A family history of prostate cancer is one of the strongest predictors of disease risk, along with age and race/ethnicity. Deepening our understanding of familial or hereditary prostate cancer (HPC) and the genetic mutations involved is an important research goal. Findings could provide new clues to help diagnose, treat, cure and even prevent prostate cancer in future generations.
The Prostate Cancer Genetic Research Study (PROGRESS), launched by Fred Hutchinson Cancer Research Center in 1995, aims to identify inherited genetic mutations that contribute to prostate cancer susceptibility in high-risk families. It was initially funded by the Prostate Cancer Foundation (1995–1998), then a grant from the National Cancer Institute (1999–2011) and additional support from the Hutch.
Janet Stanford, Ph.D., MPH, an adjunct research professor in the Department of Urology and a professor of epidemiology in the School of Public Health, is the principal investigator for PROGRESS. She co-directs the Program in Prostate Cancer Research at Fred Hutch. Dr. Stanford seeks to identify risk and preventive factors related to prostate cancer incidence and disease progression, and she investigates how the disease and its treatment affect men’s lives.
As this landmark study approaches the 20-year mark, Dr. Stanford highlights some of the findings to date, below. I hope you find this summary interesting, and I look forward to bringing you more news from the Institute for Prostate Cancer Research in the next newsletter.
PROGRESS is one of the largest, most extensive collections of data on families with hereditary prostate cancer (HPC) in the world, and — as you will see — it is an extraordinary resource for identifying genetic mutations that cause prostate cancer.
Inherited gene mutations may explain about five to 10 percent of hereditary prostate cancer cases and account for the disease pattern observed in some families. Such high-risk HPC families have at least one of the following features: 1) three or more first-degree relatives (father, brother or son) have been diagnosed with prostate cancer; 2) at least two relatives have been diagnosed at or before age 55; or 3) men from multiple generations in either the father’s or mother’s family have been diagnosed with prostate cancer.
To recruit HPC families, PROGRESS launched a national advertising and media campaign in 1995. To date, more than 2,200 people from 307 high-risk families with a pattern of HPC have participated, providing questionnaire data and a blood sample for genetic studies. Participating family members reside in all 50 U.S. states and several other countries.
2,292 PROGRESS participants in 307 families: 1,074 men with prostate cancer, 644 unaffected male relatives, 574 female relatives.
Almost half of the families in PROGRESS include five or more men diagnosed with prostate cancer. Study participants also include male relatives without prostate cancer and some female relatives. In addition, the study collects medical records from men diagnosed with prostate cancer and includes pertinent clinical and pathological information in data analyses.
Collecting information from prostate cancer survivors and their non-afflicted relatives helps establish the inheritance pattern of cancer, which is essential for creating detailed family trees or pedigrees.
Prostate cancer is a heterogeneous disease in its clinical features and biological behavior. For example, some tumors grow slowly, whereas others grow rapidly and may become life-threatening. We have found that grouping HPC families by the number of men who were diagnosed with a more aggressive form of the disease or who were diagnosed at younger ages has helped to strengthen study results.
Initial efforts to identify genes harboring mutations for HPC began with family-based, genome-wide linkage studies in the 1990s. These studies led to the discovery of more than two dozen chromosomal regions of interest.
Subsequent advances in next-generation sequencing technology allowed us to evaluate the exact sequence of DNA across a person’s entire genome. A change in the order of the DNA code, which includes four chemical bases — A, T, C, G — compared to the normal sequence could represent a mutation responsible for causing disease.
Next-generation sequencing also can be used to study only the regions of genes (exons) that carry the code for building proteins (whole-exome sequencing).
Our group recently completed the first whole-exome sequencing (WES) project focused on HPC, which included 91 members of 19 PROGRESS families. All the families included five or more men diagnosed with prostate cancer, and at least three men had a more aggressive form or were relatively young (less than 65 years) at diagnosis.
WES identified 130 genetic alterations. Follow-up work genotyped these alterations in more than 1,300 members of an additional 270 PROGRESS families. These analyses confirmed two rare genetic changes in the DNA sequence of the BTNL2 gene (a gene involved in immune system regulation and several inflammatory conditions). These changes were only found in men with prostate cancer in two of the 19 WES families and in nine of the 270 additional families; these genetic changes were not found in men who did not have prostate cancer.
