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About BRCA1, BRCA2, and Hereditary Breast and Ovarian Cancers

  1. How do BRCA1 and BRCA2 gene mutations function?
  2. What are the population estimates of the likelihood of having a BRCA1 or BRCA2 gene mutation?
  3. How do BRCA1 and BRCA2 gene mutations affect risk of cancer?
  4. What are the clinical recommendations for BRCA risk assessment and referral to genetic counseling and testing?
  5. What are the benefits of BRCA risk assessment and genetic counseling and testing (when appropriate)?
  6. What are the clinical recommendations for women assessed as being NOT at increased risk for a BRCA1 or BRCA2 gene mutations?
  7. What clinical options are available to reduce cancer risk in BRCA mutation carriers (confirmed through genetic counseling and testing)?

How do BRCA1 and BRCA2 gene mutations function?

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.17,18

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.19 BRCA1 or BRCA2 prevalence varies by population – 0.2 to 0.3 percent in the general population - http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestes101.pdf. The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families (e.g. founder mutations in Ashkenazi Jewish families), most have not been reported in more than a few families.

Source: National Cancer Institute Genetics of Breast and Ovarian Cancer PDQ - http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq

What are the population estimates of the likelihood of having a BRCA1 or BRCA2 gene mutation?

Among the general population, prevalence of having a BRCA mutation is as follows:

  • General population: 0.2 to 0.3%
  • Women with breast cancer: 3%
  • Women with breast cancer onset before age 40 years: 6%
  • Women with ovarian cancer: 10%
  • High-risk families: 20%

Source: http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestfinalrs.htm

Among Ashkenazi Jewish individuals, the prevalence of having any BRCA mutation is as follows:

  • General Ashkenazi Jewish population (2.5%)60
  • Women with breast cancer (any age) (10%)61
  • Women with breast cancer (younger than 40 years) (30%–35%)61-63
  • Men with breast cancer (any age) (19%)64
  • Women with ovarian cancer or primary peritoneal cancer (all ages) (36%–41%)65-67

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 54,68 and BRCA2 54 mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals.54,68 The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.54

A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of BRCA1 and BRCA2 mutations. Deleterious BRCA mutations were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2);69 21 of the 189 (11%) deleterious BRCA mutations identified were large rearrangements, of which 13 (62%) were BRCA1 ex9-12 deletions. In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 ex9-12 deletion was found in three patients, suggesting that this mutation may be a Mexican founder mutation and may represent 10% to 12% of all BRCA1 mutations in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent mutations, which accounted for 53% of all mutations observed in this cohort, suggesting the existence of additional founder mutations in this population.

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.67 Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).70 Estimates of the frequency of fallopian tube cancer in BRCA mutation carriers are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.6,67,70,71

Source: National Cancer Institute Genetics of Breast and Ovarian Cancer PDQ - http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq

How do BRCA1 and BRCA2 gene mutations affect risk of cancer?

Clinically significant mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of breast, ovarian, tubal, peritoneal, and other cancers. BRCA testing looks for these variations, which can help patients and health care providers understand a person’s risk for these cancers. For women who have a BRCA mutation, the risk of developing breast or ovarian cancer is greatly increased, with current cumulative risk estimates ranging from 45 - 65% for breast cancer and 10 - 39% for ovarian cancer by age 70. Men with BRCA mutations, especially BRCA2 mutations, are also at increased risk for breast cancer. Certain other cancers may be more frequently seen in mutation carriers of either sex. BRCA gene mutations may increase risk of fallopian tube, peritoneal (lining in the abdomen), and pancreatic cancer in women. BRCA gene mutations may increase risk of pancreatic, prostate, and breast cancer in men.

Facts about BRCA1 and BRCA2

  • BRCA mutations account for 5%-10% of breast cancer and 10%-15% of ovarian cancer cases in the U.S. each year
  • Genetic tests are available to check for BRCA1 and BRCA2 mutations. Genetic counseling is recommended before and after the tests, to make sure that the risks and benefits are understood, that informed consent is achieved, and that the appropriate test is being ordered.
  • If a harmful BRCA1 or BRCA2 mutation is found, several options are available to help reduce cancer risk. Different screening regimens may be recommended. For more information on clinical management, see the National Cancer Institute Genetics of Breast and Ovarian Cancer PDQ - http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq
  • Many research studies are being conducted to find newer and better ways of detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutation carriers.

Source: CDC Public Health Genomics – Genomics Implementation – Detailed Information on Tier 1 Applications – Hereditary Breast and Ovarian Cancer - http://www.cdc.gov/genomics/implementation/toolkit/HBOC_1.htm

What are the clinical recommendations for BRCA risk assessment and genetic counseling and testing?

