Liquid Biopsy Assay May Predict Drug Resistance in Prostate Cancer Patients

NEW YORK (GenomeWeb) – Researchers from the University of Trento in Italy and the Institute of Cancer Research, London have shown that a next-generation sequencing-based assay that evaluates alterations to the androgen receptor genes from prostate cancer patients' blood, may be able to explain why patients with castration-resistant prostate cancer develop resistance to androgen inhibitors.

Reporting the results of a 97-patient study in Science Translational Medicine today, the researchers found that patients without alterations to the AR gene before being started on abiraterone had significantly longer overall and progression-free survival compared to patients with mutations in the AR gene or with copy number gains of AR. In addition, they identified two point mutations associated with the development of resistance.

The study is important because although prostate cancer patients can usually initially be treated with androgen deprivation therapy, the majority eventually progress and develop castration-resistant prostate cancer. Typically, these patients are treated with drugs that inhibit the AR gene, but these drugs are not curative and patients usually develop resistance within one year, according to an accompanying editorial about the study.

"Understanding the molecular events driving this drug resistance is critical and may enable the identification of new therapeutic targets and biomarkers for use in clinical decision-making," the researchers from the University of Washington and Johns Hopkins University wrote in the editorial.

To try and figure out the molecular drivers of resistance, researchers sequenced the entire coding region of the AR gene in 217 plasma samples from 80 patients with castration-resistant prostate cancer who were being treated with the AR inhibitor abiraterone.

Mutations to the AR gene tend to be rare in prostate cancer before primary hormone treatment, but emerge with castration resistance. The researchers wanted to test whether mutations to and copy number gains of AR were associated with resistance to abiraterone. Because obtaining serial biopsy samples would be very invasive and challenging, they settled on a noninvasive approach to evaluate circulating tumor DNA in patients' plasma.

From 97 total patients, they were able to obtain enough ctDNA to evaluate 217 samples from 80 patients.

With regards to load of ctDNA, the team found that pre-treatment samples tended to have less ctDNA than samples analyzed at disease progression. In addition, patients with a lower ctDNA burden tended to have better outcomes.

The team found that 81 of 217 samples from 32 out of 80 patients had a copy number gain to AR. In addition, 41 plasma samples from 16 patients had somatic nonsynonymous mutations to AR.

Overall, patients with either a copy number gain of AR or point mutations to AR fared worse than patients with a normal AR gene. Out of 80 patients, 36, or 45 percent, had either a copy number gain or a point mutation. Those patients were 4.9 times less likely to have a greater than 50 percent decline in prostate specific antigen after being treated with abiraterone and were 7.8 times less likely to have a 90 percent decline in PSA levels.

Patients with normal AR also had significantly longer overall and progression-free survival when compared to patients with an AR gain or point mutation.

In addition, the team was able to identify two point mutations that were not present in patients' baseline samples but that occurred over the course of treatment. Seven patients developed these mutations in the AR gene, which the researchers hypothesized occurred due to selective pressure from the drug.

By contrast, patients with AR copy number gains did not experience any further gains of the gene during treatment.

Other studies have previously supported a link between AR gain and resistance to abiraterone, however, one previous study also found AR gains to be associated with abiraterone sensitivity, the authors wrote. "Future studies may shed light on the explanation for this discordance, including possible genomic differences between prostate tumors and plasma DNA," they wrote.

In addition, they wrote that an expanded sequencing panel might uncover additional mutations that explain abiraterone resistance.

Finally, around 30 percent of patients who did not have an AR copy number gain at progression had developed an AR point mutation, which could be "observed several months before confirmed clinical progression," the authors wrote. "This suggests that analysis of plasma AR could complement other modalities for evaluating CRPC patients and allow early treatment change before overt radiological progression."

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