'Liquid Biopsy' May Help Guide Treatment in Prostate Cancer

Roxanne Nelson, BSN, RN

January 05, 2016

The idea of using circulating tumor cells (CTCs) as a "liquid biopsy" to monitor treatment and assess outcomes has been gaining ground in cancer research over the past few years, and a new study shows how this could be very useful in prostate cancer.

"In prostate cancer, in particular, performing routine biopsies in metastatic disease is not part of routine practice," said lead investigator Howard I. Scher, MD, a medical oncologist and chief of the genitourinary oncology service at the Memorial Sloan Kettering Cancer Center in New York City. And yet, he pointed out, "to improve patient outcomes requires the ability to characterize the biology of the individual patient's tumor when a treatment decision is being made."

The study shows that analyzing single cells from patients with metastatic castration-resistant prostate cancer (CRPC) is feasible and can be used to assess tumor heterogeneity, Dr Scher explained during a press briefing held in advance of the Genitourinary Cancers Symposium 2016 in San Francisco.

Therapies targeting the androgen receptor and androgen-receptor signaling, such as abiraterone acetate (Zytiga, Janssen) and enzalutamide (Xtandi, Astellas), and taxane-based chemotherapies prolong survival in patients with CRPC. However, the optimal sequence for administering them to maximize survival for an individual is not known, Dr Scher noted.

"When used sequentially, the response to enzalutamide after abiraterone acetate or abiraterone after enzalutamide is generally of shorter duration and less frequent," he explained. The information from the CTC provides information on tumor heterogeneity that could be useful in making decisions about which therapy to use when.

High Heterogeneity, Shorter Survival

In their study, Dr Scher and his colleagues studied heterogeneity in CTCs on a cell-by-cell basis, with the goal of developing predictive biomarkers of sensitivity that could be used at decision points in treatment management to better sequence available therapies.

The team looked at 221 blood specimens from 179 patients with metastatic CRPC who were about to begin therapy with either enzalutamide or abiraterone therapy (n = 150) or taxane chemotherapy (n = 71).

The samples were analyzed for 20 discrete phenotypic cell features. The 9225 single CTCs were characterized into 15 phenotypically distinct CTC subtypes. A subset of 741 CTCs from 31 patients was also individually sequenced.

"CTCs were analyzed, using a known selection platform at the single-cell level, for morphology, protein chemistry, and genomics, which can be considered similar to facial recognition that is often used to identity specific individuals," said Dr Scher.

Individual patient samples were then analyzed for the frequency and heterogeneity of CTC subtypes and monitored for clinical end points. Samples were ranked on the basis of the cell's heterogeneity or diversity.

The investigators determined that high CTC phenotypic heterogeneity predicted shorter survival time in patients treated with abiraterone or enzalutamide, but not taxane chemotherapy (docetaxel or cabazitaxel). Median radiographic progression-free survival was shorter in patients with a high heterogeneity score than in those with a low heterogeneity score (5 vs 17 months; hazard ratio [HR], 2.2; P = .00182), as was overall survival (9 vs not reached; HR, 5.51; P < .0001).

Dr Scher noted that clinical trials to validate these findings are currently in development.

Tools in Hand

"This is really fascinating work," said presscast moderator Sumonta Pal, MD, from the City of Hope Comprehensive Cancer Center in Los Angeles. "We have usually relied on a patient's tumor to obtain genetic information, but that can be complicated for a number of reasons."

"First, patients with advanced prostate cancer can have tumors in areas where it is difficult to obtain a sample, such as a tumor embedded in bone," Dr Pal explained. "We also think that tumors change over time, and sticking a needle into a tumor repeatedly to ascertain those changes is painful to the patient."

Dr Scher and his team also showed that prostate cancer appears to become more complex over time as the disease evolves. "The genetic diversity increases, potentially suggesting that the cancer cell is crafting machinery to resist treatment," said Dr Pal. "The team also collected data pertaining to the types of treatment patients received and, in this manner, they were able to link certain CTC characteristics to response, or lack of response, to specific therapies."

He added that these findings are of "incredible value because we have a number of new treatments for advanced prostate cancer that right now have little means of personalizing therapy in offering the right treatment to the right patient."

"With the study that Dr Scher has proposed, which could potentially validate this modality, we would have this personalized selection tool in our hands," said Dr Pal.

This study received funding from the Prostate Cancer Foundation, MSKCC SPORE, and MSKCC Core Grant. Dr Scher reports serving in a consulting or advisory role for AstraZeneca, Astellas Pharma, Bristol-Myers Squibb, Endocyte, Ferring, Genentech, OncologySTAT, Palmetto GBA, Pfizer, Sanofi, Takeda, Ventana Medical Systems, WIRB-Copernicus Group, Medivation, BIND Therapeutics, Janssen, Chugai Pharma, Blue Earth, and Med IQ; being on the speakers' bureau for WebMD; receiving travel, accommodations, and/or expenses from Janssen Pharmaceuticals, Sanofi, Endocyte, AstraZeneca, Genentech, Bristol-Myers Squibb, Pfizer, Takeda, Ferring, WIRB-Copernicus Group, Astellas Pharma, BIND Therapeutics, Celgene, and Medivation; receiving research funding (institutional) from BIND Biosciences, Exelixis, Janssen Pharmaceuticals, Medivation, Janssen Diagnostics, and Innocrin Pharma. Several coauthors report relationships with industry. Dr Pal reports receiving honoraria from Astellas, Pharma, Medivation, and Novartis; serving in a consulting/advisory role with AVEO, Genentech, Myriad Pharmaceuticals, Novartis, and Pfizer; and receiving research funding from Medivation.

Genitourinary Cancers Symposium (GUCS) 2016: Abstract 163: To be presented January 7, 2016.

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