Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer

Abstract

Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a percentage of total DNA and as a binary variable (detectable and undetectable). Meth-HOXA9 status and its dynamics during palliative treatment were correlated with overall survival (OS) as the primary endpoint. At baseline, meth-HOXA9 was detected in 65.9% (83/126) of the patients. The median OS was 8.9 and 17.9 months in patients with detectable and undetectable meth-HOXA9 at baseline (hazard ratio: 2.04, p = 0.002), which remained significant in the multivariate analysis. Median OS in patients with an increase in meth-HOXA9 after one treatment cycle was 5.3 months compared to 33 months in patients with undetectable meth-HOXA9 (p < 0.001). Meth-HOXA9 was significantly related to poor survival and may serve as a prognostic marker in patients with recurrent EOC. The longitudinal monitoring of meth-HOXA9 is clinically feasible with the perspective of aiding clinical decision making.

Liquid biopsy in ovarian cancer in China and the world: current status and future perspectives

“…Survival outcomes were significantly inferior in patients with detectable HOXA9 methylation in ctDNA than in those without HOXA9 methylation (median progression-free survival [PFS]: 5.1 vs. 8.3 months, P < 0.0001; median OS: 9.5 vs. 19.4 months, P < 0.002) (100). Faaborg et al reported similar findings in a study of 126 patients (38.9% platinum sensitive and 81.7% with recurrent OC undergoing treatment with chemotherapy followed by maintenance therapy with PARP inhibitors or bevacizumab (101); with the increasing use of PARP inhibition in earlier lines of therapy, validation of these biomarkers in first line will be increasingly important.…”

“…Faaborg et al. reported similar findings in a study of 126 patients (38.9% platinum sensitive and 81.7% with recurrent OC undergoing treatment with chemotherapy followed by maintenance therapy with PARP inhibitors or bevacizumab ( 101 ); with the increasing use of PARP inhibition in earlier lines of therapy, validation of these biomarkers in first line will be increasingly important.…”

“…In addition to mutations and structural aberrations in cfDNA or ctDNA, methylation of various genes, including COL23A1 , C2CD4D , WNT6, ESR1 , and HOXA9 , has been shown to be associated with resistance to chemotherapy and could be used to predict or monitor treatment response ( 25 , 99 – 101 ), suggesting that LB-based molecular testing may be useful in this setting, particularly in patients ineligible for tissue biopsy or for whom archival tissue is not available.…”

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“…This was recently illustrated in a study on patients with ovarian cancer. 41 Raunkilde et al ., 42 used the same methylation assay in a cohort of patients treated for mCRC with first-line therapy. An early evaluation of ctDNA response after the first cycle of chemotherapy revealed that PFS was 10.1 and 7.6 months, in ctDNA responders and nonresponders, respectively ( p = 0.02, HR = 0.43).…”

Comments on “The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020”

“…5 On the other hand, a significant increase after the first treatment cycle seems to imply a poor prognosis. 6 The classification of the ctDNA kinetics should be based on objective criteria. The confidence interval (CI) of the measurement seems to be a reasonable measure in this respect and this approach is well-known from other analytics in clinical biochemistry.…”