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Dan Lin, MD

Research to find biomarkers that indicate which low-grade prostate cancer will become aggressive

Enrollment for this study began in July of 2008 and now there are over 650 active surveillance participants at the nine sites in the U.S. and Canada. This prospective study seeks to discover and validate biomarkers that will identify prostate cancers that will become aggressive. The research is scheduled to continue for ten years, until 2018, with an estimated enrollment of 1000 men. (A list of the nine research sites appears at the end of this interview.)


Background:

New medical technologies have led to rapidly expanding biomedical research that focuses on discovering and developing biomarkers that will identify serious medical conditions and risks factors, even before symptoms appear. With proven and tested biomarkers, physicians will be able to track and treat various medical conditions more effectively. Biomarker research is being widely conducted at universities, government laboratories, and biomedical research companies. Already, useful biomarkers for breast cancer and other cancers are being used to guide the choice of treatment and lessen the impact of disease.


What is a biomarker?

Biomarkers may be cells, molecules, genes, gene products, enzymes, hormones or proteins. One familiar biomarker is the PSA (prostate-specific-antigen) test that measures the level of a protein in the blood that is produced by cells of the prostate gland

The PSA biomarker was first introduced in the 1980s. Though extremely useful since it can often find prostate cancer at an early stage, the PSA biomarker also proved to sometimes provides misleading results: PSA levels can be elevated by conditions other than cancer, a positive result may lead to an unnecessary biopsy, and some men with negative results are later diagnosed with prostate cancer.

For men with low-grade prostate cancer who are following a regimen of active surveillance, there are currently no biomarkers that can predict aggressive prostate cancer.


Dr. Lin, how important are biomarkers in your view?

Many of us think that the Holy Grail for prostate cancer treatment is to understand more about unique biological signatures within the person or tumor that allows us to predict which cancers will advance to a more aggressive disease. We may also find biomarkers which suggest worse disease that may have been missed by a biopsy. Thus, the development of new biomarkers for prostate cancer can lead to more appropriate treatment options.


What is the primary intent of this study?

The primary focus of our study is to discover, confirm and validate biomarkers that predict more aggressive cancer.

First, we enroll men who have chosen active surveillance as a management approach for prostate cancer. The men agree to donate biospecimens: blood, urine, DNA, tissue from biopsies, etc. We collect the specimens, bank the specimens, and begin studying the specimens. It’s a long, involved process, but of course we are hopeful that useful biomarkers will be found that will predict aggressive prostate cancer. From preliminary research, we determine which specific genes and proteins will be examined in depth. For example, we will be examining hundreds of genes to see which ones are “turned on” and “turned off.” We may also examine the DNA in blood. We will also be studying certain proteins and hormones.

All the specimens are stored at a central biorepository at the Fred Hutchinson Cancer Research Center in Seattle, while the lab work will be performed at individual sites by experts in the biomarkers of interest.


Have you published papers on this research?

The first preliminary findings of our biomarker research, conducted in collaboration with Gen-Probe, were presented at the Genitourinary Cancers Symposium on February 2, 2012 in San Francisco. Specifically, we are studying the ability of two urine biomarkers (PCA3 and TMPRSS2) to predict grade or volume of disease, and preliminarily, we have found that these markers actually do correlate to both grade and volume of cancer. These findings are based on an interim analysis of data collected from 401 men in this study. Prostate biopsies are invasive and don’t always pick up all of the cancer. Post-digital-rectal exam urine collection is much less invasive. If a diagnostic test could be developed that would help predict aggressive disease or disease progression, that would be ideal.


What criteria determine a man’s eligibility for this study?

The inclusion criteria are very broad and general. Most important is the patient’s willingness to contribute biospecimens and other follow-up data while participating in an active surveillance protocol.

