
ER -