In 2013, the U.S. Preventive Services Task Force (USPSTF) updated and reaffirmed its 2005 recommendations for BRCA testing stating: “The USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing (B recommendation).”

The USPSTF is an independent panel of non-Federal experts in prevention and evidence-based medicine. The USPSTF conducts scientific evidence reviews of a broad range of clinical preventive health care services and develops recommendations for primary care clinicians and health systems.

The USPSTF guidelines focus on family history in unaffected individuals in the general population. The Tier 1 application, which follows the USPSTF guidelines, therefore focuses on this public health approach as well.

Women might be at increased risk of having BRCA mutations if their family history includes one or more of the following in their first- or second-degree relatives (maternal and paternal sides of the family are equally important):

  • Multiple relatives with either breast or ovarian cancer;
  • Breast cancer at a young age (under 50 years);
  • Presence of breast and ovarian cancer among relatives;
  • A relative with primary cancers of both breasts;
  • One or more family members with two primary types of BRCA-related cancer;
  • Presence of breast cancer in one or more male relatives;
  • Ashkenazi Jewish ancestry;
  • A relative with a known BRCA mutation.

The USPSTF recommendation notes that “several familial risk stratification tools are available to determine the need for in-depth genetic counseling, such as the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, and FHS-7 .”

Source: CDC Public Health Genomics – Genomics Implementation – Detailed Information on Tier 1 Applications – Hereditary Breast and Ovarian Cancer - http://www.cdc.gov/genomics/implementation/toolkit/HBOC_1.htm

The National Comprehensive Cancer Network also provides guidelines for Genetic/Familial High-Risk Assessment for Breast and Ovarian Cancer. These guidelines can be viewed after registering for a free account: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.

What are the benefits of BRCA risk assessment and genetic counseling and testing (when appropriate)?

Genetic counseling and appropriate genetic testing for BRCA1 and BRCA2 based on the USPSTF guidelines, followed by appropriate management, are expected to reduce morbidity and mortality due to breast and ovarian cancer.

For women with BRCA mutations, interventions that might reduce the risk of cancer or reduce mortality include “earlier, more frequent, or intensive cancer screening; risk-reducing medications (i.e., tamoxifen or raloxifene); and risk-reducing surgery (e.g., mastectomy or salpingo-oophorectomy) ”; however, the USPSTF found that the strength of evidence varies across the types of interventions. In studies cited in the USPSTF recommendation, prophylactic bilateral mastectomy reduced breast cancer risk by 85% or more, and prophylactic oophorectomy reduced ovarian cancer risk by 85% or more and breast cancer risk by 53% or more. The USPSTF found the evidence lacking regarding the effect of intensive screening on clinical outcomes in women who are BRCA mutation carriers. The USPSTF cited randomized controlled trials finding that the medications tamoxifen and raloxifene reduced the incidence of invasive breast cancer among women at increased risk, but also noted that clinical trials of these medications have not been conducted specifically in women who are BRCA mutation carriers.

2010 National Health Interview Survey data is used to monitor the Healthy People 2020 objectiveto "Increase the proportion of women with a family health history of breast and/or ovarian cancer who receive genetic counseling." Survey data reveal that approximately 47% of women with relevant first-degree family histories have not had genetic counseling for HBOC. It is not known to what degree this is due to their providers not alerting them to their increased risk status and offering them genetic counseling and/or testing. Extrapolating from the National Health Interview Survey one can assume that in the United States a very large number of women with relevant family histories who might benefit from genetic counseling and possible genetic testing for HBOC have not utilized these services. Genetic counseling and evaluation for BRCA genetic testing based on the USPSTF recommendation is a preventive service now covered under the Affordable Care Act (ACA). Both genetic counseling and testing, if appropriate, are included in the ACA-covered preventive service for women whose family histories are consistent with USPSTF guidelines.

Note: Some but not all health insurers cover genetic counseling and testing for BRCA1 and BRCA2 when recommended by a provider. Some financial assistance may be available through testing providers or advocacy organizations. The Affordable Care Act (ACA) requires coverage of genetic counselling and testing as described in the USPSTF recommendation.

Source: CDC Public Health Genomics – Genomics Implementation – Detailed Information on Tier 1 Applications – Hereditary Breast and Ovarian Cancer - http://www.cdc.gov/genomics/implementation/toolkit/HBOC_1.htm

What are the clinical recommendations for women assessed as being NOT at increased risk for a BRCA1 or BRCA2 gene mutations?

It is important to confirm family history of breast and ovarian cancer with all patients. In addition, it is good practice to confirm that the patient does not have a strong family history of other cancers that may be linked to BRCA1 and BRCA2 gene mutations including fallopian tube, peritoneal, prostate, and pancreatic cancers.