The criteria include:

  • Confirmed clinically localized adenocarcinoma of the prostate
    Biopsy with at least 10 cores.
  • The patient has chosen active surveillance as a management plan
  • The patient consents to the donation of biospecimens and other data
  • Biospecimens include blood, serum, plasma, white cells, DNA, urine, prostate tissue, etc.
  • Patient is accessible for follow-up including filling out questionaires
  • No previous prostate cancer treatment that includes surgery, radiation, hormonal therapy, or chemotherapy.

If the patient has chosen active surveillance and if he chooses to contribute biospecimens for our research, he will then be put on a study calendar and come in for regular visits. We also include men who have already been on active surveillance, not just newly diagnosed, although the majority of our participants are within a year of their initial diagnosis.


What are the requirements for participation in the active surveillance phase of the program?

The actual active surveillance care that the men receive is independent from their ongoing contribution of biospecimens and other data. The men receive what we consider to be the community standard of care: Digital rectal examinations (DREs), PSA measurements, serial prostate biopsies and so forth. The requirements or criteria for active surveillance (PSA, number of cores that are positive, percentage of positive cores, DRE, and other clinical measures) are determined by the treating physicians at the individual institutions, and these criteria may vary. There are a number of clinicians at each site who see and treat these active surveillance patients.

The principal investigators at the various sites have flexibility to include virtually any patient who chooses active surveillance to be enrolled in the study. For example, while some active surveillance programs do not allow more than three cores to be positive for cancer, in our cohort of over 650 patients, we have approximately 5% who have four or more cores positive. Our program strives to be inclusive of all patients who choose active surveillance because it is clear that many patients choose surveillance, even when their cancer does not fit the classic definition of low risk prostate cancer (e.g. low grade, low volume, low PSA, normal DRE). Despite this very broad criteria in our study, over 90% of our participants are indeed the typical low risk prostate cancer patients.


How many patients have had disease progression requiring treatment?

As of October 28, 2011, 78 patients underwent treatment. Approximately 30% of the patients who underwent treatment did not have clear progression of disease. in other words, these men opted for treatment even with no increased grade, volume, or PSA progression, and treatment with no disease progression has been seen in all active surveillance programs.

The majority of the men who underwent treatment had progression where their cancer went from a Gleason 6 to a Gleason 7, although approximately 10-15% had significant increases in volume of cancer (e.g. number of positive cores) or increases in PSA.

Of those undergoing treatment, approximately 75% of them had surgery and 25% underwent some form of radiation. Of those undergoing surgery after a period of active surveillance, the cancer in their prostates appeared similar to other men who underwent immediate surgery without active surveillance. For all men receiving treatment, we still have the ability to examine their biospecimens in the future to determine if there are any bomarkers that correspond to recurrence or progression.


How does the academic community now view active surveillance?

Active surveillance is now on the forefront of academic practices because we know that about half the men who get diagnosed with prostate cancer yearly may be eligible for active surveillance, yet only about 10% of men adopt active surveillance. With effective dissemination of information, more patient education, and continued research in this area, we expect that more men will start adopting active surveillance as a safe management strategy. Currently, it is vastly underutilized.


From your perspective, what makes active surveillance a prudent option?

In those patients who are eligible for active surveillance but choose to opt for treatment with surgery or radiation, there is a high cure rate or non-recurrence rate. I’m speaking about patients that start out with a low-grade, low volume, low PSA, localized prostate cancer who choose to undergo surgery or radiation with curative intent. In that population of men, the cure rates are at least 80%, and there are few solid tumors with equal cure rates. However, the major problem with primary treatment of prostate cancer by surgery or radiation is the frequency of side effects, including incontinence, voiding dysfunction, and impotence. Additionally, from multiple studies, we know that a very large proportion of men with newly diagnosed, low risk prostate cancer will die of other causes and suffer minimal or no morbidity from their prostate cancer, even if undergoing no treatment for their prostate cancer. Thus, these patients could avoid radical treatment and the associated side effects if they pursued active surveillance. These issues make active surveillance a prudent option, unless treatment seems indicated.


What particular message would you like to share with patients?

