Uterine artery pulsatility index and serum BMP-9 predict resistance to methotrexate therapy in gestational trophoblastic neoplasia: A cohort study

• Published in: Current problems in cancer 2021-02, Vol.45 (1), p.100622-100622, Article 100622
• Main Authors: Harvey, Richard A., Elias, Kevin M., Lim, Adrian, Bercow, Alexandra, Short, Dee, Horowitz, Neil S., Berkowitz, Ross S., Agarwal, Roshan, Seckl, Michael J.
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Biomarkers, Tumor - blood; BMP-9; Chemotherapy resistance; Cohort Studies; Drug Resistance, Neoplasm; Female; Gestational Trophoblastic Disease - drug therapy; Gestational trophoblastic neoplasia; Growth Differentiation Factor 2 - blood; Growth Differentiation Factor 2 - drug effects; Humans; Methotrexate; Methotrexate - pharmacology; Pregnancy; Prognostic biomarkers; United Kingdom; Uterine Artery - diagnostic imaging; Uterine Artery - physiopathology; Uterine artery pulsatility index
• ISSN: 0147-0272; 1535-6345
• DOI: 10.1016/j.currproblcancer.2020.100622

Background: Methotrexate is the most common first-line chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Uterine artery pulsatility index (UAPI) is an ultrasound marker for tumor vascularity that has been associated with an increased risk of methotrexate resistance. The combination of circulating angiogenic factor levels with UAPI data may improve the capacity of this model to predict chemoresistance. Methods: This was a single-center cohort study of women newly diagnosed between January 2008 and June 2012 with low-risk GTN during postmolar surveillance and treated with single-agent methotrexate at Charing Cross Hospital, a UK national center for treatment of gestational trophoblastic disease. Two hundred seventeen women underwent an ultrasound for UAPI measurement prior to initiation of chemotherapy. To examine serologic markers of methotrexate resistance among this cohort, we performed a case-control study using archived serum from 76 patients who could be matched based on prognostic risk score. Serum samples were examined by immunoassay to measure 8 different angiogenic factors (VEGF-A, FGF-basic, PLGF-1, PDGF-BB, EGF, ANGPT2, BMP-9, and ENG). Receiver-operator characteristic area under the curve (AUC) values were calculated for the ability of each analyte to correctly classify patients as methotrexate sensitive (MTX-S) or resistant (MTX-R). Results: Total human chorionic gonadotropin levels were similar between the MTX-S and MTX-R groups. UAPI values were significantly higher in MTX-S (median 1.30 [interquartile range {IQR} = 0.80-1.90]) compared to MTX-R patients (median 0.875 [IQR = 0.60-1.30]; P < 0.0001) with AUC 0.68 (95% confidence interval 0.61-0.76; P < 0.0001). In univariate analysis, only BMP-9 concentrations were significantly different between groups, lower among MTX-S (median of 225 ng/L, IQR = 170-287) compared to MTX-R patients (median 280 ng/L [IQR = 200-339]; P= 0.03). Combining UAPI with BMP-9 concentration improved prediction for chemoresistance with AUC 0.77 (95% confidence interval 0.66-0.88; P < 0.0001). Conclusion: Circulating levels of BMP-9 are elevated in newly diagnosed women with low-risk GTN destined to fail primary methotrexate therapy. A combined test using serum BMP-9 plus UAPI might improve prediction of MTX-R in low-risk GTN.