A new ctDNA blood test from a Japanese team identifies those metastatic, castration-resistant prostate cancer (mCRPC) patients most likely to benefit from 223Ra radiopharmaceutical therapy. The test also monitors their progress throughout treatment.
The study appeared in the July issue of The Journal of Nuclear Medicine. The lead author is Masaki Shiota, MD, PhD, associate professor in the Department of Urology in the Graduate School of Medical Sciences at Kyushu University in Fukuoka, Japan.
Prostate cancer is very biologically heterogeneous. Patients who appear clinically similar may have different responses. Better tests are needed to match patients to therapies and determine the optimal treatment sequence or combination of therapies.
223Ra dichloride targets bone metastases and can improve overall survival and quality of life in CRPC patients. It is an alpha-particle–emitting radionuclide that behaves chemically like calcium. It is therefore preferentially incorporated into areas of increased bone turnover, including the osteoblastic lesions commonly produced by prostate cancer bone metastases.
But the treatment is expensive, clinical outcomes vary among patients, and there is not yet a reliable biomarker to predict or monitor treatment response.
This study used a research-based 88-gene panel with deep sequencing of plasma circulating tumor DNA (ctDNA) and matched leukocyte DNA. “The leukocyte analysis was important for distinguishing true tumor-derived alterations from germline variants and age-related clonal hematopoiesis,” Shiota told Inside Precision Medicine.
Prostate cancer is one of the most commonly diagnosed malignancies in men. Metastatic castration-sensitive prostate cancer arises either de novo as a cancer, or as a recurrence after radical local therapy for localized disease. It accounts for approximately 10% of newly diagnosed prostate cancer cases in Japan.
This team tracked associations between ctDNA profiles and clinical outcomes, including biomarker response, radiographic progression-free survival, and overall survival.
Patients with a higher amount of tumor DNA in the blood or certain gene changes, such as TP53, PTEN, and cell cycle pathway alterations, detected through ctDNA testing before treatment, had worse outcomes. Further, changes in tumor DNA reflected treatment response and disease trajectory.
“While 223Ra is an important treatment for prostate cancer that has spread to the bones, not all patients benefit equally,” said Shiota. “Our findings suggest that a blood-based genomic test may help identify patients who are more likely or less likely to benefit from the therapy. This could help doctors choose treatment more carefully and monitor patients more closely, with the goal of providing more personalized care.”
One of the biggest hurdles to the test’s advancement is reimbursement.
This depends on the country, the clinical indication, and the specific assay used. In Japan, Shiota explained, certain approved comprehensive genomic profiling tests using blood, such as FoundationOne Liquid CDx, can be covered by the national health insurance system under defined conditions. These tests are primarily used to identify potentially actionable alterations in patients with advanced solid tumors, particularly when obtaining adequate tumor tissue is difficult.
“The research assay used in our study is not currently reimbursed for selecting patients for radium-223 or for monitoring their response during treatment,” said Shiota. “Before insurance coverage could be considered for this particular use, our findings would need to be externally validated, and prospective studies would need to demonstrate that ctDNA-guided treatment decisions improve patient outcomes.”
ctDNA has several important applications in precision oncology. For example, it can: identify actionable genomic alterations and thereby help select targeted therapies, be used to monitor treatment response and detect emerging resistance mechanisms, capture tumor heterogeneity more comprehensively than a biopsy from a single metastatic site, detect minimal residual disease after treatment, and identify molecular relapse before it becomes apparent on conventional imaging.
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