1. Carlson, Robert H.

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Metastatic castration-resistant prostate cancer is a heterogeneous disease, and single site biopsies hardly represent its diversity.

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But tumor heterogeneity itself is being developed as a predictive biomarker of sensitivity for agents that target the androgen receptor pathway, a known driver of resistance in patients who progress on standard androgen deprivation therapy. At the Genitourinary Cancers Symposium 2016, a researcher from Memorial Sloan Kettering Cancer Center described a test using single circulating tumor cell (CTC) characterization to identify phenotypic and genomic heterogeneity, in order to predict response to abiraterone and enzalutamide (Abstract 163).


"Not all men respond equally to either enzalutamide or abiraterone, and some men don't respond at all. If the test is validated, it could be used to help select the treatment to which a patient is more likely to respond, sparing the toxicities that may result from one that is ineffective," lead author Howard I. Scher, MD, Chief of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, said in a presscast before the meeting

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CTC Heterogeneity

Patients with advanced disease have heterogeneous clonal CTC populations that harbor different genetic alterations. The test described here takes advantage of the fact that prostate cancer becomes more complex over time as the disease evolves and the genetic diversity increases.


Scher said CTC heterogeneity was analyzed on a cell-by-cell basis using a no-selection platform at the single-cell level for morphology, protein chemistry, and genomics. The technology is from Epic Sciences.


"This works very much like facial recognition software used at airport security," Scher said.


The study focused on 221 samples from 179 patients with metastatic prostate cancer about to begin either hormonal therapies targeting the androgen receptor (enzalutamide or abiraterone) or taxane chemotherapy.


Patients with higher heterogeneity scores-more variation in CTC appearance and genetic make-up-did not respond well to hormone therapy, the researchers found.


"Compared to patients with a low heterogeneity score, patients with a high heterogeneity score experienced shorter median progression-free survival-five months versus 17 months-and shorter overall survival while on androgen-receptor inhibition therapy," Scher reported.


As well, patients with high heterogeneity scores had a median overall survival of nine months, while median survival had not been reached in the group of men with low heterogeneity.


In contrast, heterogeneity scores did not appear to affect patients' response to taxane chemotherapy, Scher said. This suggests that patients likely to fail anti-androgen therapies but potentially benefit from chemotherapy can be identified, he said.


Comments on Report

ASCO spokesperson Sumanta Pal, MD, moderator of the presscast and Assistant Professor and Co-Director of Kidney Cancer Program at City of Hope, commented: "We've always relied on a patient's tumor to get genetic information, but that can be incredibly complicated because tumors may be difficult to access such as when they are embedded in bone, and because repeated biopsies to assess serial changes in tumor are painful for the patient.


"We have a number of new treatments for advanced prostate cancer but right now we have little means of personalizing therapy and offering the right treatment to the right patient. If this modality is validated, we would have this personalized selection tool in our hands."


The study received funding from the Prostate Cancer Foundation, MSKCC SPORE, and MSKCC Core Grant.


The Genitourinary Cancers Symposium 2016 is sponsored by the American Society for Radiation Oncology, American Society of Clinical Oncology, and the Society of Urologic Oncology.