Liquid Biopsies in Prostate Cancer: Ready for Prime Time?

Beltran and Lab
(From L to R) Dr. Himisha Beltran, Dr. Raymond Pastore and Dr. Bishoy Faltas

Recent studies in advanced prostate cancer have identified emerging treatment targets and mechanisms of treatment resistance. At the 2017 European Society of Medical Oncology (ESMO) Annual Meeting, Dr. Himisha Beltran chaired and moderated a session evaluating the use of liquid biopsies – blood tests used to glean information about tumors – as a useful clinical tool for prostate cancer management.

While there are no formal guidelines on who, when, how and what to test for in prostate cancer, Dr. Beltran’s expertise provided important guidance to the global oncology community on this topic, as the prospect that a blood test might reveal many insights about the cancer and the tumor makeup has led oncologists to feel excited. Several steps are still needed for broad clinical implementation.

As tumors grow, some of their cells may enter into the bloodstream. These cells are known as circulating tumor cells (CTCs) and travel throughout the body along with fragments of tumor cell DNA known as circulating tumor DNA (ctDNA). Compared with traditional biopsies which extract tissue directly from the tumor, liquid biopsies offer a less invasive way for doctors to detect molecular biomarkers and learn more about what’s going on with someone’s cancer. Liquid biopsies can also better capture tumor heterogeneity, as CTCs and ctDNA can provide a window into the entire tumor (and metastatic sites), compared with a traditional biopsy in which typically only one part of the tumor is sampled. Thus, with a simple blood test, doctors can potentially access a more comprehensive view of an individual’s cancer, which can then help them determine the best treatment for that person. Blood testing can also be more easily repeated throughout the course of treatment in order to monitor disease changes in response to therapy, so liquid biopsy offers ways to detect treatment resistance and resistance mutations early on and throughout the course of the disease.

Red Blood Cells

There is an emerging role for molecular testing in advanced prostate cancer since this information can better inform treatment decisions involving targeted therapies, such as PARP inhibitors, platinum-based chemotherapy, and immunotherapies. Liquid biopsies such as ctDNA may provide information about the genomic alterations present in the cancer, which can be used to help predict how people might respond to certain therapies.

Through liquid biopsies, physicians and researchers can also better detect signs of therapy resistance that may be emerging. For example, if a patient has a gene amplification or mutation detected in ctDNA that involves the androgen receptor (AR) gene, or AR splice variants expressed in CTCs, this may indicate that potent AR-targeted therapies may be less likely to work. This is because the cancer cells may develop various ways to reactivate androgen receptor signaling by acquiring extra copies of the AR gene (gene amplification), activating AR mutations, and/or AR splice variants (such as the AR-V7 variant), all of which result in downstream over-activity of the AR-pathway. Knowing this information up front may spare people from the side effects from a treatment likely to be ineffective. Current research is focused on developing more effective AR pathway inhibitors in this setting. CTCs may also identify other features of the cancer such as localization of the AR in response to taxanes as observed in the TAXYNERGY trial, tumor heterogeneity, and expression of emerging therapeutic targets.

Through a grant from the Prostate Cancer Foundation (PCF), Dr. Beltran and colleagues at WCM are working as part of an international consortium to develop, validate, and implement a ctDNA platform for prostate cancer. This targeted genomic sequencing test, called PCF SELECT, identifies tumor mutations in ctDNA from metastatic prostate cancer patients to guide treatment selection based on precision medicine. It is currently undergoing centralized development, and the long-term goal is that this ctDNA test will be widely used by the clinical prostate cancer community for precision medicine applications.

While liquid biopsies do have promise for these indications and can help guide decisions on the most appropriate treatments for prostate cancer patients, it is important that both patients and clinicians understand the advantages and limitations of available and emerging technologies. Undergoing treatment at a center of excellence that contributes to research on emerging trends allows individuals the opportunity to be among the first to access cutting-edge technologies that may benefit them.

New Clinical Trial Open for Men with Prostate Cancer

lab-researchProstate cancer grows and spreads via the androgen receptor (AR) pathway. In the beginning of treatment, most men with prostate cancer respond to androgen deprivation therapy (ADT) which cuts off this pathway. Unfortunately, the tumors are smart and evolve to create work-arounds. As a result, most men become resistant to this treatment. We call this later, more evolved form of prostate cancer, castration-resistant prostate cancer (CRPC), as it is molecularly different from the initial tumor.

taxane-figure-with-backgroundTaxane chemotherapies – docetaxel and cabazitazel– are the only treatments to demonstrate a survival benefit in men with CRPC. At Weill Cornell Medicine and NewYork-Presbyterian, we have shown that the mechanism of docetaxel taxane action in prostate cancer is inhibiting the androgen receptor pathway on the cellular level by preventing the cancer cells from being able to communicate with other cancer cells using microtubules. Dr. Scott Tagawa explains our prior research in the below video. This suggests that docetaxel may complement other therapies that target the AR pathway, including hormonal-based therapies such as ADT.

Recent trials of docetaxel plus ADT validated our scientific findings, demonstrating very impressively significant improvement in survival in men with metastatic prostate cancer who had not previously received hormonal therapy (also known as hormone-naïve metastatic prostate cancer). Taken together, these studies in both hormone-naïve and CRPC suggest that combining drugs that independently target AR signaling (what the scientific literature refers to as forming a “vertical pathway blockade”) will be more effective than sequentially using these treatments to combat the spread of the cancer.