Paul Schellhammer is a famous urologic surgeon who treats prostate cancer, and he also had prostate cancer. Dr. Schellhammer spoke recently at an active surveillance conference and shared his perspective on this treatment strategy. He characterized active surveillance as a paradigm shift in the way patients will and should view their prostate cancer. He explained that when most men are diagnosed with cancer, they think about wanting a cure, and they think of themselves as being at war with their cancer. It also turns out that due to the relatively low mortality rate of prostate cancer, patients usually end up considering themselves a cancer “survivor” and a cancer “warrior”. Conversely, men opting for active surveillance will have a completely different outlook in that they are not seeking a cure for their cancer, they are not at war with cancer, and the goal is to be at peace and co-exist with the cancer. This is counter-intuitive to most other cancers where the entire focus is on cancer cure.

In the coming years, I hope we’ll be able to develop biomarkers that will predict the development of aggressive cancer so that men, at an early stage, can select an option that better fits their specific needs, can comfort them in their peaceful co-existence with cancer, or prompt them to seek curative treatment if their cancer is destined to become worse.

(Dr. Daniel Lin is a urologist and chief of urologic oncology at the University of Washington Department of Urology. He attended Vanderbilt University School of Medicine, followed by an internship and residency at the University of Washington School of Medicine and a fellowship at Memorial Sloan-Kettering Cancer Center in New York City.)

The Prostate Active Surveillance Study (PASS) research is funded by the Canary Foundation(www.canaryfoundation.org) and the Early Detection Research Network (EDRN) of the National Cancer Institute (NCI) at the National Institutes of Health (NIH).

Below is the list of sites & contacts where this biomarker research is conducted along with active surveillance regimens.

Enrollment is open at all sites.

  • California
    • University of California at San Francisco, CA
    • Contact: Imelda Tenggara-Hunter 415.353.7348 itenggara@urology.ucsf.edu
    • Contact: Hazel Dias 415.353.7790 Hdias@urology.ucst.edu
    • Principal Investigator: Peter Carroll, MD
    • Stanford University, Palo Alto, CA
    • Contact: Michelle Ferrari, RN 650.725.5543 mferrari@standford.edu
    • Principal Investigator: James Brooks, MD
  • Massachusetts

    • Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA
    • Contact: Brianna Kalmykow, RN 617.735.2108 bkalmyko@caregroup.org
    • Principal Investigator: Martin Sanda, MD
  • Michigan

    • University of Michigan, Ann Arbor, MI
    • Contact: Rabia Siddiqui 734.763.7508 rabia@med.umich.edu
    • Principal Investigator: John Wei, MD, MS
  • Texas

    • University of Texas Health Sciences Center, San Antonio, TX
    • Contact: Linda Hernandez, BSN, RN 210.450.1741 hernandezmh@uthscsa.edu
    • Principal Investigator: Ian M. Thompson, MD
  • Virginia

    • Eastern Virginia Medical School, Norfolk, VA
    • Contact: Leigh Ann Brand, CCRP 757.457.5169 laallen@sentara.org
    • Principal Investigator: Raymond Lance, MD
  • Washington

    • University of Washington, Seattle, WA
    • Contact: Leslie Butler, LPN 206.598.0850 leslie@u.washington.edu
    • Principal Investigator, Daniel Lin, MD
    • Veterans Affairs Puget Sound Health Care System, Seattle, WA
    • Contact: Crystal Kimmie 206.277.5598 Crystal.kimmie@va.gov
    • Principal Investigator, Daniel Lin, MD
  • British Columbia, Canada

    • University of British Columbia, Vancouver
    • Contact: John Ma 604.875.4111 ext. 66557
    • Principal Investigator: Martin Gleave, MD
“The overwhelming evidence says that for men over 65 who are diagnosed with low-risk disease. The first question should be whether any therapy is appropriate for them, not which therapy.”

---Dr. H. Ballentine Carter
of Johns Hopkins


“For men with low-risk tumors... treatment after surveillance is as likely to cure as immediate treatment.”

---Matt Cooperberg, M.D.
MPH, Department of Urology, University of California at San Francisco