Category: Prostate Cancer

The Cancer Conundrum: To Screen or Not to Screen?

For many cancers, the value of screening is well established. As the saying goes, “knowledge is power” and early diagnosis is usually linked with better outcomes. For prostate cancer, this topic has been more controversial. That’s because many of the tumors we discover through screening are what we call indolent tumors – prostate cancers that may never lead to symptoms or require treatment in their lifetime.

The men who are diagnosed with slow growing prostate cancers can potentially be harmed by the label, particularly if they undergo treatment and have long-term side effects as a result.

We have a number of different screening tools available to both detect the presence of prostate cancer and distinguish between the sub-types that don’t require treatment versus those that need to be treated as early as possible. One of the most common and least invasive ways to screen for prostate cancer is through Prostate Specific Antigen (PSA) testing.

PSA is a blood test that since the early 1990s has been widely used to detect prostate cancers and to follow response to treatment. This blood test is frequently incorporated as part of routine blood testing during annual physical exams for men aged 40 or older. PSA values above a “normal” threshold are associated with a greater risk of prostate cancer.

In 2012, the U.S. Preventative Health Task Force (USPSTF) recommended against routine PSA-based prostate cancer screening for healthy men, regardless of age. This recommendation was based, in large part, on results from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a large randomized trial designed and funded by the National Cancer Institute (NCI) to determine the effect of PSA screening on prostate cancer deaths in the United States. At the time, it was determined that there was no benefit to PSA testing.

Contrary to this landmark study, a new study led by Jim Hu, MD at Weill Cornell Medicine and NewYork-Presbyterian found evidence that now demonstrates that PSA testing can help reduce the number of fatal cases of prostate cancer.

DrJimHuProstateCancerScreening

Researchers from the Genitourinary Oncology Program at NewYork-Presbyterian and Weill Cornell Medicine will be presenting their findings at the 2016 American Urology Association (AUA) Meeting on Monday, May 9. They discussed their findings in this week’s New England Journal of Medicine in a letter to the editor questioning the results of the PLCO trial due to limitations in the study’s methodology.

According to this letter, more than 80% of the participants in the PLCO control group (who were not supposed to have PSA tested) reported having had PSA testing within three years of starting the trial or during the trial. Thus the trial was not truly studying men who had not been screened in contrast to those who had been screened.

Dr. Jonathan Shoag, urology resident and lead author on the article further explains, “We demonstrate that the PLCO study did not compare a group of men who received PSA screening to a group of men who were not screened, but compared men who were screened to other men who were screened, and we should therefore reconsider any decisions based on the study.”

While PSA testing isn’t perfect (PSA can rise due to other conditions aside from prostate cancer), it can be a very good screening tool when viewed as one piece of the larger puzzle of what’s going on in the body.

Stay tuned for additional blog updates on the topic. Next week, we’ll have continuing coverage on research from the 2016 AUA meeting, including updates on PSA as a prostate cancer screening tool, other ways to detect prostate cancer, and additional biomarkers that can be used to distinguish between aggressive and non-aggressive prostate cancers.

Together, this information allows us to see a clearer picture of what’s going on in the body in order to increase our cure rates and the number of people we’re able to treat effectively, while simultaneously minimizing interventions for those who don’t need them.

Marking their Territory: Using Cell Markers to Find Cancer and Stop its Spread

Cancer Cell Markers and AntibodyA key way to detect cancer cells in the body is to find “markers” on the cancer cells that don’t exist in healthy cells. For prostate cancer, we use a marker called the prostate specific membrane antigen (PSMA). PSMA is a protein on the cell surface of most prostate cancer cells, but it is not usually present elsewhere in the body. As a result, we’re able to use PSMA in order to track the presence of prostate cancer tumor growth and metastasis. At AACR 2016, the Weill Cornell Medicine (WCM) and Meyer Cancer Center investigators presented the results of two new studies that further hone in on the role PSMA plays in prostate cancer.

While we’ve known about the presence of PSMA for many years, we have recently discovered more about its biology and the tight relationship it has with the key driver of most prostate tumors, the androgen receptor (AR) pathway. As the AR pathway becomes more abnormal (is more dysregulated), the amount or expression of PSMA increases. This means that more aggressive tumors will have more PSMA on the cells.

How do we measure or quantify the amount of PSMA?

At the Weill Cornell Genitourinary (GU) Oncology Program, one way we do this is by using non-invasive methods to locate active tumors in prostate cancer patients. By tagging an antibody or small molecule with a particle that gives off energy, we can “see” the PSMA using imaging techniques. In this case, we can give people an injection to bring these tagged molecules into the body and then follow the “energy” the molecules are giving off with a scan that visualizes the tumors. In some cases, this approach helps us locate tumors that might otherwise be hidden.

However, we may also be able to assess the biology of tumors without a biopsy (non-invasively). To do this, we analyzed men who had undergone molecular PSMA imaging. Following infusion of the anti-PSMA monoclonal antibody J591 which was tagged with a particle, men underwent scanning. Based upon a system we previously published, we scored how bright their tumors were with the belief that brighter tumors would be more aggressive. In long-term follow up of the men who underwent imaging between 2000-2015, our hypothesis was confirmed. The men with the brighter tumors had higher rates of mortality, even among those who received the newer, better therapies. This type of non-invasive molecular imaging may assist physicians in determining prognosis, which may in turn guide therapy choices for especially aggressive cancers.

