TY - JOUR
T1 - Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy
AU - Majercakova, Katarina
AU - Virgili Manrique, Anna Cristina
AU - Salazar, Juliana
AU - Valverde, Sandra
AU - Bagué Rosell, Sílvia
AU - Sebio, Ana
AU - Cerdà, Paula
AU - Bell, Olga
AU - Fernández Garrido, Manuel
AU - Quintana Ruiz, Maria Jesús
AU - López Pousa, Antonio
AU - Artigas-Baleri, Alícia
AU - Arranz, María Jesús
AU - Gracia, Isidre
AU - Peiró, Ana
AU - Trullols, L.
PY - 2022
Y1 - 2022
N2 - Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are sub-stantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chem-otherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to es-tablish their clinical utility.
AB - Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are sub-stantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chem-otherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to es-tablish their clinical utility.
KW - Pharmacogenetics
KW - Anthracyclines
KW - ABCC2
KW - ABCB1
KW - Ifosfamide
KW - ALDH1A1
KW - Soft tissue sarcoma
KW - Neoadjuvant
U2 - 10.3390/jpm12040618
DO - 10.3390/jpm12040618
M3 - Article
C2 - 35455734
SN - 2075-4426
VL - 12
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 4
ER -