Patients with a Family History of Cancer: Identification and Management

Identifying Patients at Increased Cancer Risk Because of Family History

Family history is best assessed via construction of a pedigree covering at least 3 generations. In general, family histories of cancer that suggest increased susceptibility include: 2 or more relatives on the same side of the family with the same or a related cancer, earlier than average age of diagnosis (typically ≤50 years of age for most cancers), and the presence of more than 1 primary cancer in a family member, exclusive of metastatic disease. (Although not a focus of this study, the presence of specific medical conditions [eg, ulcerative colitis] may also be associated with an increased risk of developing certain types of cancer.) It is important to note that hereditary cancers also may occur in the less typically affected sex (eg, male breast cancer).4 In such cases, evaluation by a genetics professional should be considered to be assured of comprehensive assessment and appropriate counseling as a prelude to possible genetic testing.6

Although collecting family history data on each family member is essential to identifying patients at increased risk, it is clear that such data are not routinely or comprehensively collected by most physicians. Although most charts contain some information on family history, cancer history, and age at diagnosis, the presence of high-risk lesions (eg, colonic polyps, atypical ductal hyperplasia on breast biopsy) and updated information are often absent.5,7

Several barriers to adequate pedigree construction exist. Time constraints on physicians may make pedigree construction challenging; furthermore, physicians may feel unprepared to discuss genetic issues and manage the emotions that may arise.5 Computerized tools and preintake questionnaires may help physicians overcome some of these barriers.5 Physician concerns regarding potential medicolegal issues and employer discrimination may also hinder efforts to screen patients for familial cancer risk.3 Ultimately, physicians will need to view genetic counseling as an ongoing communication process.8 National guidelines, and other resources, can assist primary care physicians in discussing genetic risk with their patients.

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), as well as other professional specialty societies, have developed recommendations regarding genetic counseling and possible cancer gene testing for patients with a personal and/or family history of cancer that meets certain syndrome-specific criteria based on clinical, pathologic, and/or testing features (Strength of Recommendation Taxonomy [SORT] level C).9,10 ASCO emphasizes that all genetic testing must be accompanied by comprehensive pre-test and post-test counseling, as well as informed consent.9 The full set of NCCN guidelines can be accessed at http://www.nccn.org. ASCO clinical practice guidelines can be accessed at http://www.asco.org/ac.

Family History and Breast/Ovarian Cancer

A family history of breast cancer and/or ovarian cancer increases risk for both of these cancers. Women with at least one first-degree relative with breast cancer have 2 to 4 times the risk of developing breast cancer.11 Factors such as a greater number of affected relatives, younger age at diagnosis, and closer kinship each further increases the risk.12,13

Approximately 5% to 10% of breast cancer cases are caused by known mutations in cancer susceptibility genes, the most common being BRCA1 (BReast CAncer 1) and BRCA2, identified in the early to mid-1990s.14,15 These mutations are inherited in an autosomal-dominant manner.16 Although the prevalence of BRCA1 mutations in the general population is estimated to be 1 in 800,17 the prevalence of BRCA2 is unknown.18 Whereas hundreds of different mutations in these genes have been identified across affected families,19 3 specific mutations are more common (2.5%) in women of Ashkenazi Jewish ancestry.20,21 An extensive study of Jewish BRCA mutation carriers reported the lifetime risk of breast cancer was approximately 56% (95% CI, 40% to 73%), whereas the risk for ovarian cancer was 16% (95% CI, 6% to 28%).15,20 Other reports have estimated that by age 60, 54% (95% CI, 27% to 71%) of BRCA1 mutation carriers may have breast cancer, whereas 30% (95% CI, 8% to 47%) may have ovarian cancer.9,11 Genetic specialists use various risk assessment models to estimate risk for breast cancer and the likelihood of detecting a BRCA mutation, as well as providing clinical and pedigree evaluation to assess for this and other breast cancer genetic syndromes.22

Identification and surveillance strategies for women who are at increased risk for breast cancer are summarized in Table 1. Patients with an increased risk of breast cancer because of family history factors should be informed of this concern and instructed regarding a surveillance plan. Appropriate surveillance is dependent on mammographic screening beginning either at 30 years of age or 10 years before the earliest age at breast cancer diagnosis in a family member (SORT level C).23 It has been found that BRCA mutation carriers may benefit from mammography beginning at age 25 years or sooner, depending on the earliest diagnosis in the family.24 So far, the utility of breast magnetic resonance imaging for breast cancer surveillance in high-risk women has not been established. Although evidence is inconclusive, women at increased risk for breast cancer may benefit from lifestyle changes, including increased exercise, as well as chemoprevention with agents such as tamoxifen.3

