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Cancer Genetics Risk Assessment and Counseling (PDQ®) 4/7 –Health Professional Version - National Cancer Institute

Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version



Components of the Risk Assessment Process

This section provides an overview of critical elements in the cancer risk assessmentprocess.
A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1-5] Except where noted, the discussion below is based on these guidelines.
The cancer risk assessment and genetic counseling process consists of one or more consultative sessions and generally includes the following:
  • A detailed, multifaceted assessment including medical, psychosocial, and family history.
  • A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
  • Education and counseling about familial/hereditary cancer risks.
  • If appropriate, review of genetic testing options as well as potential limitations, risks, and benefits of testing.
  • Establishment of a cancer risk management plan.
  • Discussion of follow-up plans, provision of referrals, educational materials, etc.

Assessment

At the outset of the initial counseling session, eliciting and addressing the consultand'sperceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

Psychosocial assessment

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or after the session, particularly after genetic testing. Information collected before and/or during the session may include the following:
  • Motivations for seeking cancer risk assessment.
  • Beliefs about the causes of cancer.
  • Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
  • The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
  • Cultural, religious, and socioeconomic background.
  • General psychological history, such as depression or anxiety, and medication use.
  • Coping mechanisms.
  • Support systems.
Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status.

Risk perception

Perceived risk can play an important role in an individual’s decision to participate in counseling,[6] despite the fact that perceived risk often varies substantially from statistical risk estimates.[7-9]

Clinical Evaluation

Personal health history

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:[1,3]
  • Current age.
  • Race, ancestry, and ethnicity.
  • History of benign or precancerous tumors or polyps, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
  • Screening practices and date of last screening exams, including imaging and/or physical examinations.
  • Environmental exposures.
  • Past and current alcohol intake and tobacco use.
  • Diet, exercise, and complementary and alternative medicine practices may also be assessed.
For consultands with a history of cancer, additional information collected includes the following:
  • Site/type of primary malignancy and any metastasis or recurrence.
  • Age at diagnosis.
  • Pathology findings/staging.
  • Prior germline genetic testing results.
  • Prior tumor testing results (including genomic profiling). (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about the implications of tumor testing.)
  • Treatment (e.g., surgery, chemotherapy, radiation therapy, targeted therapy), including whether genetic risk assessment may affect treatment.
  • Bilaterality of disease, if applicable.
  • Current surveillance plan.
  • Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
  • How the cancer was detected (e.g., self-exam, screening test, presenting symptoms) may also be assessed.

Physical examination

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

Family history

Documenting the family history
The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information.[10] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [11] and that the use of these questionnaires is an acceptable and understandable family history collection method.[12] Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. However, on average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[13] It has been reported that questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[14] Collecting family history from multiple relatives in a single family has been shown to increase the number of family members reported to have cancer, compared with family history information provided by a single family member.[15]
Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[16,17]
Standards of pedigree nomenclature have been established.[16,17] Refer to Figure 1 for common pedigree symbols.
ENLARGEStandard pedigree nomenclature; diagram shows common symbols used to draw a pedigree.
Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.
Refer to the paragraph below for descriptions of factors suggesting inherited cancer risk.
Documentation of a comprehensive family cancer history typically includes the following:
  • A three-generation pedigree consisting of a minimum of first- and second-degree relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.[18]
  • Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific pathogenic variants in some genes are known to occur with increased frequency in some populations (founder effect).[18]
  • Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
  • Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm).
A three-generation family history includes the following:
  • First-degree relatives (e.g., children, brothers and sisters, and parents).
  • Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
  • Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
  • Additional distant relatives are included if information is available, especially when there are known cancer histories among them.
For any relative with cancer, collect the following information:[19]
  • Primary site of each cancer. Obtaining medical documentation of key cancers (e.g., pathology reports, clinical documents, and death certificates) is especially relevant to risk assessment and/or management recommendations. (Refer to the Accuracy of the family history section of this summary for more information.)
  • Age at diagnosis for each primary cancer.
  • Where the relative was diagnosed and/or treated.
  • History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
  • Current age (if living).
  • Age at death and cause of death (if deceased).
  • Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
  • Prior germline genetic testing results.
  • Prior tumor testing results (including genomic profiling).
  • Other significant health problems.
For relatives not affected with cancer, collect the following information:
  • Current age or age at death.
  • Cause of death (if deceased).
  • History of any surgeries or treatments that may have reduced the risk of cancer.
  • Cancer screening practices.
  • Any nonmalignant features associated with the syndrome in question.
  • Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
  • Prior germline genetic testing results.
  • Prior tumor testing results (including genomic profiling).
  • Other significant health problems.
Accuracy of the family history
The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[20] However, people often have incomplete or inaccurate information about the cancer history in their family.[17,19,21-27] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[28] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[23,29]
Accuracy varies by cancer site and degree of relatedness.[25,30,31] Reporting of cancer family histories may be most accurate for breast cancer [25,31] and less accurate for gynecologic malignancies [25,31] and colon cancer.[25] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[23,29,31] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.

