Review

Correspondence *Surgical Oncology Genomics Research Unit, Department of Surgery, Ioannina University School of Medicine, GR–451 10 Ioannina, Greece

Email droukos@cc.uoi.gr

Introduction

Dramatic advances in the 12 years since the discovery of the familial breast cancer susceptibility genes BRCA1 and BRCA2^{1, 2} have propelled genetic counseling and cancer prevention management in clinical practice to the point at which it is considered essential for every individual at high risk of developing familial breast and/or ovarian cancer.³ It is now well established that heterozygous germline mutations in BRCA1 and BRCA2 confer susceptibility to breast and ovarian cancer and to a lesser extent to other tumors.^{4, 5} BRCA1 and/or BRCA2 mutations (hereinafter also referred to as BRCA1/2 or BRCA) account for a disproportionately large share of life-years lost due to cancer because familial breast and/or ovarian cancer tend to occur in women at relatively young ages.⁶ The considerable costs and technical limitations of BRCA1/2 mutation analysis, however, still prohibit wide application of these tests in all women at high risk, and it is not yet established as to whom genetic testing should be offered.⁷ Advances in our understanding of BRCA functions and the DNA-damage repair networks, might help improve the outcomes for healthy carriers and patients with hereditary breast ovarian cancer (HBOC) syndrome.^{8, 9} This Review focuses on how preventive and therapeutic approaches can be tailored to individuals by integrating the latest translational and clinical research findings. We propose an individualized management algorithm based on existing evidence, and discuss the challenges related to genetic testing, prevention and treatment strategies.

Prevalence and screening for BRCA1/BRCA2 Mutations

Breast cancer is the most common cancer in females; more than 1 million women worldwide are diagnosed with breast cancer every year.¹⁰ In the US, approximately 170,000 new cases of invasive breast cancer are projected to be diagnosed in 2007.¹¹ Familial susceptibility to breast cancer accounts for approximately 25% of all breast cancer cases. In familial breast cancer, mutations in the BRCA1, BRCA2 and CHEK2, TP53 and PTEN genes account for approximately 5–10% of breast and ovarian cancer cases overall (i.e. HBOC syndrome).⁴ It is likely that the majority of these cancers could be avoided if appropriate genetic screening and preventive interventions were applied.¹²

The prevalence of BRCA1 or BRCA2 mutations varies considerably among ethnic groups and geographical areas. In North America, 1 in every 300–500 people are estimated to harbor BRCA germline mutations.¹³ A small number of prevalent mutations, so-called "founder" mutations, have been identified in different ethnic groups. In Ashkenazi-Jewish women, two mutations in BRCA1 and one mutation in BRCA2 account for more than 90% of HBOC.¹⁴ Testing for founder mutations is a relatively inexpensive approach that can facilitate large-scale national epidemiologic and preventive clinical studies on HBOC. Nevertheless, nonfounder mutations in both BRCA genes can occur and so screening the entire sequences of both genes for mutations is, therefore, necessary in individuals suspected of harboring BRCA1/2 mutations because of the genetic heterogeneity.¹⁵

Mutations in BRCA1 and BRCA2 are not the only hereditary genetic factors. Loss-of-function mutations in these two genes are estimated to account for about 20–25% of inherited susceptibility to breast cancer.¹⁶ Despite intensive research to identify other susceptibility genes, a third high-penetrance BRCA3 gene has not been identified. Instead, genes with low-to-moderate penetrance have been proposed to play a role.^{17, 18} CHEK2 is the most important breast cancer susceptibility gene identified since BRCA2. Women with the CHEK2^*1100delC germline mutation have a twofold greater risk of breast cancer than women in the general population.^{19, 20, 21, 22}

