"We found that CTC genomic alterations in several key genes were able to predict for widely different outcomes," Dr. Andrew Armstrong of Duke University Medical Center in Durham told Reuters Health by email. "These genes were altered prior to therapy or emerged during treatment over time. They regulate prostate cancer cellular differentiation, DNA repair, AR signaling, cell death, and proliferation, and offer important personalized targets for treatment development to overcome hormone therapy resistance."
"Our findings are hypothesis-generating right now and require external validation before individual genetic alterations can be used clinically to guide therapy," he said. "Some alterations, such as TP53, PTEN, and MYC, are well known to be associated with poor outcomes in general. One of our more novel findings - the association of CHD1 loss with poor outcomes - is well supported from recent preclinical work. If further validated, then assessment of patients for CHD1 loss in their tumor or CTCs could be useful to predict hormone therapy outcomes."
"Our findings of gains in DNA repair enzymes conferring differential outcomes with abiraterone or enzalutamide also require external validation," he noted, "but suggests potential mechanisms of resistance to PARP inhibitors as well."
As reported in Molecular Cancer Research, Dr. Armstrong and colleagues conducted a secondary analysis of the PROPHECY trial (https://bit.ly/3s6AaLV), involving men with mCRPC receiving enzalutamide/abiraterone.
They analyzed pooled CTC and germline DNA for whole-genome copy number alterations (CNAs) in 73 liquid biopsy samples (45 baseline and 28 progression) over time. They also looked for genomic alterations associated with acquired resistance by performing pooled CTC versus matched germline whole-exome sequencing on 22 paired samples taken before and after progression on the AR inhibitors.
They saw broad inter-patient and longitudinal CTC genomic heterogeneity from AR-V7-negative men, including gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN.
Men with worse outcomes - i.e., progression-free survival of less than three months despite enzalutamide/abiraterone treatment - were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC.
In samples from patients who progressed on abiraterone/enzalutamide, the researchers observed clonal evolution of CTCs harboring TP53 mutations, gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2.
The CTC genomic findings were independently confirmed in an analysis of a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (https://clinicaltrials.gov/ct2/show/NCT02204943).
Summing up, the authors state, "We identified common and reproducible genomic alterations in CTCs from AR-V7 negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.
Dr. Alex Sankin, Associate Program Director, Department of Urology at Montefiore Health System and associate professor at Albert Einstein College of Medicine in New York City, commented by email to Reuters Health. "The authors are proposing a new technique of using liquid biopsies to monitor in real time a tumor's acquisition of genetic events that lead to therapy resistance. This technique has potential to enhance personalized treatment regimens based on an individual's tumor signature by tailoring therapy in real time to keep up with the tumor's clonal evolution."
"To determine if the novel genomic alterations detected can truly guide treatment decisions," he said, "a prospective clinical trial should be conducted with patients assigned to treatment arms based on their CTC biomarker panel."
"The CTC preparation and sequencing technology used is not widely available to the general public," he added. "If patients are interested in receiving this technique...they will need to (be eligible to) participate in clinical trials at academic medical centers."
SOURCE: https://bit.ly/3s6lhcg Molecular Cancer Research, online April 2, 2021.
By Marilynn Larkin
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