Study Populations
Use of Levels of Evidence
        Evidence related to screening
        Evidence related to cancer prevention
        Evidence related to treatment
Analytic Validity
Clinical Validity
Clinical Utility

PDQ cancer genetics summaries focus on the genetics of specific cancers, inherited cancer syndromes, and the ethical, social, and psychological implications of cancer genetics knowledge. Sections on the genetics of specific cancers include syndrome-specific information on the risk implications of a family history of cancer, the prevalence and characteristics of cancer-predisposing mutations, known modifiers of genetic risk, opportunities for genetic testing, outcomes of genetic counseling and testing, and interventions available for people with increased cancer risk resulting from an inherited predisposition.

The source of medical literature cited in PDQ cancer genetics summaries is peer-reviewed scientific publications, the quality and reliability of which is evaluated in terms of levels of evidence. Where relevant, the level of evidence is cited, or particular strengths of a study or limitations of the evidence are described.

Creating evidence-based summaries on cancer genetics is challenging because the rapid evolution of new information often results in evidence that is incomplete or of limited quality. In addition, established methods for evaluating the quality of the evidence are available for some but not all aspects of cancer genetics. Varying levels of evidence are available for different topics, and PDQ summaries are subject to modification as new evidence becomes available. As in other areas of medicine, testing and treatment decisions must be based on information that sometimes falls short of the optimal level of evidence. Recognizing the limits inherent in certain observations will alter the weight given to recommendations based on that evidence and serves to keep our minds open to new improved information, as it comes along.

The quality of evidence depends on the appropriateness of the study to the question being evaluated and on how well the study was designed, implemented, analyzed, and interpreted. For evaluating outcomes of both medical and social interventions, the strongest evidence is obtained from well-designed and well-conducted randomized clinical trials. For evaluating other questions, particularly those related to the prevalence of gene variants and inherited syndromes and determining the clinical validity of genetic tests, the strongest evidence is obtained from well-designed descriptive studies. Particular elements of study design, such as the nature of the population studied or the duration of observation, may be crucial to assessing the quality of a study.

During the early phases of research in a new area, information relevant to the needs of patients and clinicians may come from work at all levels of evidence, including well-designed quasi-experimental studies (nonrandomized, controlled single-group, pre/post, cohort, time, or matched case-control series) or nonexperimental studies (case reports, clinical examples, qualitative or narrative studies, or theoretical work). Such research may yield information important to patients and clinicians, who must make management decisions before full data on the risks and benefits of cancer genetic testing are available. In addition, such work helps to inform future research using more rigorous designs.

The level of evidence required for informed decision making about genetic testing depends on the circumstances of testing. Evidence from a sample of high-risk families may be sufficient to provide useful information for testing decisions among people with similar family histories but is likely to be insufficient to make early recommendations for, or decisions about, testing in families with less dramatic histories or in the general population. Even among people with similar family histories, however, other contributing genes or different exposures could modify the effect of a gene mutation in different families. In evaluating evidence, the most important consideration is the relevance of the available data to the patient for whom a genetic assessment is being considered. In summaries addressing the cancer risk associated with genetic polymorphisms and mutations, the study populations used for each risk assessment will be noted, according to the following categories.

1. Population-based.
2. Proxy for population-based. (The study population selected is assumed to be generally representative of the population from which it is drawn. For example: Persons participating in a community-based Tay-Sachs screening program, as a proxy for persons of Jewish descent.)
3. Public recruitment of volunteers, e.g., using a newspaper ad.
4. Sequential case series.
5. Convenience sample.
6. An affected family or several families.

The PDQ editorial boards use a ranking system of levels of evidence to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. For any given therapy, results of prevention and treatment studies can be ranked on each of the following two scales: (1) strength of the study design and (2) strength of the endpoints. Together, the two rankings provide a measure of the overall level of evidence. Screening studies are ranked on strength of study design alone. Depending on perspective, different expert panels, professional organizations, or individual physicians may use different cut-off points related to overall strength of evidence in formulating therapeutic guidelines or in taking action; however, a formal description of the level of evidence provides a uniform framework for the data, leading to specific recommendations.

There are varying levels of evidence related to screening, prevention, and treatment that support a given summary. The summaries are subject to modification as new evidence becomes available. The strongest evidence would be that obtained from a well-designed and well-conducted randomized controlled trial. It is not always practical, however to conduct such a trial to address every question in the fields of cancer screening, prevention, and treatment.