Our recently-opened phase I study combines the approved 1st line taxane chemotherapy (docetaxel), approved potent inhibitor of testosterone production (the CYP17 inhibitor abiraterone) and a novel AR signaling inhibitor (apalutamide) in men with chemotherapy-naïve metastatic CRPC.

We hypothesize that combining these three agents that all target the same pathway using different mechanisms will result in a synergy that leads to improved cancer outcomes. We previously reported the safety and initial efficacy results of docetaxel plus abiraterone in a multicenter study. The combination was well tolerated and the preliminary efficacy results were promising, confirming the enthusiasm in the prostate cancer community to explore “early” chemotherapy combined with AR-targeted therapy for mCRPC.

As in all phase I clinical trials, there are two aims to this study. The first will provide safety and preliminary efficacy data on this combination treatment. Additionally, we will be performing molecular analysis of blood/tumor samples to identify biomarkers that are able to help predict which patients are most likely to respond to treatment, as well as to determine why some cancers become resistant to treatment. This would allow us to develop biomarker-driven clinical trials that have the potential to shift the treatment paradigm and improve outcomes for men with advanced PC.

To learn more about this clinical trial or to make an appointment with a physician in the Weill Cornell Genitourinary (GU) Oncology program, please call 646.962.2072.

6 Myths About Chemotherapy

Scott Tagawa, M.D.

dr-scott-tagawaChemotherapy often gets a bad rap due to the perception that the side effects of this cancer treatment are severe. What many people don’t know is chemotherapy refers to an umbrella category for different medications that work in a similar way. Just as different cancers are unique, chemotherapies are also unique and use different formula compounds. They also have brand and generic names.

I want to dispel some of the things I hear from patients about chemotherapy. Here are 6 of the most common chemo myths and misconceptions:

  1. It doesn’t work. False! While new cancer treatments are continuously being researched and developed, chemo remains the treatment gold standard for many types of cancers – including testicular cancer and metastatic prostate and bladder cancers – because it works. Through rigorous research, chemo has been shown to improve survival and increase the cure rates for many cancers, especially genitourinary (GU) cancers. Testicular cancer now has an approximately 99% cure rate which was not possible before chemotherapy. Additionally, chemotherapy increases the cure rates for bladder cancer and was more recently shown to have one of the most significant increases in survival compared to any other prior therapy for prostate cancer. Unfortunately, chemo doesn’t always work on every single type of cancer. In addition to the development of novel therapies, work is ongoing to help us select patients that will have more or less benefit from chemotherapy.
  2. It has significant side effects. This is partially true depending on what type of chemo you’re taking and what you perceive to be a negative side effect. Some chemotherapies cause hair loss as they attack the cancer cells, and this is one of the most “visible” side effects of treatment. What many people don’t realize, however, is that chemo can make patients feel better almost immediately because of its ability to control the cancer. For example, the first chemotherapy approved for prostate cancer (mitoxantrone) was approved because it made men feel better. The next generation chemotherapy (docetaxel) made men feel even better when compared to mitoxantrone. Moreover, the impact chemo has on quality of life is often short-term. Longer term, patients who undergo chemo report feeling better. A recently presented study showed that while overall quality of life was worse at an early time point during chemotherapy, men with metastatic prostate cancer had a superior quality of life a year later. This is likely due to the combination of better long-term cancer control and the fact that most chemo-related side effects are temporary. Additionally, while new treatment options, including immunotherapies, hold promise for many types of cancers, these do not work for everyone and are not without side effects either.
  3. It isn’t a one-size-fits-all approach. There are over 200 types of chemotherapies, each differing in function and specific use. For example, platinum-based chemotherapies are mainly used for bladder cancers while taxanes are used for prostate cancer.
  4. It isn’t a targeted treatment. Chemo is targeted in certain ways because it acts on specific receptors. For example, taxanes, which are one type of chemotherapy agent, have the ability to stop cells from growing by targeting structures inside the cell that help it multiply. In prostate cancer specifically, taxanes kill cancer cells by blocking the movement of specific receptors that promote cancer growth. At Weill Cornell Medicine and NewYork-Presbyterian, we are able to analyze the tumor for genomic mutations that can tell us whether you are more or less likely to respond to this type of treatment.
  5. It is painful. When you are receiving cycles of chemotherapy, it should not hurt. Some patients receive chemo through an IV (intravenously), while other chemos are given as oral medications that you can take at home. Most genitourinary cancer patients undergo treatment on an outpatient basis. If you experience discomfort, burning, or coolness speak to your nurse or another member of your cancer healthcare team.
  6. Chemo suppresses the immune system. I commonly hear this from patients as a reason to avoid chemo. While there is an infection risk associated with chemotherapy if blood counts are low, current data indicates that combining chemo with immunotherapy (either together or sequentially with one followed by the other) may be better than immunotherapy alone.

Oncologists and researchers are always looking for the best treatment options to bring cures to the greatest number of cancer patients. For many patients, chemo remains the best option at controlling the cancer growth and ultimately curing the cancer. For some patients, newer approaches such as immunotherapy or other biologic agents are more tailored to fighting their disease. At Weill Cornell Medicine, we continue to work on identifying which chemotherapy is best for the right tumor in the right patient at the right time, as well as developing strategies to deliver chemotherapy preferentially to tumors (sparing normal organs), and continuing to develop new immunotherapies and biologic-based approaches to treatment.