Mutations in CTC could predict outcomes in some castrate-resistant prostate most cancers sufferers

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Various genetic changes in circulating tumor cells (CTCs) have been associated with clinical outcomes and resistance to hormone therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC). This is evident from results published in Molecular Cancer Research, a journal of the American Association for Cancer research.

While only a minority of men with mCRPC have primary resistance to the androgen receptor (AR) inhibitors enzalutamide (Xtandi) or abiraterone acetate (Yonsa or Zytiga), most men will develop acquired resistance within a few years, said senior author Andrew Armstrong , MD, MSc, a medical oncologist at the Duke Cancer Institute Center for Prostate and Urological Cancer at Duke University.

In the previously published PROPHECY study, Armstrong and colleagues found that the presence of the AR-V7 splice variant in CTCs from patients with mCRPC was associated with fewer responses and shorter overall progression-free survival after treatment with enzalutamide or abiraterone. Based on these findings, the National Comprehensive Cancer Network has included the proposed AR-V7 tests in guidelines for clinical practice for patients with mCRPC who have made progress after hormone therapy, Armstrong said.

"While these results were encouraging, only about 5 to 40 percent 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," he added added.

The latest study is a retrospective secondary analysis of the PROPHECY study. In this new analysis, Armstrong and colleagues identified genomic changes in AR-V7 negative CTCs from patients with mCRPC and examined associations between these changes and clinical outcomes.

Armstrong and colleagues analyzed individual pooled CTC DNA from patients versus germline DNA for changes in total genomic copy number – indicative of the gain or loss of genetic material – in 73 liquid biopsy samples taken by 48 men over time AR inhibitors were taken from treated mCRPC in the PROPHECY study. They also looked for novel genomic changes associated with acquired resistance over time by performing pooled CTC sequencing versus total germline sequencing on 22 samples taken before and after the progression of enzalutamide or abiraterone. Performed exome sequencing of individual patients.

In addition to confirming previous work suggesting that poor AR inhibition results were associated with PTEN loss, MYCN gain, AR gain, and TP53 mutations in CTCs, the researchers identified several new changes associated with the response AR inhibitors were linked. Gains in ATM, NCOR2, and HSD17B4 were associated with sensitivity to AR inhibitors, while gains in BRCA2, APC, KDM5D, CYP11B1, and SPARC, and losses in CHD1, PHLPP1, ERG, ZFHX3, and NCOR2 were associated with primary resistance to AR inhibitors .

"We were surprised to see that gain in BRCA2 was associated with poorer results on mCRPC resistant to AR inhibitors, as previously not described. Typically, loss of BRCA2 was associated with poorer results," said Armstrong . "Our finding could explain some resistance to DNA damaging agents and AR therapies that has not been well understood and requires further mechanistic investigation." The present study is also the first to confirm that the loss of CHD1 in CTCs is associated with poorer outcomes for patients with mCRPC in a clinical setting, Armstrong added. It has previously been shown that loss or mutations in CHD1 promote lineage plasticity in prostate cancer.

Patients who benefited from AR inhibitors (defined as progression-free survival of at least six months) were more likely to have CTCs with changes in genes involved in DNA repair, steroid metabolism, lineage plasticity, and PI3K and WNT Signals are involved. In addition, chromatin and epigenetic gains associated with a loss of CHD1 and a gain of KDM5D were also observed in patients who benefited from AR inhibition. In contrast, patients who progressed with AR inhibitors showed clonal development of CTCs with gains in the ATM, FOXA1, UGT2B17, KDM6A, CYP11B1, and MYC genes, and acquired losses in NCOR1, ZFHX3, and ERG.

"Our study confirms that analysis of CTC genomics has the potential to identify and track disease resistance or efficacy with AR inhibitors over time," said Armstrong. "The novel changes that we have identified need further research to validate, but may be prime candidates for new drug targets."

One of the limitations of this study is the small sample size, which limited the researchers' ability to perform statistical tests between individual changes and clinical outcomes. The burden of disease and differences in sensitivity of genome tests at different time points due to changes in CTCs in response to therapy and over time can lead to biased genomic findings. Finally, some changes noted may represent a minor change in passengers related to disease burden or genomic instability rather than cancers. The identified genomic changes require mechanistic studies to determine their biological and clinical relevance for treatment, Armstrong noted.

The team identifies blood biomarkers in drug-resistant cancer tumor cells

More information:
Molecular Cancer Research (2021). DOI: 10.1158 / 1541-7786.MCR-20-0975

Provided by
American Association for Cancer Research

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