We confirmed these results in two population-based studies in King County, Wash. Genotyping approximately 2,400 study participants showed that two percent of the men with prostate cancer had one or both of the genetic sequence variants compared to only 0.9 percent of the men without prostate cancer. Men with one or both of these variants have about a 2.5-fold higher risk of developing prostate cancer. Although rare, these gene variants appear to be important risk factors in both HPC families and in men from the general population, most of whom did not have a family history of the disease.
This exciting finding highlights the significance of our family-based study and the use of novel technologies and approaches to identify causal mutations for prostate cancer. Further next-generation sequencing studies are under way in a larger set of families, and they are aimed at finding additional genetic sequence variants that contribute to the development of prostate cancer.
We hope this work will highlight causal genes and molecular pathways that can lead to the development of new approaches to prevention and therapy for prostate cancer.
We continue to maintain contact with members of these HPC families, update information such as new cancer diagnoses, maintain the biospecimen (DNA) resource and complete analyses of next-generation sequencing data and follow-up studies.
If you would like to learn more about our work, please contact Mike Rubin at 206.667.5377 or mrubin@fhcrc.org or Colin Ware at 206.685.5412 or warec2@uw.edu.
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For decades we’ve known that cancer is caused by variation and mutations in genes; those a person is born with and those that become mutated during one’s life. We’ve also known for some time that while cancers can be categorized into broad types such as breast cancer, lung cancer, prostate cancer and so forth, at the gene level the cancers within each type are still significantly different between cancer victims. Finally, more recently, we have learned that drugs specifically developed to attack the abnormal gene(s) present in some cancer types can kill tumor cells and put its victims into remission often without debilitating side effects. This is co-called “targeted therapy” to be distinguished from classical “chemotherapy” which non-specifically poison susceptible cancer cells but also normal cells and thus is usually associated with significant side effects. Two dramatic examples of targeted therapy are Herceptin in breast cancer and Gleevac in chronic myelogenous leukemia (CML) that specifically neutralizes the abnormal gene product of the Her2/neu gene and the BCR-abl gene in breast and CML cancers respectively. But not all breast and CML cancers have these defective genes and it is clear that other genetic changes drive these cancers. Thus the dream of many cancer researchers is to sequence all the genes in the cancer, find which ones are abnormal and critical to abnormal growth, and then find (or develop) specific drugs that target these abnormal genes as they develop and/or gain prominence in the cancer’s growth. Until recently this dream was totally impractical if not impossible. That’s because it used to take years to totally sequence and compute a person’s normal or tumor genome at a cost in the hundreds of thousands of dollars.
Now that dream is a possible. Using very sophisticated sequencing and computing techniques whole genomes can be determined within 2 months for costs that are declining rapidly and currently are in the range of 10 thousand dollars and dropping quickly. Thus research teams who possess advanced sequencing techniques and patient resources such as exist within the Institute for Prostate Cancer Research (IPCR) are rushing to make this revolutionary opportunity available for patient treatment.
Thus several years ago the IPCR launched an ambitious program which we called ACT-SMART. In a word we intend to sequence the whole genome of patients and their prostate cancers, determine the most important abnormal genes of the cancer, identify agents that target these abnormal genes and so treat the patient. This very ambitious endeavor requires a major commitment of talent and resources.
In this issue I have asked Dr. Peter Nelson to begin an explanation of this milestone enterprise. He is a medical oncologist who treats advanced prostate cancer patients, directs a large gene research laboratory, and now is our leader of the IPCR research team. A complete discussion of this effort will take several Director Corner issues but I am confident that when completed you will be convinced of its promise, persuaded that the IPCR is in a very unique position to exploit this opportunity, and excited about the prospects that this activity will move us closer to much better control if not cure not only of prostate cancer but also of other cancers as well.
Dr. Lange asked me to share some groundbreaking developments by researchers within the IPCR ACT-SMART research initiative that pertains to Cancer Genomics. We embarked on this ambitious endeavor in response to the evolving field of so-called “Precision Medicine” and its exciting relevance to cancer treatment.
