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Liquid biopsy identifies prognostic factors, therapeutic targets for prostate cancer

Jackey Suen
24 Feb 2017

Research on the role of circulating tumour DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) gains momentum, as a new study finds ctDNA assessment promising in the monitoring and prognosis of mCRPC and in identifying new therapeutic targets for the disease.

The study investigators performed liquid biopsy in 514 patients with mCRPC and found that 94 percent of the patients had gene alterations in ctDNA. [ASCO GU 2017, abstract 149]

The most common somatic mutations were in TP53 (36 percent), androgen receptor gene (AR) (22 percent), APC (10 percent), NF1 (9 percent), EGFR (6 percent), CTNNB1 (6 percent), ARID1A (6 percent), BRCA1 (5 percent), BRCA2 (5 percent) and PIK3CA (5 percent). Meanwhile, the most common genes with increased copy numbers were AR (30 percent), MYC (20 percent) and BRAF (18 percent).

“There are currently no approved prostate cancer treatments that target these alterations, but several are being tested in clinical trials,” said lead author Dr Guru Sonpavde of the University of Alabama at Birmingham, Alabama, US.

The investigators also identified several prognostic factors from ctDNA of 163 patients whose clinical outcomes were available for analysis. “A higher number of ctDNA alterations was associated with shorter time to treatment failure [TTF] [hazard ratio (HR), 1.05; p=0.026]. AR alterations showed a trend for shorter TTF [HR, 1.42; p=0.053] and survival [HR, 2.51; p=0.09],” reported Sonpavde. “New alterations in AR were more frequently observed in previously treated vs treatment-naïve patients [56 vs 37 percent; p=0.028].”

In addition, serial ctDNA profiling of a subset of 64 patients revealed evolution of AR, BRCA1 and BRCA2 alterations following therapy. “These suggest that salvage agents targeting AR alterations and PARP inhibition may hold promise in mCRPC treatment,” noted Sonpavde.

Notably, the genetic alterations identified in ctDNA testing were similar to those previously reported in analyses of tumour tissue specimens, suggesting that ctDNA testing may be a viable alternative to tissue biopsy. The test can also be performed regularly to look for the emergence of treatment resistance necessitating switch of medications.  

Guardant360, the liquid biopsy test used in this study, requires only two teaspoons of blood and examines changes in 70 cancer-related genes.

“This is one of the largest clinically annotated datasets looking at ctDNA in metastatic prostate cancer,” commented ASCO expert Dr Sumanta Pal from City of Hope Cancer Center in Los Angeles, California, US. “As we work to tailor treatment to the molecular changes driving cancer growth in each patient, these blood tests appear very promising, especially for those who are unable to undergo a tumour biopsy.”

“ctDNA testing is now a valuable research tool to discover new molecular targets,” said Sonpavde. “Eventually, it may also serve as a noninvasive alternative to traditional tumour biopsy. However, we will need a controlled, prospective clinical trial to evaluate if there is improvement in patient outcomes with treatment selection based on the molecular information from ctDNA.”

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