Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: There is a clinical need for biomarkers predictive of resistance to taxane therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Based on existing evidence for the role of ATP-binding cassette (ABC) transporters in taxane resistance, we sought to assess the association between ABCB1 gene amplification and primary resistance to docetaxel or cabazitaxel in mCRPC patients using sparse whole genome sequencing from plasma-derived cell-free DNA (cfDNA). Because sparse whole genome sequencing is more cost-effective than traditional cfDNA profiling and less invasive than tissue biopsies, a clinically useful biomarker of taxane resistance discovered using this technique has the potential to be broadly applied in clinical practice. We did not detect a statistically significant association between ABCB1 amplification detected by this method and docetaxel or cabazitaxel resistance in our cohort. Future studies with larger samples including ABCB1 amplification in a suite of putative biomarkers are warranted to draw definitive conclusions. ABSTRACT: There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.