Liquid Biopsy Paves Way for Personalized Selection Tool in Prostate Cancer

Howard I. Scher, MD

Despite numerous advances in androgen receptor (AR) therapies to treat patients with metastatic castration-resistant prostate cancer (mCRPC), resistance continues to challenge clinicians, but a blood test that analyzes circulating tumor cells (CTCs) may hold promise.

The non-invasive liquid biopsy, if validated, could lead to the development of a personalized selection tool in men with advanced prostate cancer. CTCs are released both from the original tumor site, as well as from areas where the cancer has metastasized. Prior research has shown that individual patients have a range of different kinds of CTCs.

Howard I. Scher, MD, and researchers measured 221 blood samples taken from 179 men using the Epic Sciences platform to develop biomarkers of heterogeneity. Historically, after primary treatment with either abiraterone or enzalutamide, the response to either agent is decreased over time, as is the duration of response. Next-generation sequencing (NGS) of mCRPC shows a range of disease phenotypes and genotypes that are associated with increased tumor heterogeneity.

“To improve patient outcomes requires the ability to characterize the biology of an individual patient’s tumor when the decision about a particular therapy is being made,” said Scher during a presscast ahead of the 2016 Genitourinary Cancer Symposium, January 7 to 9, 2016 in San Francisco, California.¹

Scher, who is chief of the Genitourinary Oncology Service at the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan Kettering Cancer Center, collected samples of men treated with AR therapies (n = 150) or taxanes (n = 71), which were analyzed for 20 discrete phenotypic cell features including AR, anti-cytokeratin (CK), size, and shape. The researchers reported that more than 9000 CTCs were analyzed for frequency and heterogeneity, with phenotypic features clustered and categorized into 15 distinct subtypes.

In addition, a subset of CTCs (n = 350) were analyzed and assessed for clonality, gene amplification, and deletion, to help assess genomic heterogeneity. These characteristics were combined and assigned a diversity measure called a Shannon Index.

Results suggest that a diversity of CTC phenotypes were observed for each therapy. The researchers noted that patients with a higher heterogeneity score did not respond well to hormone therapies. Compared with patients who had a low heterogeneity score, patients with a high score had a shorter median progression-free survival (5 months versus 17 months) and overall survival (9 months versus not reached). In contrast, heterogeneity scores were not associated with taxane resistance, the researchers noted.

The blood test involves placing a specimen onto a glass slide and staining it with special dyes to distinguish normal blood cells from CTCs. A machine then scans the slide and analyzes the various features of the CTCs, such as size and shape. Researchers can then select individual cells of interest, pick them up from the slide, and perform an analysis of genetic abnormalities.

In the study, Scher and colleagues were able to demonstrate that single-cell morphology and protein and genomic characterization are feasible and can be used to assess tumor heterogeneity.

“Heterogeneity measures increased by line of therapy,” said Scher. “A higher heterogeneity index was associated with shorter survival times for patients administered abiraterone and enzalutamide. In contrast, heterogeneity scores did not appear to affect patients’ response to taxanes.”

“We have usually relied on a patient’s tumor to obtain genetic information, but that can be complicated for a number of reasons,” said the moderator of the presscast, Sumonta Pal, MD. “Patients with advanced prostate cancer can have tumors in areas [of the body] where it is difficult to obtain a sample. 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,” continued Pal, assistant clinical professor, Department of Medical Oncology and Therapeutics Research, and co-director, Kidney Cancer Program at City of Hope.

Using this liquid biopsy modality, the researchers 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 Pal.

“They also collected data pertaining to the types of treatment patients received,” continued Pal. “In this manner, they were able to link certain CTC characteristics to response, or lack or response, to specific therapies.”

Pal noted that the findings hold “incredible value because we have little means of personalizing therapy in offering the right treatment to the right patient. This study, which uses the liquid biopsy modality, could be a way to develop this personalized selection tool.”

1. Scher HI, Graf R, Louw J, et al. Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies (AR Tx) in mCRPC patients. Presented in press cast of the 2016 Genitourinary Cancers Symposium; San Francisco, CA; January 7-9, 2016. Abstract 163.

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