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Liquid Biopsy-Based Androgen Receptor Alterations Associated With Advanced Prostate Cancer Outcomes

NEW YORK (GenomeWeb) – A team from Sweden, Belgium, and the UK has found evidence that an increasing number of androgen receptor splicing shifts and alterations in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may be promising blood markers for treatment resistance and survival outcomes in advanced prostate cancer patients with TP53 mutation-free tumors.

"Our goal is to create a test that can be used routinely in clinical practice, so that patients can receive more personalized treatment," senior author Johan Lindberg, medical epidemiology and biostatistics researcher at the Karolinska Institute, said in a statement.

"To our knowledge, the data represent the first demonstration of the clinical validity of the 'AR burden' contributed to by multiple [androgen receptor] gene body alterations and/or [AR splice variant] expression occurring during progression of mCRPC under treatment selection pressure," he and his co-authors wrote, noting that "[b]iomarker output from the [androgen receptor] locus appears to be a ubiquitous property of mCRPC."

Based on findings from prior prostate cancer liquid biopsy studies, the researchers suspected that different types of androgen receptor alterations may ultimately turn up in all prostate cancer cases treated with chemical castration and other cancer treatments, prompting a search for several types of androgen receptor-based markers in 109 individuals with TP53-wild type, metastatic, castration-resistant prostate cancer (mCRPC).

For their new analysis, published online today in a research letter in JAMA Oncology, they focused on patients with wild type version of TP53 in their tumors, since alterations in that tumor suppressor gene provide their own prognostic clues.

Using a combination of low-coverage whole-genome sequencing on ctDNA and targeted RNA sequencing on CTCs nabbed by CellSearch, Lindberg and colleagues successfully profiled androgen receptor alterations and splice variants in CTC and ctDNA isolated from baseline blood samples for 80 of the androgen receptor signaling inhibitor-treated mCRPC patients. In more than 61 percent of those cases, the androgen receptor changes identified showed significant ties to decreased progression-free survival.

"Our method can identify patients who are likely to have a poor outcome to these treatments and therefore should be offered other alternatives, if available," first and corresponding author Bram De Laere, a post-doctoral researcher at the Karolinska Institute, said in a statement.

When they dug into patient outcomes in relation to the number androgen receptor perturbations in CTCs or ctDNA, meanwhile, the researchers found that outcomes tended to decline as more of these androgen receptor changes turned up in the blood. In the 16 mCRPC patients with one significant androgen receptor change in the liquid biopsies at baseline, for example, the median progression-free survival time was just over 10 months.

In contrast, the team reported that the 17 individuals with two significant androgen receptor perturbations had progression-free survival that barely surpassed six months, on average, while the presence of three significant androgen receptor shifts coincided with an average progression-free survival time of less than three months in another 16 mCRPC patients. The patients who were androgen receptor perturbation-free at baseline had median progression-free survival times that reached nearly 14 months.

The researchers saw similar risk stratification when they considered survival in relation to the number of androgen receptor changes in liquid biopsy samples from a subset of 57 patients treated with the anti-androgen hormone drug abiraterone (marketed as Zytiga by Janssen Pharmaceutical Companies of Johnson & Johnson) and in 23 patients treated with the hormone therapy enzalutamide (sold as Xtandi by Astellas Pharma and Pfizer). 

"We see that the prognosis is poorest for men with three or more resistance markers in AR," Lindberg said. "This suggests that patients with a normal TP53 gene, without or with a small number of [androgen receptor] resistance markers would benefit more from continued hormonal treatment with medicines such as Zytiga and Xtandi."

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