Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity score-based study.
DNA repair
IDH1
IDH2
cholangiocarcinoma
homologous recombination deficiency
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 10 2022
15 10 2022
Historique:
revised:
18
05
2022
received:
04
02
2022
accepted:
03
06
2022
pubmed:
21
6
2022
medline:
27
8
2022
entrez:
20
6
2022
Statut:
ppublish
Résumé
Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.
Substances chimiques
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1310-1320Informations de copyright
© 2022 UICC.
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