Recent dramatic advances in the understanding of inherited susceptibility to several common adult-onset cancers have made possible the identification of individuals who may be at significantly increased risk of developing malignant disease. These advances may translate into some of the first opportunities for cancer prevention.
The most notable examples of successful gene isolation that hold such promise include identification of the genes for inherited colon, breast, ovarian, and thyroid cancer. However, these same successes open a Pandora's box of predictive testing that health-care providers have not had to consider previously. Concerns about the possibility for error or misinterpretation, costs, potential discrimination, financial vulnerability from loss of insurance or employment, psychological harm, and uniform accessibility have all been raised in the international debate on how to use these newly discovered genes to best advantage. Dr. Holtzman raises the question, "Are we ready to screen for inherited susceptibility to cancer?" and concludes, based on many of these concerns, that we are not ready.
Arguments Against Screening
The arguments against screening put forth in his article center largely on our current lack of knowledge in the following areas: (1) the predictive value of the test, which is decreased when not all mutation carriers develop disease and when the age of onset and clinical course of the disease cannot be accurately determined; (2) the effectiveness of interventions being offered; (3) the potential risks of screening; and (4) the cost-effectiveness of screening programs.
Dr. Holtzman argues that mutations in the currently known cancer susceptibility genes have been studied in only a small number of severely affected families, that the role of these same mutations in the general population remains unknown, and that quality of life and long-term survival may not be affected in individuals undergoing screening. He further argues that the use of screening in children and pregnant women is of even more questionable benefit, and that there is potential for exploitation by the entry of corporate concerns into the genetic testing arena, in the form of aggressive marketing practices and pricing that may place such testing beyond the reach of many individuals. Dr. Holtzman thus urges restraint in offering genetic testing for cancer susceptibility as a screening tool and suggests that screening efforts be limited to pilot studies linked to randomized clinical trials of prevention strategies.
Screening vs Testing: A Key Distinction
The critically important concept in evaluating the concerns raised by Dr. Holtzman is the distinction between screening and testing. By definition, "screening" denotes the application of a test to a large population, in this case, the American public (or at least American women with regard to breast and ovarian cancer). Examples of screening tests in current use include mammograms, Pap smears, and stool occult blood tests. These tests have in common low cost, ease of performance, minimal risk, and the ability to detect potentially curable disease. They have been recommended at regular intervals for all men and/or women over a specified age in the United States.
In contrast, the term "testing" generally is used to indicate the performance of a test for specific indications, such as breast ultrasound to further define a previously detected breast mass, colposcopy to examine the cervix of a woman with atypical cells on Pap smear, or colonoscopy to evaluate an individual with occult blood detected in stool. These tests are not recommended for routine screening of asymptomatic individuals, as they may be expensive and/or inconvenient and would result in a negative cost-benefit ratio if indiscriminately applied to a large population. Nonetheless, they are extremely valuable tools when used in the proper setting. Genetic predisposition tests should be evaluated with this same distinction in mind.
I agree with Dr. Holtzman that we are not ready to screen people for inherited susceptibility for cancer, and further suggest that we may never be. However, testing individuals with defined risks for inherited susceptibility to cancer clearly offers great promise. To withhold such testing because we are not ready for screening would be a great disservice to members of cancer-prone families who have, in many cases, been trying to understand and deal with the early loss of multiple family members spanning several generations.
To members of such families, as well as to patients who develop cancer at an age significantly below the median age of onset in the general population, we can offer explanations, reassurance, and hope. In addition, from long-term follow-up of these patients, we can derive answers to currently unanswerable questions about intervention. Finally, these individuals will pave the way for insurance reform and antidiscriminatory legislation. While decisions on the advisability of population-based screening clearly must await the results of the pilot studies proposed by Dr. Holtzman, we must not curtail efforts to educate health-care providers and consumers about the power and the pitfalls of predisposition testing for defined individuals, the established need for associated counseling, and the selection of appropriate testing candidates.