Related Experiment Video
Updated: Jul 21, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All "BRCAness" Is Created Equal
Deborah Blythe Doroshow1, Wei Wei2, Meenakshi Mehrotra3
1Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
Abstract:
Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.
Insights
Patients with IDH1/2 mutations in intrahepatic cholangiocarcinoma did not show improved outcomes with platinum chemotherapy, contrary to preclinical hypotheses. This suggests tumor-specific factors influence platinum sensitivity and homologous recombination repair defects.
Area of Science:
- Oncology
- Genetics
- Biochemistry
Background:
- Preclinical studies indicate IDH1/2 mutations impair homologous recombination repair (HRR).
- This suggests potential for enhanced platinum chemotherapy sensitivity in IDH1/2-mutated (IDH1/2mt) tumors.
- Intrahepatic cholangiocarcinoma (IHCC) is a challenging cancer with limited treatment options.
Purpose of the Study:
- To investigate the clinical benefit of first-line (1L) platinum chemotherapy in patients with IDH1/2mt IHCC compared to IDH wildtype (WT) tumors.
- To determine if defective HRR in IDH1/2mt IHCC translates to improved response to platinum-based therapy.
Main Methods:
- A multicenter retrospective study included 81 patients with unresectable IHCC.
- Patients received 1L platinum chemotherapy.
- Clinical benefit rate (CBR) was the primary endpoint; objective response rate (ORR) was also assessed.
Main Results:
- No significant difference in CBR was observed between patients with IDH1/2mt tumors (59%) and IDH WT tumors (54%; p=0.803).
- Objective response rates were also similar between the two groups.
- These findings challenge the hypothesis that IDH1/2 mutations predict platinum sensitivity in IHCC.
Conclusions:
- The study did not support the hypothesis that IDH1/2 mutations confer benefit from platinum chemotherapy in IHCC.
- The relationship between platinum sensitivity and HRR defects appears to be context-specific.
- Further research is needed to understand the complex interplay of genetic mutations and treatment response in IHCC.