The U.S. Preventive Services Task Force (USPSTF) recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes. (D recommendation).

Women assessed as “not at increased risk for a BRCA gene mutation” may still have a family history and other risk factors that increase their risk for developing cancer and thus impact their screening recommendations.

The following guidelines provide information on recommended screening for patients at increased risk for developing breast and ovarian cancers:

The following guidelines provide information on recommended screening for patients at average risk for developing breast and ovarian cancer:

What clinical options are available to reduce cancer risk in BRCA mutation carriers (confirmed through genetic counseling and testing)?

The U.S. Preventive Services Task Force (USPSTF) recommends that women with positive BRCA risk assessment results should be referred for genetic counseling and, if indicated after counseling, BRCA testing. (B recommendation). Genetic services should be provided by a trained genetics expert (e.g., genetic counselor, advanced practice nurse in genetics).

There are many available interventions to manage and reduce risk in people with a confirmed genetic susceptibility to breast and ovarian cancer. These may include modified screening plans and additional screening modalities (such as breast MRI), risk-reducing surgeries, and chemoprevention. Increasing data are available on the outcomes of these interventions; uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

The following resources provide detailed information on clinical interventions to reduce cancer risk in BRCA mutation carriers:

 

About the Know:BRCA Assessment

  1. How does Know:BRCA work?
  2. What algorithm does Know:BRCA use to estimate risk for BRCA gene mutations?
  3. What is the sensitivity of the algorithm?
  4. What are the benefits and limitations of the algorithm?
  5. Important note on the effectiveness of the Know:BRCA Assessment

How does Know:BRCA work?

The Know:BRCA Assessment collects detailed information about a patient’s personal and family history of breast and ovarian cancers. It uses the BRCAPRO Probability Model to provide an estimate of the likelihood that the patient carries either a BRCA1 or BRCA2 gene mutation.

The patient receives one of two results upon completing the Assessment:

  • At Increased Risk: A patient at increased risk has a probability of having a BRCA1 or BRCA2 gene mutation that is greater than 1%. That is, more than 1 in every 100 patients who have a similar cancer family history will have a BRCA mutation.
  • Not at Increased Risk: A patient NOT at increased risk has a probability of having a BRCA1 or BRCA2 gene mutation that is less than 1%. That is, fewer than 1 in 100 patients who have a similar cancer family history will have a BRCA mutation.

If your patient shared their results with you electronically, you can download a provider report of the patient’s risk assessment results. This provider report contains the patient’s risk result (either At Increased Risk or Not at Increased Risk) and a Mutation Probability Score. The tool categorizes patients as increased risk if their score is above .010. Patients who have a score between 0 and .010 are considered not at increased risk.

What algorithm does Know:BRCA use to estimate risk for BRCA gene mutations?

The Know:BRCA Assessment uses the BRCAPRO model and software. “BRCAPRO is a statistical model, with associated software, for assessing the probability that an individual carries a germline deleterious mutation of the BRCA1 and BRCA2 genes, based on family history of breast and ovarian cancer, including male breast cancer and bilateral synchronous and asynchronous diagnoses. BRCAPRO uses a Mendelian approach that assumes autosomal dominant inheritance. This assumption is supported extensively by previous linkage analyses. Age-dependent penetrances and prevalences are based on a systematic review of the literature.

BRCAPRO was originally developed as part of the Duke SPORE in breast cancer from 1995 to 1999, with Don Berry and Giovanni Parmigiani as project leaders. It is currently distributed free of charge for research and counseling use via stand-alone softwares HRA or CaGene, the BayesMendel R library, or a Web Risk Service. CaGene has been licensed to over one thousand sites, including most high risk clinics within large academic medical centers, who are using the model in both counseling and research.” (http://bcb.dfci.harvard.edu/bayesmendel/brcapro.php).

The Know:BRCA Assessment includes recent updates to the BRCAPro Software which include:

  • “BRCAPRO has been re-calibrated and improved with updated penetrances for contralateral breast cancer
  • Package now allows for input on ethnicity for each family member, in order to better characterize families containing more than one ethnic groups, each of which may present different allele frequencies for the mutations of interest.
  • Mastectomy as an intervention has been added to BRCAPRO.
  • Improved the error message returned when there is a problem with the Twins input.”

Source: http://bcb.dfci.harvard.edu/bayesmendel/brcapro.php

What is the sensitivity and specificity of the algorithm?

