FROM THE GENITOURINARY CANCERS SYMPOSIUM

ORLANDO – New research indicates that genetic changes over time in circulating cell-free tumor DNA of patients with advanced prostate cancer could help clinicians detect emerging treatment resistance and adjust treatment regimens accordingly. Also, specific genetic changes were associated with worse outcomes, suggesting a role in prognosis for these “liquid biopsies.”

In addition, the genetic changes detected in the 10-mL blood samples were similar to those seen in traditional tissue biopsies, indicating a noninvasive strategy could be a viable alternative in the future.

“Metastatic castration-resistant prostate cancer [CRPC] is incurable with current therapy. We need a better understanding of tumor biology, which probably requires repeated analysis of the tumor cells and somatic DNA,” said Guru Sonpavde, MD, of University of Alabama in Birmingham and lead author of the research presented at the Genitourinary Cancers Symposium. “But repeated DNA analysis in metastatic CRPC patients is difficult – it often requires biopsy of the bones.”

In contrast, circulating tumor DNA testing is noninvasive and not confounded by sampling bias of the biopsy, Dr. Sonpavde said during a press briefing prior to the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Sonpavde and his colleagues analyzed blood samples from 514 people with metastatic castration-resistant prostate cancer. They used a commercially available test to assess the cell-free, circulating tumor DNA (ctDNA) for 73 cancer-related, potentially actionable genes.

An overwhelming majority of patients, 94%, had at least one genetic change. “The most important takeaway is that ctDNA is frequently seen in patients with metastatic castration-resistant prostate cancer,” Dr. Sonpavde said. “So it looks rather promising for studying this tumor with ctDNA assays.”

“Circulating tumor DNA offers a simple and convenient way to assess an individual patient’s tumor DNA composition, and often, it can reveal new mutations clinicians like me can use to personalize therapy,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif. and moderator of the press briefing.

A likely target will be the androgen receptor (AR) gene, which was found in 22% of patients in the study. Other common recurrent somatic mutations occurred in TP53, APC, NF1, EGFR, CTNNB1, ARID1A, BRCA1, BRCA2, and PIK3CA genes, affecting from 36% to 5% of patients. The AR gene was also one of the most commonly amplified genes in the study, with an increase in copy numbers observed in 30% of patients. Increased cancer gene copies can spur an overabundance of proteins that drive cancer growth.

Alterations and outcomes

Investigators also performed a subanalysis of 163 patients for whom they had clinical values and outcome information. “What we found was something interesting,” Dr. Sonpavde said. “A higher number of overall ctDNA gene alterations and AR alterations appeared associated with poor clinical outcomes.”

For example, a higher number of any alterations of the genes on the panel was associated with a shorter time to failure (hazard ratio, 1.05; P = .026). In addition, AR gene changes were associated with a trend for shorter time to failure (HR, 1.42; P = .053) and survival (HR, 2.51), although the survival difference in this instance was not statistically significant (P = 0.09). The investigators also report that treatment-naive patients were less likely to develop AR gene changes, compared with previously treated patient (37% versus 56%; P = .028).

Changes over time could be prognostic

Of the group of patients with outcomes information, 63 underwent serial blood testing. “What we found in this subset is that the evolution of alterations in AR was the most frequent new alteration found,” again underlining its importance as a therapeutic target, Dr. Sonpavde said. Another important implication of emerging mutations is development of treatment resistance and a need to switch individual patients to a more effective treatment.

“New mutations in AR protein are important … because AR is the most common target of hormone therapies for prostate cancer,” Dr. Pal said. “This suggests that developing new agents that target this protein more effectively is certainly a good direction for future research.”

Guiding new treatment targets

An estimated 161,360 men in the United States will be diagnosed with prostate cancer in 2017 and close to 27,000 will die from the disease, according to American Cancer Society Facts & Figures 2017 . Although no treatments are yet Food and Drug Administration–approved to treat prostate cancer based on specific genetic mutations, several therapies are in development. Results from the study could be used to identify novel molecular targets for future therapy, the authors said, provided a prospective, controlled trial confirms that treatment guidance based on the blood test in the study improves patient outcomes.

“In terms of next steps, it would be interesting to look at patients given therapy based on the alterations found, which would help us develop tailored and more efficient medicine,” Dr. Sonpavde said.

Dr. Sonpavde is a consultant/advisor for Bayer, Genetech, Sanofi, Merck, Novartis, Pfizer, Argos Therapeutics and Agensys; a member of the speakers’ bureau for Clinical Care Options/NCCN; receives honoraria from UpToDate; and receives institutional research funding from Onyx, Bayer, and Boehringer Ingelheim. Dr. Pal had no relevant financial disclosures.

op@frontlinemedcom.com

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