Determining Cancer Risk

Analysis of the family history

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:
  1. What is the evidence that a cancer susceptibility syndrome is present in this family?
    The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:[18]
    • Multiple cancers in close relatives, particularly in multiple generations.
    • Early age of cancer onset (younger than age 40 to 50 y for adult-onset cancers).
    • Multiple primary cancers in a single individual.
    • Bilateral cancers.
    • Recognition of the known association between etiologically related cancers in the family (e.g., breast and ovarian cancers; colon and endometrial cancers).
    • Presence of congenital anomalies or precursor lesions that are known to be associated with increased cancer risk (e.g., presence of atypical nevi and risk of malignant melanoma).
    • Recognizable mendelian inheritance pattern.
    • Specific tumor types or pathologies associated with germline pathogenic variants in cancer susceptibility genes, regardless of family history (e.g., ovarian cancer, medullary thyroid cancer, triple-negative breast cancer, sex cord tumors in ovarian cancer). (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about these tumor types and the associated genes.)
    • Abnormal results from colon or endometrial tumor testing with microsatellite instability or immunohistochemistry, suggestive of Lynch syndrome. (Refer to the Genetics of Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
    • Somatic variants identified from tumor genomic profiling that may be present in the germline.
    Clinical characteristics associated with different cancer genetic syndromes are summarized in the following comprehensive set of personal and family history criteriaExit Disclaimer published by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[32] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.
  2. If a syndrome is suspected, what are the differential diagnoses?
    The most commonly encountered indications for genetic counseling/testing are for suspected hereditary breast cancer or hereditary colon cancer syndromes.
    For hereditary breast cancer, genetic counseling and testing criteria are broad.[32,33] Multigene panel testing has revealed that pathogenic variants in several other high- and moderate-penetrance genes other than BRCA1 and BRCA2 contribute to this phenotype, such as PALB2, CHEK2, and ATM.
    For hereditary colon cancer syndromes, differential diagnoses are based on several factors, including the number and type of colorectal polyps and histopathology of gastrointestinal and other malignancies.[34,35] However, in the absence of polyposis and rare pathologies, Lynch syndrome is frequently in the differential. Furthermore, Lynch syndrome may be in the differential diagnoses list even when there are cases of breast and/or ovarian cancer in the family that are not consistent with hereditary breast and ovarian cancer.[36,37] (Refer to the Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
    Diagnostic and testing criteria exist for several rare syndromes such as Li-Fraumeni,[38] Cowden,[39,40] multiple endocrine neoplasias,[41] and familial adenomatous polyposis.[34] In some cases, pathognomonic features are also an indicator for a likely diagnosis.[39,40]
    Based on these considerations, genetic testing options may consist of limited targeted testing for pathogenic variants in one or a small number of genes, or may consist of larger gene panels.
  3. What could make the family history difficult to interpret?
    Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology.[42-44]
    Common examples of complicating factors related to family history structure include the following:
    • Small family size.
    • Incomplete information due to lack of knowledge of family history (e.g., due to adoption or lack of information about cancers in relatives).
    • Gender imbalance (e.g., few women in a family suspected of hereditary breast cancer).
    • Deaths at particularly early ages.
    • Removal of the at-risk organ, either for risk reduction or as a result of a medical condition (e.g., hysterectomy due to history of uterine fibroids or endometriosis may hamper the identification of Lynch syndrome).
    • Misattributed parentage.
    • Consanguinity.
    Genetic factors that may affect family history interpretation include:
  4. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?
    The mode of inheritance refers to the way that genetic traits are transmitted in the family.
    Most commonly, inheritance patterns are established by a combination of clinical diagnosis with a compatible, but not necessarily in itself conclusive, pedigree pattern.[45] Most recognized hereditary cancer syndromes are autosomal dominant or autosomal recessive. Clues to recognizing these patterns within a pedigree are described below. (Refer to question 3, What could make the family history difficult to interpret?, for a list of situations that may complicate pedigree interpretation.)
    Autosomal dominant
    • Autosomal dominant inheritance refers to disorders that are expressed in the heterozygote (i.e., the affected person has one copy of a variant allele and one allele that is functioning normally). All the major hereditary breast/ovarian cancer syndromes including BRCA1/BRCA2, Li-Fraumeni, and Cowden, as well as the major hereditary colon cancer syndrome, Lynch syndrome, are inherited in this fashion. Autosomal dominant inheritance is characterized by the following:
      • Vertical occurrence (i.e., seen in successive generations).
      • Usually seen only on one side of the family (i.e., unipaternal or unimaternal).
      • Males and females may inherit and transmit the disorder to offspring.
      • Male-to-male transmission may be seen.
      • Offspring have a 50% chance of inheriting a pathogenic variant and a 50% chance of inheriting the normal allele.