Surveillance recommendations (Table 2) for women at increased risk of ovarian cancer based on family history include pelvic examination, CA-125 testing, and vaginal ultrasound monitoring (SORT level C).24,25 Frequency of testing is best addressed via referral to a comprehensive cancer center where broad clinical experience and a variety of support services are also available.

Ideally, women with a family history of breast and/or ovarian cancer can be referred for genetic counseling and, if judged appropriate, offered genetic testing (SORT level C).26 Testing often begins with an affected relative, if available. If a mutation is identified in an affected person, genetic testing for the specific mutation can be extended to other family members.4 Based on an autosomal-dominant pattern of inheritance, the children of a carrier will have a 50% chance of having the same mutation.6 Prophylactic mastectomy for mutation carriers has been shown to reduce the risk of breast cancer by as much as 90%, as well as increase life expectancy by as much as 5 years.3 Similarly, prophylactic oophorectomy may decrease subsequent breast and ovarian cancer rates and increase life expectancy.3 For both these procedures, however, any potential benefits must be weighed along with long-term quality-of-life issues.

Finally, it should be noted that application of empiric risk breast cancer assessment models (eg, Gail or Claus) should not automatically occur for women at increased risk because of family history, because these models have limitations yielding both underestimates and overestimates of risk.3 In general, Gail risk estimate figures are typically higher than Claus risk estimates, with both models being more accurate for women at low to moderate risk. The use of mutation probability models should be used in those patients whose family history is suggestive of the presence of a genetic mutation.3

Family History and Colorectal Cancer

Risk of colorectal cancer is increased among persons with one or more affected first-degree family members27; the relative risk exceeds 5 among persons with an affected first-degree relative diagnosed before age 45 years.27 In families with more than one person diagnosed with colorectal cancer, the cause may be multifactorial, including environmental influences and inheritance of genetic factors.28 Cases of colorectal cancer (CRC) can be classified into 3 categories: (1) sporadic (no family history), accounting for approximately 60% of all cases; (2) familial (several affected family members), accounting for 30% of cases; and (3) hereditary (caused by defined genetic syndromes), which represents the remainder.29 Colorectal cancer screening guidelines issued by the American Cancer Society classify these categories as “average,” “moderate,” and “high risk,” respectively.29

Colorectal cancers in a family can be caused by mutations in a single gene. Familial adenomatous polyposis (FAP) is an autosomal-dominant multisystem disorder, with the classic form characterized by the formation at an early age of hundreds to thousands of adenomatous polyps within the colon and rectum.30 Although FAP accounts for 1% of all colorectal cancer cases, persons with FAP have a nearly 100% chance of developing cancer by age 50.30 Because FAP is caused by mutations in the adenomatous polyposis coli (APC) gene, genetic testing can be offered to at-risk patients and their families (SORT level C).30 Affected persons, and others deemed to be at risk for FAP, require surveillance beginning as early as age 10 to 15 years (SORT level C).31

Hereditary nonpolyposis colorectal cancer (HNPCC) is another autosomal-dominant condition manifesting as early-onset CRC, as well as other malignancies, involving the endometrium, small bowel, ureter, or renal pelvis.28 HNPCC accounts for 6% of all colorectal cancers and is not typically preceded by formation of polyps.32 Persons with HNPCC have a lifetime risk of CRC ranging between 70% and 80%.32,33 Women with HNPCC have a lifetime risk of 30% to 60% for developing endometrial cancer.34

In 1990, the Amsterdam criteria were developed by the International Collaborative Group to aid in the identification of HNPCC families. The classic guidelines recommend further investigation of those patients for whom CRC occurs in 3 or more family members, affecting 2 successive generations, involving at least 2 persons who are first-degree relatives of another, and include one case diagnosed before age 50 years. Furthermore, FAP should be excluded in all cases of CRC, and tumors must be verified by pathologic evaluation.35 The Amsterdam criteria were expanded in 1999 to include other HNPCC-associated tumors (eg, cancers of the endometrium, small bowel, ureter, or renal pelvis).36 For the HNPCC-affected family, surveillance guidelines from the NCCN recommend colonoscopy beginning at age 20 to 25 years, or 10 years before the youngest age at diagnosis in the families. Colonoscopy should be repeated every 1 to 2 years until age 40 years, when surveillance colonoscopy should be performed annually (SORT level C). Among affected women, transvaginal ultrasound or endometrial biopsy can be considered beginning at age 25 (SORT level C).31

