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Niger, Monica; Nichetti, Federico; Casadei‐Gardini, Andrea; Rizzato, Mario Domenico; Pircher, Chiara; Bini, Marta; Franza, Andrea; Rimini, Margherita; Burgio, Valentina; Sposetti, Caterina; Fornaro, Lorenzo; Rapposelli, Ilario Giovanni; D'Amico, Francesco Enrico; Aprile, Giuseppe; Vivaldi, Caterina; Frassineti, Giovanni Luca; Milione, Massimo; Leoncini, Giuseppe; Cappetta, Alessandro; Vasile, Enrico; Fassan, Matteo; Morano, Federica; Perrone, Federica; Tamborini, Elena; Pruneri, Giancarlo; Lonardi, Sara; Mazzaferro, Vincenzo; Pietrantonio, Filippo; Di Bartolomeo, Maria; de Braud, Filippo
International journal of cancer, 15 October 2022, Letnik: 151, Številka: 8Journal Article
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. Whats's new? IDH1/2 mutations are frequently observed in intrahepatic cholangiocarcinoma (iCCA). Preclinical evidence shows that IDH1/2 mutations result in homologous recombination deficiency that could potentially be used as a therapeutic target for platinum chemotherapy and PARP inhibitors. Here, the authors provide first clinical evidence that IDH1/2 mutations are not associated with increased efficacy of platinum salts in iCCA patients, nor with higher homologous recombination deficiency in Cancer Genome Atlas cholangiocarcinoma cases. The findings suggest that future trials targeting homologous recombination deficiency in IDH1/2‐mutant tumours should harness new therapeutic combinations rather than PARP‐targeting monotherapies.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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