Early versions of BRCAPRO reported genetic testing sensitivity estimated to be at least 85%, missing an estimated 15% of mutations, including gene mutations previously unknown to increase cancer susceptibility. About 1 out of every 100 women will be identified as having a higher risk for having a BRCA1 or BRCA2 gene mutation. About 22 out of 100 women identified by BRCAPRO as having a higher chance of having a BRCA1 or BRCA2 gene mutation WILL actually have it (true positive). About 1 out of 100 women identified by BRCAPRO as NOT having a higher chance of having a BRCA1 or BRCA2 gene mutation WILL actually have it (false negative).

As improvements to the BRCAPro probability model are made, it is anticipated that sensitivity and specificity will change.

In 2012, Schneegans et al. (2012) published a Validation of Three BRCA1/2 Mutation-Carrier Probability Models - Myriad, BRCAPRO and BOADICEA-in a Population-based Series of 183 German Families. They reported the following sensitivity and specificity of all three programs at a threshold of 10 and 20%: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365232/table/Tab2/

What are the benefits and limitations of the algorithm?

Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 mutations in individuals or families. These models include those using logistic regression,30, 72, 73, 75, 78, 89, 90, genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]),78, 91 and empiric observations,51, 54, 57, 92-94 including the Myriad prevalence tables. More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published.91

Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be identified as BRCA1/BRCA2 mutation carriers.95, 96 The power of several of the models has been compared in different studies, and currently there is no single model that is consistently superior to others.97-100 Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status.101. The updated BRCAPRO model used by the Know:BRCA Assessment includes patient information on preventive surgeries. One study has shown that the risk models are sensitive to the amount of family history data available and do not perform as well with limited family information.102

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.103 There have been variable results in the performance of the BRCAPRO model among Hispanics,104, 105 and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.106 Further information is needed to determine which model performs best in each ethnic group.

The inclusion of breast tumor markers, such as ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has been shown to improve the performance of BRCAPRO and BOADICEA.107-109. The Know:BRCA Assessment does not collect information on these markers from patients.

Table 2. Characteristics of Common Models for Estimating the Likelihood of a BRCA1/2 Mutation

  Myriad Prevalence Tables 75 BRCAPRO 78, 101 BOADICEA 78, 91 Tyrer-Cuzick 110
AJ = Ashkenazi Jewish; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; FDR = first-degree relatives; SDR = second-degree relatives.
Method Empiric data from Myriad Genetics based on family and personal history reported on requisition forms Statistical model Statistical model Statistical model
Features of the Model Proband may or may not have breast or ovarian cancer Proband may or may not have breast or ovarian cancer Proband may or may not have breast or ovarian cancer Proband must be unaffected
Considers age of breast cancer diagnosis as <50 y, >50 y Considers exact age at breast and ovarian cancer diagnosis Considers exact age at breast and ovarian cancer diagnosis Also includes reproductive factors and body mass index to estimate breast cancer risk
Considers breast cancer in >1 affected relative only if diagnosed <50 y Considers prior genetic testing in family (i.e., BRCA1/BRCA2 mutation–negative relatives) Includes all FDR and SDR with and without cancer
Considers ovarian cancer in >1 relative at any age Considers oophorectomy status Includes AJ ancestry
Includes AJ ancestry Includes all FDR and SDR with and without cancer
Very easy to use Includes AJ ancestry
Limitations Simplified/limited consideration of family structure Requires computer software and time-consuming data entry Requires computer software and time-consuming data entry Designed for individuals unaffected with breast cancer
Early age of breast cancer onset Incorporates only FDR and SDR; may need to change proband to best capture risk and to account for disease in the paternal lineage Incorporates only FDR and SDR; may need to change proband to best capture risk
May overestimate risk in bilateral breast cancer 111
May perform better in whites than minority populations 105, 112

Source: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page2#Section_1544

New research conducted on women with high-grade serous ovarian cancer found that “BRCAPRO underestimated the risk for high-grade serous ovarian cancers but overestimated the risk for other histologies (P < .001), underestimation increased as age at diagnosis decreased (P = .02), and model performance varied by institution (P = .02).”

Source: http://jco.ascopubs.org/content/early/2014/03/14/JCO.2013.50.6055.abstract

Important note on the effectiveness of the Know:BRCA Assessment

Biswas et al. (2013) found that healthcare providers need simple tools to identify patients at genetic risk of breast and ovarian cancers. They suggested that genetic risk prediction models such as BRCAPro could be most useful if they could be simplified and incorporated into Electronic Medical Records.

The Know:BRCA Assessment improves upon the stand-alone BRCAPRO model in that it provides a user-friendly means of gathering detailed family cancer history. This history can be downloaded directly into a patient’s Electronic Medical Record. The Know:BRCA Assessment should be used in collaboration with a medical provider who can review family cancer history (including history of other cancers associated with BRCA mutations not included in the model) with all patients. With this detailed information, providers can account for any limitations of the BRCAPRO model and make recommendations that are in the best interest of patients.