Table 3 summarizes the identification and management of persons at increased risk for colorectal cancer because of family history. Beginning at age 40 years (or 10 years before the age of the earliest onset in the family), persons with a mother, father, or sibling who has been diagnosed with colorectal cancer require a colonoscopy (SORT level C).31 The interval to the next colonoscopy is generally determined after the initial evaluation and may range from 1 to 5 years. Persons undergoing surveillance for increased risk of colorectal cancer require colonoscopic examination; no other test can be substituted.31

Family History and Prostate Cancer

Men with a brother or father affected by prostate cancer have approximately twice the risk of developing prostate cancer themselves; risk increases as the number of affected family members increases (SORT level B).37 In addition, men from families with a history of breast and/or ovarian cancers may also be at increased risk for prostate cancer; consultation with a genetics professional for risk assessment and possible testing for BRCA-1 and BRCA-2 mutations should be considered.6,38

Both the ACS and NCCN recommend surveillance via digital rectal examination and prostate-specific antigen testing beginning at age 45 years among men with 2 or more affected first-degree relatives (SORT level C).23,39 The American Urologic Association (AUA) recommends surveillance starting at age 40 years for men with 1 affected first-degree relative (SORT level C).40

As presented in Table 4, surveillance for prostate cancer should begin at age 40 years (or 10 years before the age of earliest diagnosis in an affected family member) and include annual digital rectal examination and prostate-specific antigen testing (SORT level C).41 Similar to issues relating to prostate cancer screening, there is insufficient evidence that prostate cancer surveillance among patients at increased risk results in reduced morbidity or mortality or improved survival. Regardless of when surveillance is begun, all patients should be counseled regarding the risks, benefits, and uncertainties of various modalities for prostate cancer surveillance.39

Counseling High-Risk Patients

Patients are increasingly becoming aware of the need to discuss family medical history with their physicians. It has been reported that patient inquiry represents the primary motivator for physicians ordering genetic tests.3 Although evidence supporting a clear benefit of counseling may be unavailable, it is clear that patients will continue to look to their family physicians for guidance in this area.

Persons identified as being at increased risk for various cancers based on their family history should have an opportunity to have questions answered either by their family physicians or through referral to a genetics professional. These patients should understand the surveillance plan that is recommended, as well as the importance of remaining up to date on other cancer screening tests. All patients should be counseled on the benefits of a tobacco-free lifestyle, a diet rich in fruits and vegetables, maintenance of a healthy body weight, and participation in regular exercise. Opportunities to participate in prevention and early detection trials are available through comprehensive cancer centers and academic health centers.

Conclusion

As our understanding of the genetic components of cancer continue to rapidly expand, several barriers to identifying and counseling at-risk families remain.4 Current genetic testing techniques are less than 100% sensitive and specific, leaving negative results open to misinterpretation.1,6 In addition, genetic tests are only useful for identifying known mutations. Such limitations highlight the importance of appropriate pre-test and post-test genetic counseling, current knowledge of relevant genetic information and resources, and commitment to the process of informed consent for patients interested in genetic testing.6 Furthermore, genetic testing results are relevant to other family members, because this information can have an impact on their health care and medical decisions and often raises concerns regarding health and life insurance and employment and reproductive issues.6 In these situations, consultation with a genetics professional can be helpful.6

Identifying patients at increased cancer risk because of family cancer history and/or hereditary cancer syndromes begins by obtaining an accurate detailed family history to determine cancer risk. Family history is best assessed via construction of a pedigree that includes at least 3 generations. Even after preparation of a comprehensive pedigree, uncertainties can remain. Clinicians must be able to assess available information and discuss the risks and benefits of genetic testing with their patients. Family physicians are well positioned to use their skills in identifying patients at increased cancer risk because of family history and/or genetic syndromes and to encourage compliance with surveillance strategies.