A blood test developed at Washington University School of Medicine in St. Louis could help determine next steps for patients whose prostate cancer has spread despite treatment.
The test is designed to help doctors determine if a patient’s disease can’t be effectively treated with a newer therapy called androgen receptor (AR) targeted therapy. Knowing this, a patient could decide whether to pursue a more traditional, and potentially more beneficial, therapy.
Results of a study evaluating whether the test can accurately predict treatment resistance suggest the technology is promising, and the researchers are continuing to refine it.
Called EnhanceAR-Seq, this “liquid biopsy” test involves looking for fragments of DNA in the blood called “cell-free DNA.” This yields helpful information otherwise available only with a more invasive biopsy of the tumor, itself. If the blood test predicts resistance to drugs that target the AR pathway, a patient can be guided to pursue another type of treatment, said researcher Aadel Chaudhuri, MD, PhD, an assistant professor of radiation oncology at the School of Medicine and a radiation oncologist at Siteman Cancer Center.
“EnhanceAR-Seq predicted survival in metastatic prostate cancer patients who were treated with AR-targeted treatment,” he said. “Every single patient who was found to be positive by EnhanceAR-Seq developed treatment resistance, and unfortunately these patients were much more likely to die from their disease.”
The findings were published online in JCO Precision Oncology, a flagship journal from the American Society of Clinical Oncology. Chaudhuri shares senior authorship with Christopher Maher, PhD, an associate professor of medicine and assistant director of the McDonnell Genome Institute, and Russell Pachynski, MD, an assistant professor of medicine and a medical oncologist at Siteman. Ha Dang, PhD, an instructor of medicine, and Pradeep Chauhan, PhD, a postdoctoral scholar in radiation oncology, both at the School of Medicine, are lead authors. Chaudhuri, Maher, Pachynski and Dang are Siteman research members.
Second leading cause of cancer death
Prostate cancer is the second leading cause of cancer death in American men, and it is estimated that one in every 41 will die of prostate cancer. The most deadly form of the disease is treatment-resistant metastatic prostate cancer, which grows despite treatment and may not be sensitive to drugs that target the androgen receptor pathway. One way to identify these high-risk patients is by tracking an alteration in the blood called AR-V7.
“Although noninvasive, this previous approach has suboptimal sensitivity, meaning that it missed some patients with treatment-resistant metastatic disease,” Chaudhuri said.
The current research builds on prior work by Chaudhuri, and by Dang and Maher. Chaudhuri previously showed that cell-free DNA-based liquid biopsies can detect minimal areas of cancer that remain, after treatment. Dang and Maher showed that advanced prostate cancers have distinct tumor genomic profiles. Together, they embarked to develop a test combining their expertise, which resulted in EnhanceAR-Seq.
“We believe our strategy significantly advances the field by monitoring the most impactful mutations to predict treatment response while maximizing the patient population that may benefit from EnhanceAR-Seq,” Maher said.
The researchers compared results from EnhanceAR-Seq with the AR-V7 blood test and showed that EnhanceAR-Seq was far more sensitive.
“While the clinical blood test for AR-V7 was an important advancement in the prostate cancer biomarker world, our EnhanceAR-Seq really takes liquid biopsies to the next level,” Pachynski said. “With vastly improved sensitivity and specificity over the current standard-of-care AR-V7 test, we are able to better detect resistance to treatment earlier.”
“EnhanceAR-Seq was good at detecting secondary resistance too,” Chauhan said. “Sensitivity of detection went up further as we monitored some patients over time, suggesting this could really help the clinician.”
The researchers believe that their method, which requires a simple blood draw, could be made even simpler in the future.
“EnhanceAR-Seq could potentially be adapted to urine too, something we are investigating in the lab,” Chaudhuri said.
“Ultimately, our goal with this is to personalize prostate cancer treatment choices at the earliest time points, to improve outcomes for these patients,” Pachynski said. “I see EnhanceAR-Seq as playing an important role, though future studies need to be done to validate our work here and show that it improves clinical decision-making for our high-risk metastatic patients.”
Participant samples were analyzed as part of the “Circulating Tumor DNA (ctDNA) for Early Treatment Response Assessment of Solid Tumors” study (ClinicalTrials.gov Identifier: NCT04354064). This work is supported by the Alvin J. Siteman Cancer Research Fund, National Cancer Institute, Cancer Research Foundation, an American Cancer Society Institutional Research Grant, a Sidney Kimmel Scholar Award, the Galen Hoskin and Dina Wolkoff Giving Fund and the Prostate Cancer Foundation.