“Liquid biopsy” analyses of circulating tumor DNA (ctDNA) from blood samples potentially reveal prognostic information about metastatic castration-resistant prostate cancer (mCRPC), and might point the way for development of new targeted treatments, according to findings presented ahead of the 2017 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida.
The study (abstract 149) found that ctDNA was detected in 94% of patients with mCRPC, with genetic alterations similar to those seen in tumor tissue, reported Guru Sonpavde, MD, of the University of Alabama at Birmingham Comprehensive Cancer Center.
“This ctDNA test is now a valuable research tool to discover new molecular targets,” said Sonpavde, in a press release. “Eventually, it may also serve as a noninvasive alternative to the traditional tumor biopsy in cases where tissue biopsy is not safe or feasible. However, we’ll need a controlled, prospective clinical trial to confirm that selecting treatment based on the molecular information from this blood test improves patient outcomes.”
A higher number of overall gene alterations and androgen receptor (AR) gene alterations appeared associated with poor clinical outcomes.
New AR alterations frequently appeared after therapy, the team found—suggesting that liquid biopsies could detect the early stages of acquired drug resistance and provide insights for the development of new treatments.
A better understanding of mCRPC biology is needed and will likely require repeated analyses of metastatic tumor biology, Sonpavde said. The disease is currently incurable. Noninvasive serial ctDNA analysis is likely to be less confounded by sampling bias than tumor tissue biopsy, which can underestimate tumors’ genetic heterogeneity.
The research team studied ctDNA from 514 patients with mCRPC using the next-generation sequencing Guardant360 blood test, a 73-cancer-gene panel for cell-free ctDNA. The median age of patients was 71 years (range, 39–91 years); 74% had metastatic bone tumors, which can be difficult to biopsy, and 11.7% of patients had visceral metastases.
Mutations were detected in TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR (6%), CTNNB1 (6%), and ARID1A (6%). Gene copy number amplifications were noted for three potentially tumor growth-driving genes: AR (30% of patients), MYC (20%), and BRAF (18%).
Clinical outcome data were obtained for 163 of the patients, among whom a higher number of gene alterations was modestly associated with shorter time to treatment failure (TTF; hazard ratio [HR], 1.05; P = .026). AR alterations might also be associated with shorter TTF and survival but these trends had statistically marginal significance (for TTF: HR, 1.42, P = .053; for survival: HR, 2.51; P = .09). Serial testing through time for 64 patients identified evolution of AR, BRCA1, and BRCA2 mutations following treatment.
Patients who had prior therapy for mCRPC had significantly more new alterations in AR (56% vs 37%; P = .028).
While there are not yet agents approved by the US Food and Drug Administration for treating the identified gene alterations in prostate cancer, Sonpavde noted that these findings suggested that salvage therapy agents that target AR mutations might be a particularly promising avenue of research.
“As we work to tailor treatment to the molecular changes driving the growth of cancer in each patient, these blood tests appear very promising, especially for patients who are unable to undergo a tumor biopsy,” said ASCO Expert Sumanta Pal, MD, of City of Hope in Duarte, California, in a press release.