Referral to specialized hereditary breast cancer clinics

Genetic counseling and testing is a very sensitive social and medical issue that raises concerns regarding appropriate clinical management. Women considered at risk for carrying a BRCA1 or BRCA2 mutation should be advised to attend a specialized hereditary breast cancer clinic for authoritative genetic counseling and management. The popularity of genetic testing and high profit expectations have fostered internet direct-to-consumer marketing of these tests, which has raised concerns among clinicians and experts.²³ Sharon Plon, Chief of the Cancer Genetics Clinic at the Baylor College of Medicine, states that "members of the public are getting tests that they don't understand and their physicians may not understand, and they may be making big decisions that are ill-informed." On 27 July 2006, the Federal Trade Commission issued a consumer alert in an effort to address such concerns as well as privacy protection. In a related perspective article, it was emphasized that DNA collection, banking, and analyses are expanding rapidly, and that a federal genetic privacy law is needed to protect people who want to know their genetic risk, as well as those who do not. It must be noted that mutation analysis is associated with considerable limitations.²⁴ Not all BRCA1/2 carriers will develop breast or ovarian cancer, and not every mutation detected is of clinical significance.¹³ Moreover, there is uncertainty about risk estimates and prevention strategies for women from high-risk families who test negative for BRCA1 and BRCA2 mutations.²⁵ The impact of such limitations on the quality of life, estimate of genetic risk and genetic privacy preservation are at present unknown. For high-risk women, however, appropriate genetic counseling helps them make informed decisions, and can improve their knowledge and perception of absolute risk and often reduce anxiety.²⁶

Who should be tested?

Women with an inherited BRCA1 and/or BRCA2 mutation have a lifetime risk of 80% of developing breast cancer and a 20–60% lifetime risk of developing ovarian cancer (Table 1).^{13, 27} This extremely high cancer risk makes genetic testing essential for identifying mutation carriers; however, a number of legal, ethical and societal consequences need to be carefully addressed.²⁸ A recent systematic review revealed that a primary care approach to screening for inherited breast and ovarian cancer susceptibility genes has not been evaluated, and the benefits and risks for the general population are so far unknown.¹³ Guidelines proposed by international expert panels recommend genetic testing and appropriate preventive intervention in all at-risk individuals.^{26, 29, 30} Current screening for inherited breast and ovarian cancer includes four major steps: risk assessment, genetic counseling, BRCA gene testing, and appropriate medical intervention.¹³

Table 1 Lifetime risk estimates of developing breast and ovarian cancer among women at normal risk and those with inherited BRCA1 or BRCA2 mutations.

Full tableFigures & Tables indexDownload Power Point slide (232K)

Ideally, mutation analysis should be offered to all at-risk women, but the low prevalence of BRCA mutation carriers in the general population and the considerable costs prohibit wide genetic screening. If a family member is known to carry a BRCA1 or BRCA2 mutation, then genetic testing in all unaffected family members is recommended. For the vast majority of at-risk families the BRCA mutation status is not known, and there is no referral standard. Familial and personal history and age at cancer diagnosis are used to predict the presence of mutations in the general population. Several tools have been developed to predict a woman's likelihood of a positive BRCA test result; however, none of these tools has been validated. The carrier prediction models that have been developed, such as the BOADICEA, BRCAPRO and Myriad II, are yet to be validated for effectiveness in primary care.³¹

On the basis of prevalence estimates, it is suggested that genetic testing should be offered to women with a 10% or greater probability of having a BRCA mutation.^{26, 29} Probability thresholds should be less strict for high-risk populations such as Ashkenazi-Jewish women. On the basis of the results of the New York area breast cancer study, which revealed high-risk individuals not only among first- or second-degree relatives but also in remote kinships, some experts advocate implementing research screening studies in populations with known founder mutations.^{32, 33}

Risk reduction

Choosing preventive intervention

Selecting the most appropriate preventive strategy for women with familial susceptibility to HBOC is not a straightforward task. Risk assessment, the limitations of genetic testing, the effectiveness of risk reduction and the adverse effects of these interventions, as well as their impact on survival and quality of life, should carefully be considered. Existing evidence is mainly based on cohort or case–control studies, although, in the case of tamoxifen, evidence has been obtained from randomized controlled trials.^{65, 66} Despite these limitations, preventive intervention for BRCA mutation carriers is urgently required, because these women are at very high risk of developing breast and/or ovarian cancer at a young age. Furthermore, without adequate prevention the mortality for these women is high because of late cancer diagnosis.⁵⁹

