Circulating HOXA9-methylated tumour DNA: A novel biomarker of response to poly (ADP-ribose) polymerase inhibition in BRCA-mutated epithelial ovarian cancer. (January 2020)

• Record Type: Journal Article
• Authors: Rusan, Maria; Andersen, Rikke F.; Jakobsen, Anders; Steffensen, Karina D.
• Is Part Of: European journal of cancer. Volume 125(2020)
• Page Start: 121
• Page End: 129
• Publication Date: 2020-01
• Subjects: HOXA9 -- Methylation -- Biomarkers -- Circulating tumour DNA -- Ovarian neoplasms; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2019.11.012
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Aim: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a novel treatment option in BRCA-mutated ovarian cancer (OC); however, responses are variable and there is a lack of prognostic and predictive biomarkers. We therefore investigated whether homeobox A9 (HOXA9) promoter methylation in circulating tumour DNA (meth-ctDNA) can serve as a biomarker in patients with platinum-resistant BRCA-mutated OC, undergoing treatment with a PARP inhibitor. Methods: Patients (n = 32) were enrolled as part of a phase II trial testing veliparib in platinum-resistant BRCA-mutated OC. HOXA9 meth-ctDNA was determined at baseline and just before each treatment cycle using digital droplet polymerase chain reaction. Methylation status and change in methylation compared with baseline were correlated with overall survival (OS) and progression-free survival (PFS). Results: Detection of HOXA9 meth-ctDNA during treatment with a PARP inhibitor was associated with worse clinical outcomes. This association was apparent after the first cycle of treatment and maintained throughout treatment. After three treatment cycles, patients with detectable HOXA9 meth-ctDNA had a median PFS of 5.1 months compared with 8.3 months for patients without, and a median OS of 9.5 months compared with 19.4 months (p < 0.0001 and p = 0.002, respectively). Patients with detectable HOXA9 meth-ctDNA at baseline, but subsequent undetectable levels, had the most favourable clinical outcome, followed by patients with undetectable levels throughout. These associations were maintained in multivariate analysis. Conclusions: Longitudinal monitoring of HOXA9 meth-ctDNA is clinically feasible and is strongly correlated to clinical outcomes (PFS, OS), suggesting that it may serve as a valuable predictive biomarker to inform clinical decision-making in the setting of platinum-resistant BRCA-mutated OC treated with a PARP inhibitor. Highlights: Predictive biomarkers in ovarian cancer treated with a poly (ADP-ribose) polymerase (PARP) inhibitor are lacking. Presence of HOXA9 methylation in circulating tumour DNA (ctDNA) during PARP treatment is correlated with poor clinical outcomes. Changes in HOXA9 methylation during treatment carry predictive value. Longitudinal detection of HOXA9 methylation in ctDNA may inform clinical decision-making.