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Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma
Background
Biliary tract cancers (BTCs) are rare malignancies with a poor prognosis and scarce therapeutic strategies. The BRCAness phenotype has been shown to correlated with a good response to platinum-based chemotherapy and PARP inhibitors in several oncologic setting, but its significance in BTC is already unknown.
Methods
Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATION Cdx technology. The BRCAness mutated group was defined if present at least one mutation in: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, and RTEL1, ARID1A, ATR, ATRX, CHEK1, RAD51L1, or RAD51L3. The analysis aimed to examine the association between the BRCAness phenotype and survival outcomes in patients with advanced or unresectable BTC receiving platinum-based chemotherapy. OS was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model.
Results
150 patients have been included in the analysis, 72/150 (48%) were BRCAness mutated and 78/150 (52.0%) were BRCAness wild type (WT). The most common mutated genes in the entire population were CDKN2A (31%), ARID1A (21%), CDKN2B (21%), KRAS/NRAS (19%), BAP1 (17%), PBRM1 (15%) and TP53 (11%). The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N=32, 44%), CDKN2A (N=23, 32%), KRAS/NRAS (N=16, 22%), CDKN2B (N=13, 18%), BRCA2 (N=13, 18%), PBRM1 (N=12, 17%), ATM (N=11, 15%), FGFR2 (N=10, 14%), TP53 (N=8, 11%), IRS2 (N=7, 10%), CREBBP (N=7, 10%). At the univariate analysis for PFS BRCAness mutation was associated with longer mPFS (HR 0.68; 95% CI 0.49-0.95; p=0.0254). At the univariate analysis for OS BRCAness mutation was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p=0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p=0.04) compared to patients without BRCAness mutation. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p=0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p=0.3652). ATM mutation was detected to be statistically significantly associated to a worse PFS in the BRCAness mutated population (HR 2.83; CI 95%: 1.14-7.05; p=0.0256).
Conclusions
BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves’ trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi after response to platinum.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
T. Macarulla: Advisory/Consultancy: (SOBI) Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Got It Consulting SL, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience, Inc, Janssen, Lilly. Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, TRANSWORLD EDITORS, SL and Zymeworks. All other authors have declared no conflicts of interest.
