“The time has come,” the Walrus said,
“To talk of many things:
Of shoes—and ships—and sealing-wax—
Of cabbages—and kings—
And why the sea is boiling hot—
And whether pigs have wings.”
—Through the Looking-Glass
And the time has come to see how goes the War on Cancer. How far have we come in defeating this dreaded enemy that still claims far too many lives despite the rapid development of armamentarium? Let us give you a headline before we delve into the details wherein the devil likes to hide. We have made it past first and second base, and yea, we are rounding third—but alas, we have yet to make it home! A plethora of metaphors, to be sure, so pick the one you like and we’ll go from there.
Since the 90’s we have managed to advance the treatment of prostate cancer and drop the number of deaths a year. And yet nearly 200,000 cases are diagnosed a year in this country alone with fatalities nearing 28,000. We’ve done that largely with a tool called the prostate specific antigen (PSA test), often followed up by biopsies, MRIs, and treatments (surgery and different forms of radiation). Even though these procedures have helped save lives, at the same time, they have drawn criticism among detractors who have cited unnecessary treatments, pointed to cases where outcomes were unsatisfactory and charged that costs involved are often inflated. So where does the truth lie? And when it comes to dealing with prostate cancer what should the patient believe and what should the patient do? Perhaps more to the point, when it comes to treatment where are we heading? Let’s take a look.
The PSA test in our view continues to be so far the best tool we have in the tool box to give us the status of the prostate. It is a simple blood test, though complicated to interpret, that doctors hope will indicate if the prostate is healthy, has an infection known as prostatitis, or is enlarged—all benign conditions. Or, if the patient has prostate cancer! But the problem is the PSA test is not fool-proof. It can sometimes give false results. If the doctor suspects the results are incorrect, s/he can follow up with a biopsy procedure. Not always, but sometimes a biopsy can be mildly uncomfortable. The biopsy is performed to determine with certainty the presence of prostate cancer. Another problem with the PSA blood test is that many of the cancers it does detect are not likely to cause harm or be life-threatening. But there is no reliable way to identify them. So a large majority of men with positive tests undergo surgery or radiation treatment. They just “want that cancer out of their bodies.” And many suffer aftereffects of incontinence and erectile dysfunction—needlessly.
To determine the aggressiveness of a cancer biopsy tissue samples are sent to a pathology lab where the patterns of the cancer cells are examined under a microscope. Normal cells are well structured while cancerous ones are poorly formed and the number and irregularity of cancer cells determines the aggressiveness of the disease. The severity of the cancer is given a graded number and referred to as a Gleason score. The doctor will then confer with the patient and based on the Gleason score suggest treatment options. The problem with Gleason scores is that they are determined by human eyes. The numbers presented by the pathologist are subject to interpretation. Obviously, experience and vision can play a vital part in providing a Gleason score. They can differ widely from one lab to another and from one pathologist to another. That is the weakness of the test and physicians are then left with having to reflect on treatment options to offer the patient.
Two things then are perfectly clear. First, with regard to the PSA test, its weakness is that it does not point to the absolute presence of prostate cancer. What is needed is a fault-proof biomarker that indicates without a doubt the presence of prostate cancer. Second, once prostate cancer is discovered, a better test must be found to indicate the aggressive behavior of the cancer—one established by a standardized procedure and not dependent on human interpretation that can vary from one individual to another. Research in both areas has been underway for some time.
Meantime, many prostate support groups have formed throughout the country urging men to be screened for prostate cancer using the PSA test. Millions of men in the country have followed the call. In 2011 a government health advisory group ( the U.S. Preventive Task Services Force ) called for an end to widespread screening. They said healthy men at low risk to prostate cancer should not be tested and it claimed millions were treated unnecessarily and subjected to great physical and psychological harm ( incontinence and sexual dysfunction). A storm of controversy broke out. The American Urological Association, cancer hospitals and urologists cried foul. They pointed out that no urologists or prostate cancer specialists were included on the panel of the task force. They expressed fear that those at high risk, including African American men, would no longer line up for screening. Their fear was in fact born out. There has been a dramatic decline in the number of high risk patients participating in screening in the country.
The position taken by the vast majority of urologists and major prostate cancer centers as well as the American Urological Association is that screening of high risk patients is a necessity to prevent them from acquiring cancer at an advanced stage when intervention is as yet, not possible. Their recommendation with regard to treatment is that men diagnosed with prostate cancer consult with their physicians and decide whether they should be treated or follow a course of Expectant Management (surveillance with periodic testing. )
Now the extraordinary good news. Research has been making rapid strides. Sophisticated new prostate cancer tests are coming to market that may well supplement the PSA test. Potentially, they can save tens of thousands of men every year from unnecessary biopsies, operations and radiation treatments. Some of these tests are aimed at reducing false alarms. If proven successful, they could help reduce anxiety brought on by elevated PSA readings. Another group of tests aims to substantiate or theoretically even replace Gleason scores. They examine genetic workings of cancer to distinguish dangerous tumors that need treatment from the slow-growing kind that can well be left alone. The idea is that these genetic findings would no longer be based solely on human visual interpretations.
