Monday, August 10, 2009

The Big PC – What Men Fear Most

Although my relative risk for Prostate Cancer came in third behind Crohn’s Disease and Type 1 Diabetes, the absolute risk of 24% certainly got my attention. It was the second item I clicked on after looking at Crohn’s. At my age I am supposed to be paying more attention to prostate screening guidelines, but I haven’t been. This risk score may provide a good incentive to do so. Let's read further to see if that’s true.

A quick Google search on recent prostate cancer announcements returned several links for radio host Don Imus and Senator Chris Dodd going public with their diagnoses. This is evidence that this disease is cheerfully bipartisan. At age 48, deCODE Genetics co-founder Jeffrey Gulcher reviewed his deCODEme data, which indicated he had a doubled lifetime risk for prostate cancer. Even though his PSA levels were fairly normal, Gulcher ended up getting a biopsy that revealed a grade 6 (Gleason scale) prostate carcinoma, which was successfully resected. “This test may have saved his life,” deCODE CEO Kari Stefansson said.

As a test for our blog readers - did you notice my risk scores for Crohn’s had been updated since our post on that subject back on July 13th? My absolute risk for Crohn’s increased from 1.5% to 1.6%. The change is because the new score is now gender specific.

Worse Than Death

The digital exam and the threat of impotence are what men seem to fear more than death from the disease, even though almost 30,000 men die each year from prostate cancer in the United States. More than 185,000 US men develop prostate cancer annually. Among men of all races in the US, prostate cancer is the most common cancer. It is also the leading cause of cancer related death among men of all races.

If I develop prostate cancer, I would get to chose from hormonal therapy, brachytherapy, radical prostatectomy, cryotherapy, or just watchful waiting. Sounds like a fun treatment menu.

My Risk and Family History

The heritability of prostate cancer is estimated to be 42-57%. This means that genetic and environmental factors contribute nearly equally to differences in risk for this condition. The MD Perspective section made strong references to family history and prostate cancer risk.

23andMe: What are the other major risk factors for prostate cancer, besides age?
Dr. Marc A. Shuman, M.D. (Professor of Medicine and Urology; Director of the Prostate Cancer Specialized Program of Research Excellence, University of California, San Francisco): Genetics and ethnic background are the main risk factors, other than age, for prostate cancer. A family history of prostate cancer also significantly increases the risk of developing prostate cancer. In addition, African-American men have a significant increase in prostate cancer compared to men of European ancestry. Asian-American men are at a significantly decreased risk of disease.
23andMe: How does heredity influence the risk of prostate cancer?
Dr. Shuman:
Family history is one of the most significant risk factors for developing prostate cancer. Men whose first-degree male relatives—fathers or brothers—have had prostate cancer are at increased risk. The risk is doubled in men who have had two first-degree relatives with the disease. Heredity is believed to contribute as much as 40% of the total risk of getting the disease.

No grandfathers, father, or uncles have had prostate cancer in my family. Besides my father, I am not aware if they have had any screenings done.

Community Comment 1

The 23andMe website has a community section that allows for people to post questions and comments. One person said he was surprised by his 23andMe result on prostate cancer. He said –

“My father and his two brothers had prostate cancer when they were in their 60's. My older brother had prostate cancer in his mid 40's. I guess this suggests a strong hereditary link. Surprisingly to me, my results say I have slightly lower probability of developing prostate cancer than the average European guy (15.2% versus 17.8%). Maybe there is still a lot to learn about genetic propensity for prostate cancer.”

I guess it is possible to have a strong family history, but not have inherited the risk-effecting genetic variants like other family members.

Odds Calculator Shows its Age

The default age range in the odds calculator shows that my lifetime risk from 35 to 79 years of age is 24.4 out of 100. This is the absolute risk that appears on my elevated risk screen. However, when I change the range for my current age, the absolute risk reduces significantly to .26 out of 100, that is nearly 100 times less! I also learn as I age every five years, the risk goes up quickly to.95 out of 100,
then 2.3 out of 100,
then 4.1 out of 100,
then 6.2 out of 100,
and then 7 out of 100 at 70 years old.

This tells me that age by itself is a big risk factor.

My Five Marker Effects (with number six to come later)

23andMe analyzes 5 SNPs associated with Prostate Cancer: rs1447295, rs6983267, rs10505483, rs1859962, and rs4430796. Based on these markers, estimates of a person's lifetime odds of getting Prostate Cancer can range from 17% to 46%. 23andMe’s estimate is applicable to people of European and African ethnicity, based on available published scientific research (for which the website lists cites of those published studies).

New Paper Points to Another SNP for Prostate Cancer – Then I Point it to Me

In the Proceedings of the National Academy of Sciences published in April 2009 two recent genome-wide association studies have independently identified a prostate cancer susceptibility locus on chromosome 10q11.2. In summary, they say that if you have the C variant for the SNP rs10993994 (tested in the 23andMe V2-chip), your odds for getting prostate cancer later in life are increased.

So I go to the Browse Raw Data section of the 23andMe website and enter in the SNP to see what I have. My 23andMe report allows me to search the more than 500,000 SNPs its microarray chip sequences, even though all of the SNPs may not be currently used in my risk assessment. I find that I have the C variant, which adds 1.47–1.82 to my current cumulative relative risk of 1.37. It will be interesting to track how quickly 23andMe updates my risk estimate.

Of course, the healthcare IT person in me thinks that this data should be in my EHR (electronic health record), and when a new variant is found to affect risk, this search should be automated and should send a message to me and my healthcare providers. (In fact, Intermountain Healthcare’s Clinical Genetics Institute is collaborating with the Partners HealthCare Center for Personalized Genetic Medicine to develop such a solution).