The PDQ Cancer Genetics Editorial Board has adopted the following definitions related to screening:

• Screening is a means of accomplishing early detection of disease in people without symptoms of the disease being sought.
• Examinations, tests, or procedures used in cancer screening are often not definitive but sort out persons suspected of harboring a clinically occult cancer from those in whom a cancer is not likely to be present.
• Diagnosis of disease is made after a work-up, biopsy, or other tests are completed in pursuing symptoms or following positive detection procedures.

Five requirements should be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice:[1,2]

1. The medical condition being sought must cause a substantial burden of suffering, measured both as mortality and as the frequency and severity of morbidity and loss of function.
2. A screening test or procedure exists that will detect cancers earlier in their natural history than when diagnosis is prompted by symptoms, and this test must be acceptable to patients and society in terms of convenience, comfort, risk, and cost.
3. Strong evidence exists that early detection and treatment improve disease outcomes, particularly disease-specific survival.
4. The harms of screening must be known and acceptable.
5. Screening must be judged to do more good than harm, considering all benefits and harms it induces, as well as the cost and cost-effectiveness of the screening program.

In order of strength of evidence, the levels for screening studies follow:

1. Evidence obtained from at least one well-designed and well-conducted randomized controlled trial.
2. Evidence obtained from well-designed and well-conducted nonrandomized controlled trials.
3. Evidence obtained from well-designed and well-conducted cohort or case-control analytic studies, preferably from more than one center or research group.
4. Evidence obtained from multiple time series, with or without intervention.
5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

Prevention is defined as a reduction in the incidence (or the rate) of new cancer, with the goal of reducing cancer-related morbidity and mortality. Examples of prevention strategies include smoking cessation, avoidance of excessive exposure to sunlight (ultraviolet) or ionizing radiation, surgical removal of an at-risk target organ before cancer develops, and use of medications (e.g., tamoxifen for breast cancer risk reduction).

For each prevention-related summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the five levels are as follows:

1. Evidence obtained from at least one well-designed and well-conducted randomized controlled trial that has:
   1. A cancer endpoint.
      1. Mortality
      2. Incidence
   2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
2. Evidence obtained from well-designed and well-conducted nonrandomized controlled trials that have:
   1. A cancer endpoint.
      1. Mortality
      2. Incidence
   2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
3. Evidence obtained from well-designed and well-conducted cohort or case-control studies, preferably from more than one center or research group, that have:
   1. A cancer endpoint.
      1. Mortality
      2. Incidence
   2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
4. Ecologic (descriptive) studies (e.g., international patterns studies, migration studies) that have:
   1. A cancer endpoint.
      1. Mortality
      2. Incidence
   2. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention).
5. Opinions of respected authorities based on clinical experience or reports of expert committees (e.g., any of the above study designs using invalidated surrogate endpoints).

In assessing a genetic test (or other method of genetic assessment, including family history), the analytic validity, clinical validity, and clinical utility of the test need to be considered.[3]

For each treatment-related summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the five levels are as follows:

1. Evidence obtained from randomized controlled trials.
2. Evidence obtained from nonrandomized controlled trials.
3. Evidence obtained from cohort or case-control studies.
   1. Total mortality (or overall survival from a defined time).
   2. Cause-specific mortality (or cause-specific mortality from a defined time).
   3. Carefully assessed quality of life.
   4. Indirect surrogates.
      1. Disease-free survival.
      2. Progression-free survival.
      3. Tumor response rate.
4. Evidence from ecological, natural history, or descriptive studies.
5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

Analytic validity refers to how well the genetic assessment performs in measuring the property or characteristic it is intended to measure. In the case of family history, analytic validity refers to the accuracy of the reported family history information. In the case of a test for a specific mutation, analytic validity refers to the accuracy of a genetic test in identifying the presence or absence of the mutation. The analytic validity of a genetic test is affected by the technical accuracy and reliability of the testing procedure and by the quality of the laboratory processes (including specimen handling).

The assessment of analytic validity is complex for some genetic tests. For example, a panel test is designed to evaluate a particular set of mutations (e.g., the Ashkenazi founder mutations in the BRCA1 and BRCA2 genes), and the analytic validity of the different components of the test may vary. Some genetic tests involve evaluating the DNA sequence of portions of a gene to determine whether any mutations are present (including mutations not previously identified). The sensitivity and specificity of these sequencing tests may vary with the laboratory techniques employed, the proportion of the gene tested, and the structural nature of the mutations present in the gene.

