Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in similar to 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.

Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity score-based study / M. Niger, F. Nichetti, A. Casadei-Gardini, M.D. Rizzato, C. Pircher, M. Bini, A. Franza, M. Rimini, V. Burgio, C. Sposetti, L. Fornaro, I.G. Rapposelli, F.E. D'Amico, G. Aprile, C. Vivaldi, G.L. Frassineti, M. Milione, G. Leoncini, A. Cappetta, E. Vasile, M. Fassan, F. Morano, F. Perrone, E. Tamborini, G. Pruneri, S. Lonardi, V. Mazzaferro, F. Pietrantonio, M. Di Bartolomeo, F. de Braud. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - 151:8(2022), pp. 1310-1320. [10.1002/ijc.34182]

Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity score-based study

F. Nichetti;C. Pircher;M. Bini;A. Franza;C. Sposetti;G. Pruneri;V. Mazzaferro;F. Pietrantonio;F. de Braud
2022

Abstract

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in similar to 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.
DNA repair; IDH1; IDH2; cholangiocarcinoma; homologous recombination deficiency; Bile Ducts, Intrahepatic; Humans; Isocitrate Dehydrogenase; Mutation; Propensity Score; Bile Duct Neoplasms; Cholangiocarcinoma
Settore MED/06 - Oncologia Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/937109
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