Table 2 summarizes the effects of surgical and nonsurgical interventions on survival and quality of life in women from HBOC families. Prophylactic surgery remains the most effective modality for reducing both cancer risk and mortality, although a direct comparison of surgical and nonsurgical preventive interventions in randomized studies is still lacking. Among all preventive interventions currently available for women who test positive for a BRCA1 or BRCA2 mutation, PBSO offers the highest overall cancer protection at acceptable levels of side effects and quality of life.

Table 2 Surgical and nonsurgical interventions: safety, reduction of cancer incidence and mortality, and impact on quality of life in BRCA1/2 mutation carriers.

Full tableFigures & Tables indexDownload Power Point slide (276K)

As surgery offers more than 90% risk protection, the key question is not the choice between surgery or screening but what type of surgery should be performed.⁵⁰ PBSO is superior to BPM because it reduces the risks of both ovarian and breast cancer, and there are now data to indicate that PBSO reduces both overall mortality and cancer-specific mortality.⁴⁶ PBSO is also associated with a lower morbidity and side-effects profile than BPM. As ovarian cancer is diagnosed later and is associated with greater mortality than breast cancer, laparoscopic PBSO is currently recommended by most experts in the field of prevention of HBOC syndrome.⁴¹ This consensus is reflected in a North American survey; among women who had a positive BRCA test, 60% underwent PBSO, 25% BPM, and only 12% received tamoxifen.³

The selection of an appropriate risk-assessment-based prevention strategy for women who tested negative for the BRCA1/2 mutation is complicated because of the uncertainty of risk estimation. For these women, risk assessment can be improved by using more-effective methods of identifying a large genomic deletion or duplication in BRCA1 or BRCA2 genes and by screening for a mutation in CHEK2.²⁰ Considering all the evidence available, we have developed an individualized management algorithm for women at risk of the HBOC syndrome (Figure 1).

Figure 1 Proposed individualized management algorithm for women at high risk for the hereditary breast ovarian cancer (HBOC) syndrome.

Bold arrowed line represents a first-choice recommendation based on existing evidence; thin arrowed line represents a second-choice recommendation based on existing evidence; dotted arrowed line represents additional/alternative biologically rational option. The + symbol indicates that these options should complement each other. ^aMember of a family with a known BRCA1/2 mutation or a woman with a strong family history of disease. Strong family history means at least three close relatives with breast or ovarian cancer, or, if two or fewer close relatives, ovarian cancer or male breast cancer. Age at diagnosis of affected member(s) with breast cancer is considered. Close relatives include first-, second-, and third-degree relatives.^30bAn uninformative or a definitely negative BRCA1/2 test result does not essentially lift the risk for women with a strong breast and/or ovarian cancer family history, given that the known BRCA1/2 mutations account for only 20–25% of familial aggregation.¹⁶ A positive family HBOC history on its own classifies these women in the high-risk group.^88cFor a woman with a negative BRCA1/2 test from an at-risk family in which no BRCA1/2 mutation has been detected, testing for CHEK2^*1100delC can be proposed. Women with this germline mutation have a twofold increased risk of breast cancer and might benefit from an individualized prevention strategy including intensive screening and preventive intervention.^{19, 20, 21, 22d}Raloxifene can be considered as an alternative treatment for women at increased risk of thrombosis or marked osteopenia.⁷⁵ Abbreviations: BC, breast cancer; HBOC, hereditary breast ovarian cancer; OC, ovarian cancer; PBSO, prophylactic bilateral salpingo-oophorectomy; PBM, prophylactic bilateral mastectomy.