Precision medicine uses a patient’s individual genetic and genomic information to more accurately design treatments that are targeted and effective. By building on the scientific and technological advances made possible by the completion of the Human Genome Project in 2003, researchers have found ways to rapidly and comprehensively identify important inherited variation in a patient’s genes – that may predispose an individual to cancer, and mutations, acquired during the development of a tumor – that are responsible for driving cancer growth. Importantly, specific mutations also signal which tumors are likely to respond to certain therapies and thus allow individualized ‘precision’ treatments designed to maximize the likelihood of success and minimize futile therapy and avoid side-effects.
The genome consists of linear sequences of four DNA nucleotides, or bases. By analogy, these four bases, A,T,G,C, can be considered the ‘letters’ of the genetic code much as 26 letters comprise our alphabet. The specific order and length of segments of these bases are what defines individual genes, much as the specific order and length of letters in our alphabet define words. In humans, every cell contains a copy of the entire genome—more than 3 billion DNA bases. The process of sequencing is determining the order of DNA bases in a genome and determining whether any letters vary between individuals or are missing or out of order, called a mutation. Most variants are harmless, but some inherited variants can put people at higher risk of developing cancer. Further, some mutations are particularly susceptible to certain drugs leading to ‘targeted therapy’. While DNA se quencing has been around for decades, the process was slow and expensive. A recent major technological advance, termed Next Generation Sequencing (NGS) provide a rapid and accurate approach for determining the order of bases for the entire genome. Using NGS, a person’s constitutional genome (what you inherited from your parents) and tumor genome (the mutations that occurred to cause the cancer cell to develop and grow) can be determined and potentially used to guide important medical decisions concerning cancer screening, preventing cancer and other diseases, and guiding treatment strategies for cancers that are detected.
Provide safer, more cost effective care by tailoring cancer treatment to the specific needs of each patient and avoiding side-effects of unnecessary therapy.
While cancer genomics serves as a key component of ‘Precision Medicine’, the full-realization of personalized medicine will include other rich sources of data that builds on information from family history, populations, the environment, exposures (e.g. to diet, infectious organisms) and importantly, is adaptable to change over time. Collectively, this ‘Information Commons’ concept has been likened to a ‘Geographic Information System’ (GIS) exemplified by Google Maps. In this map structure, key information concerning car traffic patterns, housing prices, nearby-restaurants, population density, weather, and many other data types are anchored around a geographical location. You likely use these powerful applications everyday with your smart phone. In the context of health, the information is centered around a given individual patient, and higher layers of information can be readily accessed to address, interpret and predict complex health problems and improve disease outcomes.
As you can imagine, precision medicine techniques are changing the way we think about cancer treatment. These techniques provide the tools to tackle prostate cancer with greater reliability using therapies that are tailored for the individual’s specific needs. This is the reason IPCR researchers developed the ACT-SMART research initiative briefly explained by Dr. Lange. This is a large complex effort that cannot be covered in one issue. Here we will describe what will be the first of many increasingly sophisticated cancer genetic tests that we expect to apply to the real time management of prostate cancer patients. In subsequent Director’s corner issues we will describe more of our activities and plans in the ACT-SMART initiative. Now it is important to state again that such an ambitious enterprise could not have been conceived and implemented without the generous support and encouragement of so many individuals.
UW researchers, led by Dr. Colin Pritchard and colleagues, developed a unique diagnostic test; it focuses on 200 key cancer-associated gene mutations. The UW-OncoPlex™ technology is the first nationally to detect treatable genetic changes and then use this information to recommend a specific type of treatment based on this information. The panel has undergone rigorous assessments of accuracy and reproducibility and is certified by CAP and CLIA, two key hospital laboratory accreditation mechanisms that ensure adherence to quality control standards. This test panel is currently being used for a variety of cancers, but researchers with the IPCR have developed 8 precision genome targets focused on prostate cancer. Our team is currently setting up the prostate cancer test panel for clinical use. With the support of ACT-SMART initiative funding, over the next year, we expect to use this prostate cancer panel to determine precision targets for advanced prostate cancer patients. This work hopes to integrate UW-OncoPlex™ testing for advanced prostate cancer patients into routine clinical care.
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The 2010 Prostate Cancer Survivors Celebration Breakfast, held Thurs., Dec. 9, 2010, is now history — but what a wonderful memory! Once again, volunteer Steve Fleischmann and UW Medicine Advancement, in cooperation with their counterparts at Fred Hutchinson Cancer Research Center, performed a miracle. They created a thoughtful and exciting morning, one dedicated to prostate cancer survivors and their families, and with a number of special guests: Kenny G, Walter Afanasieff, The Canadian Tenors and UW Medicine alumnus Mitchell H. Gold, M.D., president, CEO and director of Dendreon Corp.
