NEW YORK (Reuters Health) - Expression of androgen-receptor splice variant 7 (AR-V7) on circulating tumor cells (CTC) is associated with superior survival on taxane therapy versus androgen receptor signaling (ARS)-directed therapies in men with castration-resistant prostate cancer, researchers report.
"The need for a predictive test to guide treatment selection has been an unmet need for a long time," Dr. Howard I. Scher from Memorial Sloan Kettering Cancer Center in New York City told Reuters Health by email. "The data presented shows the high specificity of a test result showing the presence of AR-V7 in CTC and the lack of response (insensitivity) to ARS-directed therapies, and the survival advantage provided by the use of taxane."
In previous reports, AR-V7 expression was associated with resistance to ARS inhibitors but did not predict response to taxanes.
Dr. Scher and colleagues investigated the association between pretherapy detection of AR-V7-positive CTCs with line of therapy and objective outcomes following treatment with ARS inhibitors and taxanes in 161 men with metastatic castration-resistant prostate cancer.
The frequency of AR-V7-positive CTCs increased from 3% prior to first-line therapy to 18% prior to second-line therapy and 31% prior to third- or subsequent lines of therapy, the team reports in JAMA Oncology, online June 4.
As previously reported, AR-V7 expression on CTCs was associated with worse outcomes, including shorter radiographic progression-free survival (rPFS), shorter time on therapy, and shorter overall survival in men treated with ARS inhibitors.
In contrast, among men treated with taxanes, time on therapy and rPFS did not differ by pretherapy AR-V7 status, but overall survival was worse for those with AR-V7-positive CTCs than for those with AR-V7-negative CTCs.
Men with AR-V7-positive CTCs had significantly longer median survival with taxanes (8.9 months) than with ARS inhibitors (4.6 months), even though taxanes tended to be administered later and when disease burdens were greater.
Men with AR-V7-negative CTCs had similar outcomes after ARS inhibitors and taxanes.
"Every patient harboring AR-V7-positive CTCs was resistant to treatment with ARS inhibitors, including 3 patients with AR-V7 positivity only on CK-negative CTCs, cells not detectable with EpCAM-based CTC capture method including the previously reported AR-V7 mRNA transcript detection approaches," the researchers note. "In contrast, no association between AR-V7 positivity and PSA response to taxane-based therapy was observed."
Taken together," they conclude, "our results, and those of others, suggest that patients in whom AR-V7-positive CTCs are detected would be better served with an approved taxane over abiraterone or enzalutamide."
"Of particular importance was the demonstration of clinical utility - the clinical benefit (superior outcome) for the patient by using the test result to inform the decision incorporating the test result relative to non-use of the test result," Dr. Scher said.
"It bears emphasizing that patients with AR-V7-positive CTCs were not more sensitive to taxane than AR-V7-negative tumors, but the authors appropriately underscore that it is the ability of the assay to direct patients away from ineffective therapy that has the greatest potential for benefit," write Dr. R. B. Montgomery and Dr. Stephen R. Plymate from the University of Washington, Seattle, in an accompanying commentary.
"If the differences in response to taxanes in the study by Scher et al are confirmed in prospective trials, then AR-V7 protein in CTCs will provide an extremely useful positive response biomarker for taxane treatment," the editorial concludes. "Ultimately, this article presents further evidence that AR-variant expression in CTCs may be an important marker to direct therapy and potential targets for therapeutic intervention."
SOURCE: http://bit.ly/1XaL0yi and http://bit.ly/1XF3Fn0
JAMA Oncol 2016.
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