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Researcher Hopes Liquid Biopsies Will Make Mark in Prostate Cancer

Gina Columbus @ginacolumbusonc
Published: Monday, Nov 21, 2016

Howard I. Scher, MD

Howard I. Scher, MD

How oncologists can translate their increased understanding of the biology of prostate cancer into clinical practice is a question being raised currently in the field, explains Howard I. Scher, MD, adding, that the emergence of liquid biopsies could possibly be one way to tackle the issue.

“Over the past few years, we have learned that there are distinct molecular subtypes of prostate cancer for which certain drugs are available,” says Scher, chief of Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center. “Some are already approved and others are in development. The issue that we have learned is that an individual’s cancer changes biologically as it progresses and will also change differently, depending on what particular treatments have been given.”

Scher spoke on predicting sensitivity to prostate cancer treatment in a presentation during the 2016 OncLive State of the Science Summit on Genitourinary Cancers. In an interview, he explains the biology known thus far about multiple prostate cancer subtypes and how liquid biopsies will likely shape the future treatment landscape of the disease.

OncLive: What are the current challenges with predicting response to treatment?

Scher: We know that androgen receptor (AR)¬–directed therapies, when given the first time, work very well. However, when you go from 1 to the other, the response rate is significantly lower. Most patients don’t respond well, but there is a subset for which it does work well. The question is, “How do we identify those patients ahead of time so they benefit?” How do we identify the patients unlikely to benefit, so they will be spared of the toxicity and cost of treatment?

If we look at the genetics of prostate cancers from patients who are first diagnosed with tumors localized to the prostate versus those with metastatic disease, and we look at the metastatic lesion in addition to the primary site—or we look at patients with metastatic castration-resistant prostate cancer (mCRPC)—we see that the frequency and types of changes are very different.

If we are focused on mCRPC, it is imperative that we study the cancer at the time we are making a decision to choose drug A versus drug B versus drug C. In many tumors, this is done via a biopsy of a metastatic lesion, but the most common metastatic spread is to the bone in prostate cancer. Here, the ability to do consistent molecular profiling is actually quite low. Our experience using directed biopsies, where we know exactly where the lesion is, is only about 50%. It’s an invasive procedure and is costly. If a patient has 10 individual lesions, they are not all biologically the same. Inadvertently, we may biopsy a lesion, identify a specific gene or pathway, and that pathway is not the key driver of the resistant cell population.

A number of us have been focusing on what has been categorized as the liquid biopsy. Obviously, taking a blood test is much easier than biopsying a metastatic lesion. There are a number of different tumor products that can be identified in blood. These include circulating tumor cells (CTCs), DNA, and RNA from tumors, and vesicles called exosomes that contain DNA, RNA, and protein, which help you characterize the disease.

Our focus has been primarily on CTCs and there are 2 techniques used. One is called a capture, or selection, method where you will use an antibody to capture cells that express the particular target of that antibody and then characterize in different ways. You can look at it on a slide, visually in a chamber, or deposit it on a slide.

The method that we are most recently using is called a nonselection method where you take a blood sample, deposit the cancer cells on a slide, perform various stains, and use software that can identify and localize each of the cancer cells present. This is the technology developed by Epic Sciences.

With this technology, we have been studying a protein made by the AR-V7 splice variant. The AR loses the portion of the protein that binds testosterone and the antiandrogen such as enzalutamide (Xtandi) or bicalutamide (Casodex), which inhibit its function. When the AR-V7 splice variant is present, it alone can drive the cancer without a ligand. The AR-V7 encodes for a protein that you can identify in cells. It can also do a pathological complete response reaction to identify the gene.

What we have been focusing on is looking at cells where AR-V7 is present and looking at patients who are first progressing on hormones, those who received 1 first-generation hormonal agent, and patients who had 2 of the life-prolonging agents. By drawing blood at each of these time points, we have seen the frequency of this splice variant is relatively low in the first-line setting. It gets higher with each course. Each time we identify it, the patients treated with AR-signaling directed therapy do not respond.

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