Clinical validity refers to the predictive value of a test for a given clinical outcome (e.g., the likelihood that cancer will develop in someone with a positive test) and is primarily determined by the sensitivity and specificity with which a test identifies people with a defined clinical condition within a given population. Sensitivity of a test refers to the proportion of persons who test positive among all those who actually have a clinical condition; specificity refers to the proportion of persons who test negative from among all those who do not have the clinical condition. In the case of genetic susceptibility to cancer, clinical validity can be considered at two levels:

1. Does a positive test identify a person as having an increased risk of cancer?
2. If so, how high is the cancer risk associated with a positive test?

Thus, the clinical validity of a genetic test is the likelihood that cancer will develop in someone with a positive test result. This likelihood is affected not only by the presence of the gene mutation itself but also by any other modifying factors that might affect the penetrance of the mutation (e.g., the mutation carrier's environmental exposures or personal behaviors) or by the presence or absence of mutations in other genes. For this reason, the clinical validity of a genetic test for a specific mutation may vary in different populations. If the cancer risk associated with a given mutation is unknown or variable, a test for the mutation will have uncertain clinical validity. A summary of definitions of concepts relevant to understanding clinical validity and other aspects of cancer genetics testing has been published.[4] The test should be evaluated in the population in which the test will be used.

Clues to whether a particular familial cancer syndrome has a genetic basis can be derived informally, by inspecting the pattern of affected persons and unaffected persons in a series of families; or more formally, using an analytic technique known as segregation analysis. Segregation analysis provides quantitative data in support of, or against, the likelihood that a particular genetic mode of inheritance might explain the patterns observed in the study families.

Evidence that a particular gene might explain a specific cancer predisposition syndrome often derives initially from linkage studies that use collections of families meeting stringent clinical criteria for a specific cancer susceptibility syndrome. The demonstration of strong linkage of cancer susceptibility to a gene or genetic region in a pattern consistent with autosomal dominant inheritance provides evidence in support of both the mode of inheritance and the particular gene that might underlie the risk. Once linkage is established, a strong case for association between the genetic trait and disease can be made, even though the families used in the study may not be representative of the general population. The genetic trait measured in linkage studies is not always the causal factor itself but may be a genetic trait closely linked to it. Additional molecular studies are required to identify the specific gene associated with inherited risk, after linkage studies have determined its general chromosomal location.

Linkage studies, however, provide only limited evidence concerning either the range of cancer types associated with a mutation or the magnitude of risk and lifetime probability of cancer conferred by a mutation in less selected populations. In addressing these questions, the best information for clinical decisions comes from naturally occurring populations in which people with all degrees of risk are represented, similar to those in which clinical or public health decisions must be made. Thus, observations about cancer risk in families having multiple members with early breast cancer are applicable only to other families meeting those same clinical criteria. Ideally, the families tested should also have similar exposures to factors that can modify the expression of the gene(s) being studied. The mutation-associated risk in other populations, such as families with less dramatic cancer aggregation, or in the general population can best be assessed by direct study of those populations.

The clinical utility of the test refers to the likelihood that the test will, by prompting an intervention, result in an improved health outcome. The clinical utility of a genetic test is based on the health benefits related to the interventions offered to persons with positive test results. Theoretically, there are at least five strategies that might improve the health outcome of people with a genetic susceptibility to cancer:

• Correction of the underlying genetic defect (not currently available).
• Interventions to reduce the risk of developing cancer.
• Screening to detect early cancer or precancerous lesions.
• Specific treatment for syndrome-related cancers that differs from the treatment generally applied to the sporadic versions of the same cancer (not currently available).
• Interventions to improve quality of life.

Evaluation of interventions should consider their efficacy (capacity to produce an improved health outcome) and effectiveness (likelihood that the improved outcome will occur, taking into account actual use of the intervention and recommended follow-up). Sometimes genetic information may lead to consideration of changes in the approach to clinical management, based on expert opinion, in the absence of proof of clinical utility.

References

1. Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995.  [PUBMED Abstract]
   
   
2. Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003.  [PUBMED Abstract]
   
   
3. Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed June 28, 2007. 
   
   
4. Grann VR, Jacobson JS: Population screening for cancer-related germline gene mutations. Lancet Oncol 3 (6): 341-8, 2002.  [PUBMED Abstract]
   
   

Back to Top

< Previous Section  |  Next Section >