Full figure and legend (58K)Figures & Tables indexDownload Power Point slide (262K)

An integrated model for individualizing prevention strategy

Before genetic testing, a predefined specific preventive intervention according to whether the test result is positive or negative should be available. The likelihood of a woman having a positive genetic test result can be estimated on the basis of personal and family history. Referral to testing will depend on the thresholds set by each country. Owing to the high costs of genetic testing it is impractical to offer mutation analysis to all at-risk women. In individuals with identified germline BRCA1/2 mutations, PBSO is currently the widely accepted preventive intervention, with BPM as the second choice. Alternatively, if a woman rejects prophylactic surgery, intensive and close surveillance including MRI is offered with endocrine chemoprevention; for example, tamoxifen for postmenopausal BRCA2 carriers.

An uninformative or a definitively negative BRCA1/2 test result must not be considered good news for women with a strong family history of breast and/or ovarian cancer, because known BRCA mutations account for only 20–25% of familial aggregation.¹⁶ On its own, a positive family history of HBOC classifies these women as at risk.^{16, 88} For uninformative negative test results an individualized approach is recommended, and includes testing for CHEK2^*1100delC and close surveillance. An algorithm-based prevention strategy has been developed at the Ioannina University in Greece on the basis of these considerations (Figure 1).

Treatment

Current treatment guidelines for early-stage breast cancer recommend local therapy, i.e. surgery with or without radiotherapy, and adjuvant systemic treatment.⁸⁹ Breast-conserving therapy (BCT) is an acceptable primary treatment for early-stage tumors or following neoadjuvant treatment for larger or locally advanced breast cancers. BRCA mutation carriers are at high risk of in-breast tumor recurrence (IBTR) and contralateral breast cancer (CBC)^{90, 91, 92, 93} as well as ovarian cancer⁹⁴ after BCT. Recently, Pierce et al. compared the outcomes of 160 BRCA1 or BRCA2 mutation carriers with breast cancer with those of 445 controls with sporadic breast cancer after BCT.⁹⁰ The rate of CBC 15 years after BCT was 39% in BRCA1/2 carriers and 7% in controls (P < 0.001). Although there was no significant difference in IBTR between the groups, multivariate analysis showed a significantly higher IBTR rate among BRCA1/2 carriers than in controls when carriers who had undergone oophorectomy were removed from analysis (P = 0.04).⁹⁰ These data suggest that a more-extensive surgical procedure than BCT, such as bilateral mastectomy, or additional therapies beyond radiotherapy and tamoxifen could be considered for mutation carriers with a diagnosis of breast cancer in order to reduce the risk of breast cancer recurrence.

Conclusions

A prevention strategy consisting of genetic testing and medical intervention for young at-risk BRCA1/2 carriers is acknowledged, but there is some uncertainty about who should be tested and what the optimum management is. Criteria based on personal and family history do not accurately predict the probability of a positive test result, and thresholds for deciding who should be tested vary considerably among countries. Recent evidence indicates that PBSO is superior to PBM or surveillance in BRCA1/2 mutation carriers after completion of childbearing or in those aged 35–40 years. The long-term effects after an early surgical menopause, however, are unknown. There is uncertainty surrounding risk estimates and management of at-risk women who test negative for BRCA1/2. There is no standard treatment for BRCA1/2 carriers with a new diagnosis of breast cancer. These women might benefit from an extensive procedure at the time of surgery, but data are still limited. Decisions on systemic adjuvant treatment are made on the basis of standard clinicopathologic features and ER/HER2 status. Microarray-based profiling provides promise for tailoring treatment to individuals according to cancer subtype. Accumulating evidence indicates that an individualized clinical management approach provided by a specialized team is beneficial.¹⁰⁴

Acknowledgments

The authors would like to thank Dr Angelos Kappas, Professor of Surgery at Ioannina University for his contribution to concept and content discussions and clinical support, and Dr Dimitrios Trichopoulos, Professor of Cancer Prevention at the Harvard School of Public Health, Boston, Massachusetts and Dr Nikos Pandis, Associate Professor of Medical Genetics, University of Lund Sweden, Head of the Department of Genetics, "Saint Savas" Anticancer Hospital, Athens, Greece, for critical reading of the manuscript and insightful comments. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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