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:

Doing Better on Behalf of Bladder Cancer Patients

Scott Tagawa_IMG_5903On Monday, April 18th, Dr. Scott Tagawa presented promising bladder cancer clinical trial results at the 2016 AACR Annual Meeting.

This phase II study of the antibody-drug conjugate (IMMU-132), demonstrated positive results in a group of adults with metastatic urothelial cancer who did not respond to standard chemotherapies or relapsed after receiving several rounds of the standard chemotherapy treatment regimens.

A form of immunotherapy, antibody drug conjugates are a targeted therapy that leverages the capability of monoclonal antibodies to attach to specific targets on cancer cells. By attaching a drug to the monoclonal antibodies, treatments are able to “hitch a ride” into the cancer cells.

“In this study, eighty-four percent of patients were alive at the nearly one-year mark, compared with an average overall survival of 4-9 months in similar patients who received chemotherapy regimens,” says Dr. Tagawa.

Some side effects were reported, including neutropenia, a low count of a type of white blood cells (neutrophils) in the blood and some diarrhea, but less than would be expected with the free form of the parent drug irinotecan. Irinotecan is a chemotherapy drug mostly used for the treatment of colon cancer. In the body, it is metabolized and breaks down into SN38, which is a more potent molecule. Because of its potency, it would be too toxic to deliver SN38 into the body in general.

IMMU-132 is a drug in which SN38 is linked to an antibody which recognizes Trop2. Trop2 is a protein in the surface of several different types of cells and is over-expressed on many common cancer types, including urothelial cancer. Since the drug shuttles SN38 preferentially into tumors, patients benefit from the potent drug without as many side effects as general chemotherapy.

This drug is also known as Sacituzumab Govitecan, and has already received FDA-breakthrough designation for the treatment of patients with triple negative breast cancer.

The Weill Cornell Medicine clinical trial continues to enroll patients with advanced urothelial cancers (tumors arising from the bladder, renal pelvis, and ureters). For more information about eligibility and enrollment, click here.