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Updated: Sep 7, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity
Monica Niger1, Federico Nichetti1,2, Andrea Casadei-Gardini3,4
1Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Abstract:
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.
Insights
Isocitrate dehydrogenase (IDH)1/2 mutations in intrahepatic cholangiocarcinoma (iCCA) do not predict better outcomes with platinum chemotherapy. This study found no significant differences in progression-free survival or response rates, questioning IDH mutations as biomarkers for platinum efficacy.
Area of Science:
- Oncology
- Genetics
- Cancer Therapeutics
Background:
- Isocitrate dehydrogenase (IDH)1/2 mutations are common in intrahepatic cholangiocarcinoma (iCCA) and linked to homologous recombination deficiency (HRD).
- HRD suggests potential sensitivity to platinum chemotherapy (ChT) and PARP inhibitors, but clinical validation is lacking.
- The utility of IDH1/2 mutations as predictive biomarkers for platinum-based ChT in iCCA remains unknown.
Purpose of the Study:
- To investigate the impact of IDH1/2 mutations on treatment outcomes in iCCA patients receiving platinum-based ChT.
- To assess if IDH1/2 mutations serve as surrogate biomarkers for platinum efficacy in iCCA.
- To explore homologous recombination deficiency (HRD) estimates in IDH1/2 mutated versus wild-type iCCA.
Main Methods:
- A multicenter, propensity score-matched analysis of 120 iCCA patients (60 IDH1/2 mutant, 60 wild-type) treated with platinum-based ChT.
- Evaluation of progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR).
- Exploratory comparison of HRD estimates using TCGA data for IDH1/2 mutated and wild-type tumors.
Main Results:
- No significant differences in platinum-based PFS (7.7 vs 7.3 months), DCR (66.1% vs 74.1%), or ORR (27.8% vs 25.0%) between IDH1/2 mutant and wild-type groups.
- IDH1/2 mutations were mutually exclusive with alterations in ATM, BRCA2, MST1R, NF1, FGFR2, and CDKN2A/B, without clear survival or response differences.
- IDH1/2 mutated iCCA tumors did not exhibit higher HRD compared to wild-type tumors in TCGA data.
Conclusions:
- IDH1/2 mutations are not associated with increased sensitivity or improved outcomes with platinum-based chemotherapy in iCCA.
- IDH1/2 mutations do not appear to be reliable surrogate biomarkers for predicting platinum efficacy in this patient population.
- Further genomic studies are required to understand the HRD phenotype in IDH1/2-mutant iCCA and identify potential therapeutic vulnerabilities.