With your generosity and advocacy, the event grossed $1 million dollars, with the proceeds going to the Institute for Prostate Cancer Research (IPCR). All of us at the institute are deeply grateful, and we’re also galvanized — galvanized to remain one of the 10 top prostate cancer research centers in the nation. Thank you.
The breakfast reminded us that cancer afflicts many of our families, and that progress toward a cure is both necessary and possible. Fortunately, the Institute for Prostate Cancer Research is well positioned to make such progress.
At last count, the institutions that comprise the IPCR (UW Medicine and Fred Hutchinson Cancer Research Center) are in the top 5 prostate cancer research institutions nationally in acquiring federal funding for our research. Considering that only 7 percent of the research grants submitted to the National Institutes of Health (NIH) are currently funded, this is an amazing ranking. Yet every major multidisciplinary prostate cancer research center needs considerable private support to function at a high level.
This year, we plan to use most of the proceeds from the breakfast to fund pilot projects; we’re reviewing proposals even now. These are innovative, sometimes out-of-the-box ideas, often developed by junior researchers. Support allows these researchers to gather data needed to show proof of concept, a requirement before scientists can apply for more significant support, such as government grants. Providing the opportunity for a scientist to pursue new, high-risk, high-reward ideas is commonly what it takes for true innovation to occur in medical science. These projects have frequently made all the difference in the history of cancer research.
Here in Seattle, IPCR-funded pilot projects — some made possible by previous breakfasts — have made major differences in the field of prostate cancer research.
For example, one IPCR researcher’s “wild” pilot project set out to disprove an assumption. Sometimes prostate cancer reappears in men who received drug-based, testosterone-lowering treatments to combat the cancer. Prostate cancer does not reappear because the tumors learned to live without testosterone, as we previously assumed. Rather, it was because the tumors had learned to make their own testosterone. Data from the pilot project confirmed this theory, and the proof of concept resulted in several federal grant awards. It also generated excitement worldwide about the potential of new prostate cancer therapies, some of which are now available in clinical trials and soon will be available to all men who need it.
Another pilot project set out to disprove a long-held belief about prostate cancer: that cancer cells escape the prostate and metastasize (usually to bone) only in a few cases, and, when they do, the results were invariably bad. Instead, the study found that prostate cancer cells escape the prostate and travel to the bones early in the clinical course in many men, and only in a small fraction of the men do these cells grow and lead to the patient’s death. This project also elicited federal support, and it generated great international optimism about new biomarkers and new therapies.
I hope that, by the time of the next Survivors Celebration Breakfast, I can report other pilot project success stories, ones that will move us all closer to the cure.
Enhancing our prostate cancer specimen bank, which remains one of the best in the nation and is accessible to IPCR researchers and other prostate cancer researchers nationwide.
In closing, the IPCR’s team — more than 40 advanced-degree scientists and clinician scientists — have been invigorated by your support and interest. We pledge to you our very best efforts to make sure that the cure for prostate cancer comes as swiftly as possible and that Seattle shares in that triumphant day.
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There are many types of prostate cancer.
n the turtles. When they reach a certain size, they are apt to escape control. We know that, with prostate cancer, many more men have turtle-like tumors than bird-like ones.
With widespread PSA (prostate-specific antigen) screening in this country, approximately 250,000 men are diagnosed with prostate cancer each year; approximately 29,000 men die. With the turtle-bird model in mind, we say that most men die with prostate cancer rather than of prostate cancer.
What’s at issue is excess treatment. With early diagnosis, doctors pick up way too many “turtles.” If we treat all the cancer we find, we treat too many men, and because all treatments (e.g., radiation, surgery) have some side effects, there is a risk of causing needless harm.
Still, prostate cancer kills; it’s the second-most deadly cancer for American men.
What’s the value of screening?
The real question is this: does screening capture the “birds”? Does it prevent death from prostate cancer? And is it worth the cost?
With the therapies we have now for early disease, it sure looks like it! As delineated nicely by our own Janet Stanford, Ph.D., and her superb population science group, the death rate from prostate cancer has plunged in places where screening is widely practiced. Yet we need more proof, and, in medicine, that usually requires controlled randomized trials that are very expensive and take a long time.
