Induction of circulating ABCB1 transcripts under platinum-based chemotherapy indicates poor prognosis and a bone micrometastatic phenotype in ovarian cancer patients

The drug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, promotes acquired chemoresistance. We explored the presence and clinical relevance of circulating cell-free ABCB1 transcripts (cfABCB1^tx) in ovarian cancer patients (173 longitudinal serum samples from 79 cancer patients) using digital droplet PCR. cfABCB1^tx were readily detectable at primary diagnosis (median 354 mRNA copies/20 µl serum), paralleled FIGO-stage and predicted surgical outcome (p = 0.023, p=0.022, respectively). Increased cfABCB1^tx levels at primary diagnosis indicated poor PFS (HR = 2.329, 95%CI:1.374-3.947, p = 0.0017) and OS (HR = 2.074, 95%CI:1.194-3.601, p = 0.0096). cfABCB1^tx induction under platinum-based chemotherapy was an independent predictor for poor OS (HR = 2.597, 95%CI: 1.218-5.538, p = 0.013) and paralelled a micrometastatic phenotype, shaped by the presence of disseminated tumor cells in the bone marrow. A strong correlation was observed between cfABCB1^tx and circulating transcripts of the metastasis-inducer MACC1, which is the transcriptional activator of ABCB1. Combined assessment of cfABCB1^tx and circulating cell-free MACC1 transcripts (cfMACC1^tx) resulted in an improved prognostic prediction, with  the cfABCB1^tx-high/cfMACC1^tx-high phenotype bearing the highest risk for relapse and death. Conclusively, we provide proof of principle, that ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients, advancing a new dimension for systemic monitoring of ABCB1/P-glycoprotein expression dynamics.