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Liquid biopsies identify potential new treatment targets for advanced prostate cancer
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A liquid biopsy test identified a number of genetic changes in cell-free circulating-tumor DNA of patients with advanced prostate cancer, according to a study scheduled for presentation at the Genitourinary Cancers Symposium.
This test could potentially allow clinicians to adjust treatments faster and more efficiently, researchers said.
Assessing cell-free circulating-tumor DNA (ctDNA) through a “liquid biopsy” — a noninvasive alternative to traditional tumor biopsies — provides comprehensive information about genetic changes in a tumor and can be drawn from just two teaspoons of a patient’s blood.
“The most important takeaway from our study is that changes in ctDNA are frequently seen in patients with metastatic advanced cancer,” Guru Sonpavde, MD, associate professor of medicine at University of Alabama in Birmingham, said during a press conference. “It’s seen in 94% of our patients, so it looks rather promising for studying tumors with ctDNA assays, which would be much easier than performing repeated bone biopsies of metastatic sites.”
Evaluating tumor DNA through traditional biopsies can be “enormously challenging,” according to Sumanta Pal, MD, associate professor of medical oncology at City of Hope Comprehensive Cancer Center, ASCO expert, and a HemOnc Today Editorial Board member.
“Biopsies are especially challenging in prostate cancer, where most of the disease sits in bone,” Pal, who was not involved with the study, said during the press conference. “Bone biopsies can be expensive, painful and also risky, with bleeding and other complications. Furthermore, the yield of tumor tissue from these biopsies can be quite low.”
Sonpavde and colleagues analyzed cell-free ctDNA from 514 patients (median age, 70 years; range, 39-91) with metastatic castration-resistant prostate cancer using Guardant360 (Guardant Health). The blood test examined changes in 70 cancer-related genes.
Researchers explored the association between DNA changes and clinical outcomes in 163 patients, of whom 28.8% (n = 46) were untreated for their disease. Additionally, researchers explored how genomic changes evolved over time in 64 patients who underwent periodic blood tests.
Nearly all patients (94%) had at least one change detected in ctDNA. A higher number of genetic changes, including changes in the androgen receptor gene (AR), were associated with shorter time to failure (HR = 1.42) and poorer survival (HR = 2.51), although the association with OS was not statistically significant. Patients with a higher number of changes had shorter time to treatment failure (HR = 1.05; P = .026).
The most common recurrent somatic mutations were in TP53 (36% of patients); AR (22%); APC (10%); NF1 (9%); EGFR, CTNNB1 and ARID1A (6% each); and BRCA1, BRCA2 and PIK3CA (5% each). The most common genes with increased copy numbers — which can lead to an overabundance of proteins that drive cancer growth — were AR (30%), MYC (20%) and BRAF (18%).
A greater proportion of patients who received prior therapy had new alterations in AR (56% vs. 37%; P = .028). Periodic ctDNA profiling revealed the evolution of alterations in AR, BRCA1 and BRCA2 following therapy.
“Treatments such as chemotherapy and advanced hormone therapy tend to only slow down the worsening of disease,” Pal said. “Circulating-tumor DNA offers a simple and convenient way to assess an individual’s tumor DNA composition and, often, it can reveal new mutations that clinicians can use to personalize therapy. For example, BRAF is typically associated with melanoma, and there are approved drugs that are used in melanoma that can target this mutation. Perhaps there might be some relevance for these agents in certain types of prostate cancer that bear these same mutations.”
Sonpavde and colleagues concluded that ctDNA was frequently detected in patients with metastatic castration-resistant prostate cancer and these alterations appeared similar to those found in tumor tissues, carrying an association with poor clinical outcomes. These data suggest that developing salvage agents targeting AR alterations, in addition to PARP inhibitors, hold promise.
“Data of the AR alterations appearing to be associated with poor outcomes and the frequent evolution of AR alterations that underwent ctDNA assays really suggest that it might be promising to keep looking at new drugs targeting these AR alterations,” Sonpavde said. “As far as next steps, it would be interesting to look at patients who receive drugs based on the alterations found in these patients. That would help us develop tailored medicine and precision medicine.” – by Chuck Gormley
Disclosure: Sonpavde reports consultant/advisory roles with Agensys, Argos Therapeutics, Bayer, Genentech, Merck, Novartis, Pfizer, Sanofi; a speakers bureau role with Clinical Care Options/NCCN; honoraria from UpToDate; and research funding from Bayer, Boehringer Ingelheim and Onyx. Please see the abstract for a list of all other researchers’ relevant financial disclosures.