What do we know from these trials?
The best trial on prostate cancer screening was done in Europe. It compared the prostate cancer death rate between men who were screened and men who were not. The good news is that they found that the group that received screening had between 25-31 percent fewer prostate cancer deaths (depending on how you interpret the data).
Looked at a different way, the study shows us that, to save one man’s life, we now need to screen approximately 1,200 men and do approximately 200 biopsies (which will uncover 50 men who have cancer). Most of us believe that because the bird-type tumors take a long time to kill their host, these figures will be pared down significantly with longer follow-up. Still, that’s a lot of unnecessary medical procedures, with accompanying costs, both financial and physical.
Is the PSA test any good?
Once prostate cancer is discovered and the prostate is removed by surgery or destroyed by radiation, PSA is an outstanding blood test, one that can determine if cancer is still present.
When the prostate is present and alive, however, things are more complicated. This is because PSA is produced by both normal prostate cells and prostate cancer cells; in both kinds of cells, PSA leaks out into the blood (and it leaks more from the cancer cells unless the normal cells are inflamed). But cancer cells often make less PSA than normal cells. When all these factors are combined, deciding whether a man with a PSA level under 10 should get a biopsy makes for a complex situation involving complicated probabilities.
But — make no mistake about it — when properly interpreted by an expert, the PSA is a very valuable (though imperfect) test, one that helps physicians decide if a prostate biopsy is appropriate. Better biomarker tests need to be developed, ones that detect cancer more reliably, reduce the number of unnecessary biopsies, and pick up the “birds,” rather than the “turtles.” Many IPCR researchers, including Pete Nelson, M.D., Muneesh Tewari, M.D., Ph.D., and their associates, are looking for these biomarkers using very sophisticated technologies.
What should we think? and do?
There are many treatment possibilities, ranging from doing no screening at all to biopsying everyone and aggressively treating all the cancers found. Hutchinson Center epidemiological statistician Ruth Etzioni, Ph.D., and her associates are known internationally for defining the consequences of a variety of options. This has allowed clinicians like me to develop more informed opinions about what to do.
As detailed in the editorial I reference below, I believe we should aggressively diagnose prostate cancer in all men who are likely (all things considered) to live 10 or more years longer. We should also aggressively treat men with “serious” cancers (e.g., those with high PSAs or with a lot of cancer in their prostate, particularly if the cancer looks aggressive under the microscope).
As for the rest of our patients (approximately 30-50 percent) we should watch them carefully; we call this active surveillance. Active surveillance entails regular exams and PSA tests, periodic prostate biopsies, and aggressive treatment for those men (about 30 percent) that get worse.
IPCR faculty, led by Dan Lin, M.D., and Pete Nelson, M.D., are leading the country in active surveillance and in finding better biomarkers to make this approach more accurate and less bothersome.
The exact approaches to early diagnosis and active surveillance will be topics of subsequent commentaries. For now, you can find out more by visiting the American Urological Association’s website or the National Comprehensive Cancer Network’swebsite.
I hope this brief summary of a very complex subject is useful to some of you — and that it gives all of you a sense of some of the interests that occupy the IPCR’s many researchers. Finally, please accept my best wishes for a good and healthy summer.
On Thursday, December 9, 2010, the IPCR is holding a very special event: the 2010 Prostate Cancer Survivors Celebration Breakfast. That morning, prostate cancer survivors and their families — and members of Seattle’s business and medical communities — will come together to support prostate cancer research.
We’re looking forward to the keynote speaker: Mitchell H. Gold, M.D., president, CEO and director of Dendreon Corp. Dr. Gold is a UW Medicine alumnus and a dynamic speaker, and Dendreon is a local biotech company that works on cancer treatment; they recently received FDA approval for a new therapy to treat advanced prostate cancer.
We hope you can attend the breakfast, perhaps even assemble a table or two. To learn more, please visit the breakfast’s website. As event founder and Seattle businessman Steve Fleischmann says, December 9 is sure to be a powerful morning. We’d like to share it with you.
For more information about the Survivors Celebration Breakfast, visit the website or contact UW Medicine Advancement Special Events at (206) 543-7873 or meddev@uw.edu.