Certain genetic alterations in circulating tumor cells (CTCs) were associated with treatment outcomes with the androgen receptor (AR) inhibitors enzalutamide (Xtandi) and abiraterone acetate (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings published in Molecular Cancer Research.1
Specifically, gains of BRCA2, APC, KDM5D, CYP11B1, and SPARC and losses of CHD1, PHLPP1, ERG, ZFHX3, and NCOR2 detected by CTCs were associated with primary resistance to abiraterone and enzalutamide. In contrast, gains in ATM, NCOR2, and HSD17B4 detected by CTCs were associated with sensitivity to the androgen receptor inhibitors.
“We were surprised to observe that a gain of BRCA2 was associated with worse outcomes in mCRPC resistant to AR inhibitors, as that has not been described before. Typically, loss of BRCA2 has been associated with poorer outcomes,” study author Andrew Armstrong, MD, MSc, medical oncologist at the Duke Cancer Institute Center for Prostate and Urologic Cancers at Duke University, stated in a press release.2 “Our finding may explain some resistance to DNA-damaging agents and AR therapies that have not been well understood and requires further mechanistic investigation.”
The retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men receiving either enzalutamide or abiraterone was conducted to identify somatic genomic alterations associated with acquired resistance. Seventy-three samples from 48 patients were analyzed over time for pooled CTC and whole-genome copy number alterations by germline DNA; additionally, CTC and germline whole-exome sequencing before and after progression on AR-targeted therapy were assessed in 22 paired samples.
The PROPHECY study had previously revealed that the presence of androgen receptor splice variant 7 (AR-V7) in CTCs in this patient population was associated with a lower response rate and poorer survival outcomes with either enzalutamide or abiraterone.3
“While these findings were encouraging, only about 5% to 40% of patients with mCRPC have CTCs that are positive for AR-V7, depending on the disease context, suggesting that other genetic alterations may play a role in drug resistance,” Armstrong said.
The research was also able to confirm prior data indicating that poor outcomes with AR inhibition are associated with PTEN loss, MYCN gain, AR gain, and TP53 mutations in CTCs.
Patients benefiting the most from treatment with enzalutamide or abiraterone were more likely to have alterations in genes associated with DNA repair, steroid metabolism, linage plasticity, and PI3K and WNT signaling by CTCs. Benefits with therapy were more likely in patients with chromatin and epigenetic gains correlated with loss of CHD1 and gains of KDM5D, whereas progression was more often seen in those with clonal evolutions with gains in ATM, FOXA1, UGT2B17, KDM6A, CYP11B1, and MYC and/or acquired losses of NCOR1, ZFHX3, and ERG.
“Our study reinforces that analyzing CTC genomics has potential for identifying and tracking disease resistance or efficacy with AR inhibitors over time,” Armstrong said. “The novel alterations we identified will need to be validated by further research but may represent priority candidates for new drug targets.”
The investigators acknowledged the small sample size as a limitation to the study and pointed out that differences in sensitivity of assays at different time points may bias the findings.
1. Gupta S, Halabi S, Kemeny G, et al. Circulating tumor cell genomic evolution and hormone therapy outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). Mol Cancer Res. Published online March 26, 2021. doi: 10.1158/1541-7786.MCR-20-0975
2. CTC mutations may predict outcomes in some castrate-resistant prostate cancer patients. News release. American Association for Cancer Research. March 26, 2021. Accessed March 31, 2021. https://bit.ly/3wgIpby
3. Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J Clin Oncol. 2019;37(13):1120-1129. doi: 10.1200/JCO.18.01731