What has been hailed as the “single biggest leap forward” in understanding genetic causes of prostate cancer has just been reported in the British newspaper The Guardian. The announcement says the huge study involved more than a thousand scientists. The newspaper reports that the study was “one of the largest ever conducted to look into faulty DNA that drives cancer.” Doctors say genetic biomarkers they have uncovered could provide patients with a personalized ‘risk profile’ for diseases, paving the way for individually tailored screening for those at risk having regular health checks.
What are the implications here? The suggestion is that a test based on genetic markers for prostate cancer “could identify men whose lifetime risk is a staggering 50%. “ The authors say men could be routinely screened for prostate cancer by doctors within five years using a simple saliva test to detect the smallest genetic mutations that collectively increase the risk of developing the potentially fatal illness. They also believe that advances in detecting the many dozens of DNA mutations linked with a range of cancers, including ovarian and breast cancers, will lead to a revolution in the early diagnosis and treatment of tumors that would otherwise go undetected. In Britain, more than 40,000 men are diagnosed with prostate cancer and nearly 11,000 die from the disease.
Back in this country, a response to the Preventive Services Task Force’s assertion that “healthy men” need not be screened comes from Dr. Mathew Cooperberg, an assistant professor of urology at UC, San Francisco. He says, “it’s not that screening doesn’t work; it’s that we haven’t done a great job of targeting treatments for the tumors that need it.” Dr. Cooperberg is one of the consultants working with companies that have been working on new testing procedures. More than a dozen companies are introducing or planning to introduce new tests based on genetic discoveries. Instead of looking at a single protein like the PSA, they are investigating multiple genes and other mechanisms they call molecular markers.
It is important to emphasize here that although these new tests are intended to help men make smarter treatment decisions, the fact is that because so many companies are producing so many different tests the plain fact is the multitude of claimed results is apt to cause more confusion until a general consensus is established by medical peer review. For now among medical experts there is an air of optimism that one or more of these new tests will perform and make a difference in treating patients. They caution, however, that it could be tricky to figure out which tests apply to individual patients. Another question that comes to mind is will insurers be reluctant to pay for the new tests without evidence that men will trust results enough to forgo treatment if that is indicated. And to be sure there will always be men who don’t want to live with cancer no matter how slight some test says their risk is.
A report appearing in the New York Times March 27,2013 suggests the biggest battles likely to take place among the many companies engaged in developing new tests will involve Genomic Health and Myriad Genetics. Both companies are moving into the prostate cancer arena after successes in developing tests for breast cancer. Both companies have come up with tests that analyze gene activity levels in the tumor samples obtained by biopsy to gauge how aggressive the cancer is. As we’ve pointed out, these new tests would provide better information than the Gleason score that is presently used by pathologists.According to the New York Times, Noridian, the Medicare contractor for Utah, will not pay for Myriad’s test (called Polaris) because some prostate cancer specialists say the test has not yet been adequately validated. Cost of the test is said to be $3,400. Genomic Health expects to release supporting data for its test at the upcoming American Urological Association annual meeting in May. They plan on selling the test following the meeting. One physician, Dr. Eric A. Klein of the Cleveland Clinic who worked on the Genomic Health test told the press, “Even if we can only convince 15 to 20 percent of men that we have enough confidence that they don’t have to be treated, that will be a big step forward.”
More genetic tests are coming from an avalanche of established companies and start ups. Hologic and MDxHealth and Mitonmics say they have tests that can reduce the number of unnecessary biopsies. Opko Heath, Beckman Coulter and Metabolon are working on tests that they believe will improve PSA screening. Researchers at the University of Michigan are studying a test that relies on a particular fusion of two genes found in half of the prostate cancers. And at the Johns Hopkins Medical Institute work continues on development of a prostate cancer biomarker based on a simple blood test.
Meantime, what are prostate patients to do? For now, the majority of prostate cancer experts agree the PSA is the best tool in the tool chest. Many believe that unnecessary procedures can be reduced simply by using the PSA test less frequently. The man who helped bring the PSA to market in the 90s, Dr. William J.Catalona, director of the prostate program at Northwestern University, says of the rush of research taking place today, “This is only the start. This field is moving kind of like cellphones.”