Antibodies as a Treatment Vehicle

In addition to tagging an antibody with an imaging agent, we can label J591 with a radioactive particle capable of killing the cancer cells, termed radioimmunotherapy. For more than a decade, we have delivered different versions of this therapy to patients at WCM. A phase II clinical trial published in 2013 was shown to be very successful at delivering a large, single-dose of radioimmunotherapy to patients, also showing that those patients receiving a larger dose had better response and survival (a “dose-response”). Building on the results of this trial, we hypothesized that by splitting the radiation dose and giving half initially and half two weeks later (this is called “dose fractionation”) that we would be able to ultimately deliver a higher dose of the treatment. At ASCO in 2010, we demonstrated this to be a promising approach to treatment and will be presenting a follow up expanded version of this study in June at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.

At AACR 2016, Dr. Ana Molina presented results of a pilot study of hyperfrationated (very split doses) 177Lu-J591, which delivers the radioactive particle lutetium-177 (177Lu) to tumors via the anti-PSMA monoclonal antibody J591. In this study, small doses of the radioimmunotherapy were delivered every two weeks until blood counts started to drop, as measured by the level of white blood cells and platelets. This treatment approach allowed all patients in this small study to receive a higher total dose than could be safely delivered with a large single dose. Two patients received five and six total doses of the treatment, reflecting a range 179 – 214% higher than the single large dose. As a result, this new approach to administering this type of immunotherapy with very split dosing may have long-term merit for men with advanced prostate cancers.

Today, men with advanced prostate cancer are able to benefit from a number of new treatment options, including the common oral hormonal drugs, abiraterone and enzalutamide. These hormonal drugs help decrease the burden of the cancer, maintain or improve the quality of life, and allow men to live longer. However, none of these drugs are curative, so we still need to make advancements in the field.

This is why we continue to use what we already know about cancer “markers,” such as PSMA, and to build on this knowledge in order to better diagnose and treat prostate cancers in a way that exploits these markers and keeps the cancer at bay. We are also constantly seeking new ways to better “see” and leverage these markers, and specifically PSMA, to prevent the growth and spread of prostate cancer.

Learn more about some of our current open clinical trials exploring this approach:

Aggressive Prostate Cancers: What’s New in Research and Treatment?

This year, approximately 180,000 men in the United States will be diagnosed with prostate cancer. Prostate cancer comes in many forms and we have a slew of acronyms to help us categorize not just the stage of the prostate cancer, but its various sub-types. These sub-types are based on biological markers and the genetic makeup of the tumor and tell us a lot about how the tumor may behave. We have even found that these tumor cells can change over time to avoid detection, and in the process they can become resistant to treatments.

Aggressive prostate cancer sub-types represent approximately 25% of all prostate cancer cases. A common treatment for aggressive prostate cancer that hasn’t spread (non-metastatic prostate cancer) is “castration” through surgery or other therapies to deplete the androgen and testosterone hormones that feed the tumor.

Castration-resistant prostate adenocarcinoma or CRPC is the medical term for prostate cancer that does not respond to these therapies. Adenocarcinoma is a fancy way of saying a glandular cancer, an umbrella term for cancers that originate in different glands in the body, of which the prostate is one.

fish_lg
Microscopic images of aggressive prostate cancers. Top: castration-resistant prostate cancer (CRPC) Bottom: Neuroendocrine prostate cancer (NEPC)

New and emerging research has shown that CRPC can evolve and morph into neuroendocrine prostate cancer (NEPC), another aggressive type of prostate cancer. The mechanism by which this happens is not yet completely known, but at Weill Cornell Medicine we’re hard at work to discover the answers.

On a molecular level, neuroendocrine prostate cancers are associated with over-expression and gene amplification of MYCN (the gene that encodes the N-Myc protein). MYCN is a gene that has been proven to drive cancer (a.k.a. an oncogene) in several rare tumor types, but the role it plays in the progression of prostate cancer has not yet been well established.

On Sunday, April 17th at the 2016 American Association for Cancer Research (AACR) Annual Meeting, Dr.
Rickman and colleagues showed that by integrating a novel genetically-engineered mouse model and human prostate cancer transcriptome data (the product of the genes that were expressed in those patients’ tumors), N-Myc over-expression leads to the development of poorly differentiated, invasive prostate cancer that is similar to human neuroendocrine prostate cancer tumors on molecular and histological levels.

NMYC slide[1] copyThis research also demonstrated that N-Myc over-expression sensitizes cells to specific inhibitors targeting epigenetic modifiers that are linked to neuroendocrine prostate cancers. In plain language, this means that the controllers of the genes (the epigenome) in NEPC may be especially sensitive to certain drugs (such as EZH2 inhibitors that are in the clinic currently). This provides strong rationale for developing additional new therapeutic strategies in order to treat this aggressive subtype of prostate cancer more effectively and prevent it from becoming neuroendocrine prostate cancer.

For more information about our open clinical trial using an EZH2 inhibitor, please contact Amelyn Rodriguez, RN at amr2017@med.cornell.edu or (212) 746-1362.