Community Comment 2

Another post in the community section asks a question about prostate cancer prevention. A 23andMe representative has answered by sharing a link to the Mayo Clinic website that seems to provide a comprehensive guess. Yet another community post suggests tomato paste may be the secret.

With no family history of prostate cancer, a current absolute risk of one-quarter of 1% (which may be updated soon), and a diet heavy on pomegranate juice and tomato paste (OK, maybe not), I’m not sure that I am fully motivated yet to get that first screen done. Who wants to be the first to scold me?

Perspective from a Certified Genetic Counselor

Prostate Cancer Serious Business

Prostate cancer is the poster boy for men’s health. Sometimes in screening circles you can hear whispers like “breasts get all the money and attention!” No duh. Hmmm. Breasts versus walnut-sized internal organs… So the marketing and money battle may have been lost, but the screening banner should not sag. Prostate cancer is serious business and can be deadly serious.

Yet, Grant talks about the screening process as being half the battle in this fate worse than death—the indignity and discomfort of the exam. The 23andMe test result may provide the reason for him to seek screening. (The other tidbit offered up in screening circles: “if men had to do mammography to screen their prostates or other appendages, there would be a better machine.”)

Markers and Prostate Cancer

Once Grant read about Crohn’s disease and realized that it didn’t apply to him, he focused on the prostate cancer risk. The 24% risk, as well as the relatively long bars next to the risk percentage, got his attention. He mentions that the risk range offered by the testing is between 17% and 46%. The graph showing Grant’s markers illustrates that three of the five markers were associated with lower risk of prostate cancer. Two markers were associated with increased risk for prostate cancer. Several studies show an association between certain markers and a risk for prostate cancer. The studies do not tell us that the markers cause prostate cancer.

Some of the markers are located in places along the genome in which a known gene resides. In a few instances the product of the gene is linked to the prostate. In these circumstances, it makes sense that a change in the gene might affect the prostate. For other markers there is no nearby resident gene and so the biologic role of the marker is unknown. Knowing how and why the markers are associated with the development of cancer might allow for targeted intervention to decrease the risk or prevent prostate cancer.

As Grant indicates, new markers and their relative contribution to risk will continue to be found. He looked up a new marker just reported and found that he has it. It will be interesting to see how the additional marker changes his risk. I notice that he didn’t look or didn’t find any markers associated with decreased risk for prostate cancer. None of the markers tell him whether or not he will develop prostate cancer, and if yes, when it will develop or how aggressive it might be.

What’s a Man to Do? Do I Feel Lucky?

Grant talked about his lack of attention to screening. Unfortunately that is a typical failure in men in Grant’s age group. Technically, Grant isn’t yet of the magic prostate cancer screening age, so he really shouldn’t feel badly. But, because of this result should he start screening now anyway? What should he do? The dread digital? Or perhaps the even more dreaded biopsy?

(Just a parenthetical reminder of the recommendation agreed to in testing: Do not use these test results in making management decisions about your healthcare.)

Risk Factors Associated with Prostate Cancer

The weight of the research so far indicates that family history, ethnicity and age are well known to be associated with determining risk. Having one or more close relatives with prostate cancer (your father, brother, or son) will increase your risk. Being African or African American will increase your risk, being of Asian background reduces the risk. All men have increasing risk as they get older. The fact that Grant does not have a family history of prostate cancer is reassuring.

Most studies found the greatest risk in those individuals who had the high risk markers AND family history. Grant’s heritage is white northern European, so higher risk, but not the highest risk ethnicity. Grant is nearing the at risk age group. With the start of screening for prostate cancer should come a discussion about the limitations of the process. However, like it or not, imperfect as it is, it is what we have. At least now there is a reason (perhaps more compelling than age alone) to get the screening done. When to start? Talk to your healthcare provider.

Janet is a cancer genetic counselor and has very strong feelings about this which she will share in the subsequent blog post. In a bit of a role-reversal, Grant will react.

Perspective from a medical geneticist

An Alternative View

Jeffrey Gulcher Chief Scientific Officer of deCODE genetics (a company that offers a direct-to-consumer genomic test service called deCODEme) had a less ambivalent response than Grant to his increased risk of prostate cancer. He opted to visit his physician and had a blood test to measure his prostate-specific antigen (PSA). The test was normal, albeit in the high end of the normal range. Despite the normal result he pursued a prostate biopsy which revealed the presence of aggressive prostate cancer that fortunately had not metastasized.

Still, several questions are raised: How should a PSA test be interpreted if one has increased risk based on genotyping? (Answer we don't know.) How should a PSA test be interpreted based on the presence or absence of a family history of prostate cancer? (Answer we don't know.) Does evidence support population screening with PSA? (Answer - not according to either the United States Preventive Services Task Force and the American College of Preventive Medicine both of which in 2008 concluded that there is insufficient evidence to recommend routine population screening with PSA.)

While not denying the likelihood that these choices were likely life saving for Dr. Gulcher, if a large number of men pursued this course of action what benefits and harms would they experience? Would the situation be analogous to full-body CT scanning where 9 out of the 10 findings are incidental and have no health impact? Pursuit of these "incidentalomas" consumes scarce health care resources and, in some cases, leads to invasive procedures with attendant morbidity and occasionally mortality. I would find counseling a patient presenting to me with a test result extremely challenging.

Read the next post - Prostate cancer - Part 2

1 comment:

  1. Weren't there two recent large studies showing PSAs for prostate cancer weren't effective at reducing complications and death? It would be interesting to see if genetic screening in addition to PSAs had an effect.