      • The condition may appear to skip a generation due to incomplete penetrance, early death due to other causes, delayed age of onset, or paucity of males or females when the at-risk organ is gender-specific (e.g., prostate and ovary).
      • It is possible for an individual to have a genetic variant that has not previously been expressed as an autosomal dominant family history of cancer due to a variety of factors discussed above (refer to question 3).
      • It is possible for an individual to have a de novo (new) pathogenic variant. This person would be the first affected member of his or her family but could transmit this trait in the usual autosomal dominant manner to their offspring.
      • It is possible for an individual to have pathogenic variants in more than one gene associated with known autosomal dominant inherited cancer predisposition syndromes. In families showing a phenotype suggestive of more than one susceptibility syndrome, identifying such variants helps to clarify the diagnosis and determine the appropriate testing strategy in family members.[46]
    Autosomal recessive
    • Autosomal recessive inheritance refers to an inheritance pattern in which an affected person must be homozygous (i.e., carry two copies of an altered gene, one from each parent). Some well-defined cancer susceptibility syndromes with an autosomal recessive inheritance pattern include Bloom syndrome, ataxia-telangiectasia, MUTYH-associated polyposis, and Fanconi anemia. Autosomal recessive inheritance is characterized by the following:
      • Horizontal occurrence (i.e., seen in one generation only [affected siblings in the absence of affected parents]); generally not seen in successive generations.
      • Genetic variants must come from both sides of the family (i.e., biparental inheritance).
      • Parents are heterozygous carriers; each carries one variant copy of the gene and one functional copy.
      • Parents usually do not express the trait or the full syndrome; in some cases, parents may show a mild version of some features.
      • In cases of two heterozygous parents, there is a 25% risk of future offspring being affected (homozygous).
    Complex
    • Most cancers, and most familial cancers, appear to have a complex etiology. Within clinical settings, negative or uninformative genetic testing results are common. One possible explanation for these results may be that multiple factors contributed to the development of the observed cancer(s) which are not easy to pinpoint.
    • Complex or multifactorial disease inheritance is used to describe conditions caused by genetic and environmental factors. In contrast to mendelian diseases where carrying one specific pathogenic variant is associated with high likelihood for developing the disease, complex/multifactorial diseases are caused by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. In most cases, the effects of genetic, lifestyle, and environmental factors in aggregate determine a person’s likelihood of being affected with a condition, such as cancer.
      Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[47]
      The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although some high-risk pathogenic variants in major cancer susceptibility genes are consistent with recognizable mendelian inheritance patterns, these syndromes are rare.
  5. What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
    These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity that are discussed elsewhere.
  6. If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?
    A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

Methods of quantifying cancer risk

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[48] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[48]
Risk of harboring a pathogenic variant in a cancer susceptibility gene
The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant.[49] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features.[49,50] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.
If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominantly female in origin, adoption, and early deaths from other causes.[42,50] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[43] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[43,49,50]
When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,51] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.
Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[52] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).
Risk of developing cancer
Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[53] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]
In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[51] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[51,54]
In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[51,54] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[50] Furthermore, many of these models were constructed from data derived from predominantly white populations and may have limited validity when used to estimate risk in other ethnicities.[55]
Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[56,57] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.
In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[49] Influencing factors include the following:
  • Differential diagnosis that is consistent with the personal and cancer family history.
  • Consideration of factors that influence how informative the family history may be.
  • Population that is best suited for the use of the model.
  • Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
  • Model-specific limitations that can overestimate or underestimate calculations.[43]
A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[58] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[49]
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