KRAS mutation testing
I found the article on KRAS mutation testing methods in cases of metastatic colon cancer interesting and informative (May 2009). However, I was puzzled at our being told first that oncologists drove the demand for KRAS mutation testing (which implies pathologists were a bit behind in picking up on it) and then that we as pathologists should become instant experts in a field in which numerous issues of technique and application are in fact still under debate. I can tell you from personal experience that when I used to explain to oncologists that immunohistochemistry for KRAS or EGFR was essentially worthless, they paid no attention whatsoever.
Of greater concern to me is that the KRAS mutation test attacks the wrong end of the problem. It’s an expensive test to see if a fabulously expensive treatment of marginal utility (yes, I said marginal) might work against metastatic colon cancer. How nice that insurance companies might pay for the treatment. Why don’t they pay for screening colonoscopies? Insurance companies should pay for their clients to have fecal occult blood tests and colonoscopies. Colon cancer can be cured, and not by Tarceva. I am afraid addressing metastatic disease is locking the barn door after the horses, cows, pigs, and cats have left. “Health insurance” companies are far more aptly designated “disease insurance” companies.
William L. Wolfson, MD
Huntington Beach, Calif.
New prostate markers
The timely review on new prostate markers is most welcome (June 2009). However, diagnosis is not really the issue in prostate cancer; rather, it is the need for clinically relevant prognostic markers that can be assayed in biopsy tissue. This was made clear by Robert Getzenberg, PhD, who said in the article that it’s the “biggest need we have in the field.” Approximately one in six men will be diagnosed with prostate cancer during their lifetime,1 with more than 200,000 men diagnosed annually.2 Fewer than 10 percent of these cancers will cause death, and it is those cancers in particular that we would wish to identify and treat aggressively. Unless the new tests PCA3 and the TIMPRSS2:ERG translocation have prognostic relevance, they are too expensive for population-based screening. PCA3 levels are being used to follow men on watchful waiting, which may be an appropriate use for this relatively expensive test.
Also of relevance to this discussion, as it affects sensitivity and specificity of existing and proposed diagnostic markers, is that the true incidence of prostate cancer is surprisingly difficult to determine. Mark Rubin, MD, is quoted in the article as saying that up to 75 percent of biopsies in the U.S. don’t have cancer. I speculate that most pathologists would concur that false-negatives rather than false-positives are the larger problem in prostate biopsies. The biopsy process itself, though the gold standard for diagnosis, has a false-negative rate as high as 30 percent that is affected by the number of cores obtained.3 It is likely that the incidence of prostatic adenocarcinoma would approach 50 percent were standard 12-core biopsies routinely obtained. Many urologists now obtain 12 cores,4 and occasionally they use saturation strategies. A negative set of core biopsies therefore does not exclude the presence of cancer, and a high index of suspicion for prostate cancer may exist in the face of an initially negative set of prostate biopsies.5 From the autopsy studies of Sakr, we know that prostate cancer begins to appear in the third decade of life and steadily increases until nearly 80 percent of men have histological evidence of prostate cancer by the eighth decade of life.6 For the third through eighth decades of life, the incidence of prostate cancer in 1,051 subjects studied by Sakr, et al., is seven, 23, 39, 44, 65, and 72 percent. In another prospective single-institution study of initially benign core needle biopsies, the results of multiple repeat biopsies in 1,051 initial subjects were examined.7 Cancer rates detected on the first, second, third, and fourth repeat biopsies were 22 percent (231/1,051); 10 percent (83/820); five percent (36/737); and four percent (4/94).
In summary, the real problem in prostate cancer is not a lack of diagnostic biomarkers but understanding which prostatic adenocarcinomas to treat aggressively. We’re probably substantially overdiagnosing and overtreating biologically indolent tumors to prevent death in the 10 percent or so of men who have aggressive disease. Diagnosing more tumors more accurately will merely compound this problem. We need an imaging strategy that would make it possible to identify and follow up the lesions in vivo. Progress is being made on transrectal MRI techniques. We will need to extract maximum information from the small amounts of tumor present in the biopsies. Current technologies require at least one histologic section per test. In many cases, the small amount of tumor tissue in a biopsy would be quickly exhausted if “multiplexing” like this were done. Finally, cost of testing is a major consideration. I don’t know what the “right” cost is for a population-based screening test, but it is less than $500.
Dean Troyer, MD
Professor, Department of Microbiology and Molecular Cell Biology
Eastern Virginia Medical School
Member, Prostate Sciences
Sentara Norfolk General Hospital
Department of Pathology
UT Health Science Center San Antonio
- Fay MP. National Cancer Institute. Estimating age conditional probability of developing cancer using a piecewise mid-age group joinpoint model for the rates. National Cancer Institute Statistical Research and Applications Branch Technical Report #2002–03. www.srab.cancer.gov.
- Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8–29.
- Eichler K, Hempel S, Wilby J, et al. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol. 2006;175:1605–1612.
- Matsumoto K, Satoh T, Egawa S, et al. Efficacy and morbidity of transrectal ultrasound-guided 12-core biopsy for detection of prostate cancer in Japanese men. Int J Urol. 2005;12:353–360.
- Djavan B, Marihart S. Repeat prostate biopsies and the Vienna nomograms. In: Jones JS, ed. Prostate Biopsy: Indications, Techniques, and Complications. Totowa, NJ: Humana Press; 2008:199–216.
- Sakr W. Defining the problem: From subclinical disease to clinically insignificant prostate cancer. In: Jones JS, ed. Prostate Biopsy: Indications, Techniques, and Complications. Totowa, NJ: Humana Press; 2008:1–11.
- Djavan B, Zlotta A, Remzi M, et al. Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol. 2000;163: 1144–1148.