Breast Cancer Risk Assessment: Moving Beyond BRCA 1 and 2

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The National Cancer Institute estimates that 12.3% of all women (about 1 in 8) would be diagnosed with breast cancer throughout their lifetime. In 2015, a projected 231,840 new cases are expected in the United States, accompanied by 40,290 deaths. Presently, breast cancer is responsible for 6.8% of all cancer deaths, and roughly 30% of all cancers in women. Since the discovery of the BRCA gene in 1994, efforts have been made to develop effective screening methods for breast cancer detection. Although the BRCA gene certainly opened the door to breast cancer genetics, a wide variety of new genes have recently been linked to breast cancer risk, and the tools to screen for genes beyond just BRCA1 and BRCA2 are available. However, the indications for both screening and prevention of inherited predispositions beyond BRCA1 and BRCA2 are not entirely clear, and as a result, much of the ongoing work is aimed at determining the role of broader genetic screening in women deemed at sufficiently high risk for breast cancer based on family history. On this topic, we provide a brief overview of the genes associated with breast cancer risk as well as the technological platforms available to patients. We conclude by discussing recommendations of expert groups and what they practically mean for patients.

Introduction

Breast cancer is the most common cancer in women worldwide, and in the United States alone, it is estimated that there would be more than 230,000 patients with invasive disease in 2015 with more than 40,000 deaths expected in 2015.1 The discovery that BRCA mutations are associated with an increased risk of breast cancer (as well as ovarian and other cancers) was a seminal event in cancer genetics. For the first time, genomic linkage analysis revealed the presence of deleterious mutations on chromosome 17q21 associated with breast and ovarian cancers in high-risk families.2 These gene mutations were discovered to be located on the BRCA1 gene. A subsequent discovery of families with high risk who were not found to have a BRCA1 mutation identified BRCA2 located on chromosome 13q12-13.3 Yet, although mutations in BRCA account for between 12% and 31% of breast cancer risk among high-risk families,4, 5 it is now recognized that other breast cancer susceptibility genes also exist.

Evidence-based testing guidelines, counseling, and risk-reducing interventions have been established for hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2) as well as other less common high-penetrance autosomal dominantly inherited breast cancer conditions, including Li-Fraumeni syndrome (TP53), hereditary diffuse gastric cancer (CDH1), Cowden׳s syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).6 However, next-generation technology has enabled massively parallel sequencing at low cost, which has fostered the advent of multiplex genetic testing and the identification of other less penetrant genes carrying a predisposition to breast and other cancers.

Section snippets

TP53

Mutations involving p53 are inherited in an autosomal dominant fashion. The result is a familial predisposition to a diverse array of cancers, including breast cancer. Indeed, the estimated risk of breast cancer in women with this condition is roughly 49% by 60 years, and in several studies, up to one-third of those women diagnosed with breast cancers were diagnosed before 30 years.7, 8

STK11

Mutations in the serine-threonine kinase STK11 result in Peutz-Jeghers syndrome, which is associated with the

CHEK2

The CHEK2 gene is a member of the Fanconi Anemia (FA)-BRCA pathway and is involved in both checkpoint function and in BRCA1- and p53-mediated repair. Mutations in CHEK2, including 1100delC, have recently been associated with a 3- to 5-fold increase of breast cancer.12 In a large meta-analysis of 26,000 cases compared to as many controls, for example, the aggregated odds ratio of breast cancer in general, early-onset breast cancer, and familial breast cancer was 2.7, 2.6, and 4.8, respectively.

Moderately Penetrant Genes Not As Well Characterized

There are also a number of hereditary breast cancer genes that are not characterized very well at this time. Researchers are not certain of the risk they carry for breast and other cancers, and investigations are under way.

Approaching Risk Evaluation

In light of the evergrowing number of genes associated with an elevated risk for familial breast cancer, risk evaluation and counseling become even more important. There are a number of models available for estimation of familial breast cancer risk, as well as models that estimate BRCA carrier probability. Most experts agree that a BRCA carrier probability of 10% or higher is sufficient to warrant testing; however, meeting current national clinical criteria for BRCA testing and confirming

Claus Tables

The Claus tables are based only on family history characteristics to help estimate breast cancer risk for white unaffected women with 1-2 close female relatives with breast cancer (ie, first- or second-degree relatives) and in whom no known cancer-associated gene mutation has been identified.22

Gail Model

This model estimates a woman׳s lifetime risk for the development of breast cancer, as well as her risk over the next 5 years. The 5-year Gail calculation is often used to determine if a woman is eligible

BRCAPRO

The BRCAPRO model uses 6 predictive models for prediction of familial breast cancer. The end result is a program that can be used to construct a family history tree, which also calculates the individual׳s risk for breast (or ovarian) cancer and the probability of carrying a BRCA mutation. In a study that evaluated the validity of BRCAPRO to predict the presence of BRCA1 and BRCA2 mutations, it was found to have the highest c-statistic (0.82), suggesting that it was among the best predictors of

BRCA Mutation Testing

BRCA mutation analysis can range from straightforward to more complex testing because options include testing for a specified variant in either BRCA1 or BRCA2 (single-site analysis), full sequencing of the entire genes, and testing for gene rearrangements using polymerase chain reaction or comparative genomic hybridization.

For patients from certain ethnic backgrounds, specific mutations in BRCA are highly prevalent. Among the best characterized are 187delAG and 5385insC mutations of BRCA1 and

A Clinical Approach to Risk Testing

A reasonable algorithm for genetic testing is provided in the Figure. Genetic test results can be positive, negative (with the variable interpretation), or uncertain. A positive test result indicates the presence of a genetic alteration believed to be molecularly harmful and with evidence of associated increased cancer risks. The interpretation of a negative test result can be more challenging because the unaffected negative-result patient can either be completely relieved of cancer risk if a

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    Conflict of interest: none.

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