Breast cancer is the most common cancer and the second leading cause of cancer deaths in women in the United States.  In 2008, approximately 184,450 patients were estimated to be diagnosed with invasive breast cancer, and an estimated 40,930 were estimated to die of this disease.   Furthermore, over 50,000 female carcinoma in situ breast cases would have been diagnosed.  The etiology of breast cancer is poorly understood with multiple genetic and environmental factors involved in the initiation and progression of cancer. 

 

Scandinavian Twin Study:  For years, there has been a hot debate as to whether the cause of breast cancer is genetic or environmental.  Then in 2000, Lichtenstein and his colleagues at the Karolinska Institute in Sweden published their study of 44,788 pairs of twins from the Swedish, Danish, and Finnish twin registries.  In this study, they looked at cancer risk with 28 different types of cancers and did statistical modeling of genetic and hereditary contributions in eleven different cancer types.  For breast cancer, they clearly showed that only 27% of breast cancers were due to genetic factors.  This was an even lower hereditary component than other common cancers such as prostate and colorectal.  This study and others have confirmed the fact that over 70% of breast cancers are influenced by environmental factors.

 

BRCA genes:  Although much attention has been made about hereditary breast cancer, only two genes are commonly tested for breast cancer risk assessment.  These two genes are tumor suppressor genes named “BRCA1″ and “BRCA2″ that are involved with DNA repair.  These two genes only account for about 5% of all breast cancers.  Because of the Scandinavian twin study, most experts believed that there are other yet to be discovered genes involved with breast cancer.  Because the chance of having a BRCA mutation in the general population is so low, genetic testing is not indicated in most patients.  However, if a patient has a family history of breast cancer, then a mathematical model can be used to determine if BRCA testing is indicated.  The likelihood of being a BRCA carrier increases with the number of relatives who had cancer and if the cancers occurred earlier in life.  For example, in families with four or more cases of breast or ovarian cancer under the age of 60, over 80% are found to have a damaged version of BRCA1 or BRCA2.  If a patient is a carrier of one or both of the BRCA1 and BRCA2 genes, her risk of breast cancer dramatically increases.  According to estimates of lifetime risk, about 13.2% (132 out of 1,000 individuals) of women in the general population will develop breast cancer, compared with estimates of 36-85% (360-850 out of 1,000) of women with an altered BRCA1 or BRCA2 gene.  In other words, women with an altered BRCA1 and/or BRCA2 gene are up to eight times more likely to develop breast cancer than women without alterations in those genes.  The BRCA1 mutation confers a higher risk than a BRCA2 mutation.  Women who inherit a damaged BRCA1 gene have a 60-85% chance of developing breast cancer at some stage in their lives and a 20-40% chance of developing ovarian cancer.  For BRCA2, the risks are 40-60% and 10-20%, respectively.  

 

Family History and Breast Cancer:  Although the spotlight in hereditary breast cancer has been directed on the BRCA genes, the majority of patients with a family history of breast cancer are BRCA1 and BRCA2 negative.  Even in these BRCA negative patients, however, there is an increased risk of developing cancer with a family history of breast cancer.   Six factors (unrelated to BRCA genes) have been studied in patients with a family history of breast cancer.  They are as follows:

 

1.  Degree of relationship:  If the family member with a history of cancer is a first degree relative, the increased risk is much greater than for second degree relatives. 

2.  Number of relatives who have had breast cancer:  People with two or more family members who have had breast cancer are at higher risk than those with only one affected relative.

3.  Age of onset of cancer:  If the relative developed breast cancer at an early age (pre-menopausal), the risk is higher than if the relative developed post menopausal breast cancer.

4.  Bilateral breast cancer:  If the relative has a history of bilateral breast cancer, the risk is greater than having a relative with unilateral breast cancer.

5.  Gender of the relative:  If the family member with breast cancer is a man, the risk is higher.

6.  Other related early onset tumors:  If there is a family history of early onset ovarian cancer, this incurs an increased risk for a person.

 

How to decide whether you need the BRCA gene test

 

The following is an excerpt from the American Society of Breast Surgeons:

1.  Early onset breast cancer (diagnosed before age 50)

2.  Two primary breast cancers, either bilateral or ipsilateral
3.  A family history of early onset breast cancer
4.  Male breast cancer
5.  A personal or family history of ovarian cancer
6.  Ashkenazi (Eastern European) Jewish heritage
7.  A previously identified BRCA1 or BRCA2 mutation in the family

Any one of these features alone indicates a risk for harboring a BRCA1 or BRCA2 mutation.  The presence of more than one of these features raises that risk to greater than 10%, the traditional cutoff for recommending a BRCA test. Such patients should have access to BRCA testing.  A simple risk-calculation model based on the prevalence of mutations seen among women tested for BRCA mutations is available at http://www.brcacalculator.com.

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Using known risk factors for breast cancer, mathematical models can be developed to help answer important questions.  These mathematical models are useful tools for researchers and for patients as follows:

1. Research on risk factors – The Claus risk assessment model was used to discover the subpopulation of people who had an autosomal dominant genetic allele that increased their risk from 10% to 92%. This led to the discovery of the BRCA genes associated with breast, ovarian, and prostate cancer. 2. Clinical trial eligibility – The Gail risk assessment model was developed to help researchers determine who to enroll in the NSAPB Breast Cancer Prevention Trials

where chemoprevention was shown to reduce breast cancer risk.

3. Guidelines for doing BRCA testing – BRCA testing is very expensive and practically worthless if done on everyone (because it is so rare to be homozygous for BRCA1 or BRCA2). Mathematical models such as the BRCAPRO, BOADICEA, and Tyrer-Cuzick models can help determine what patients should undergo BRCA testing. The decision for testing is usually made when one of these models predicts a 10% or greater chance that there is a mutation of the BRCA1, BRCA2, or both genes. 4. Guidelines for doing MRI screening for breast cancer - MRI screening for breast cancer is not a cost effective screening test for the general population, but in specific groups, there are clear cut reasons to do so. In general, screening MRI is recommended for women with 20-25% or greater lifetime risk of breast cancer. The BRCAPRO and Tyrer-Cuzick models have been used to help make clinical decisions about ordering MRIs for breast cancer screening. 5. Guidelines for breast cancer therapy - The Gail model is used clinically to help

determine who should be put on tamoxifen or raloxifene for chemoprevention.  Other models have been used to help make decisions about breast cancer risk reduction with prophylactic mastectomy.

For these reasons, it is important to understand these models.  These models are collectively refered to as “risk assessment tools”.  The following paragraphs summarize the most popular and most widely used risk assessment tools.  Keep in mind that none of these risk assessment tools apply to breast cancer survivors.  No mathematical model has been widely accepted to determine cancer risk in cancer survivors. 

General Risk Assessment Tools

Gail Model:  The Gail model is a validated risk-assessment model that focuses primarily on nonhereditary risk factors, with limited information on family history.  It was developed by scientists at the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to assist health care providers in discussing breast cancer risk to determine their eligibility for the Breast Cancer Prevention Trial.  The tool allows one to project a woman’s individual estimate of breast cancer risk over a five-year period of time and over her lifetime.  It also compares the woman’s risk calculation with the average risk for a woman of the same age.  The Gail Model is an on-line quiz that has 13 questions and is interactive.  This calculator is based on published risk statistics and methods gathered from peer-reviewed journals, and has been extensively tested for its validity. 

                                                                                                               

The major limitation of the Gail model is the inclusion of only first-degree relatives, which results in underestimating risk in the 50% of families with cancer in the paternal lineage and also takes no account of the age of onset of breast cancer.  It may underestimate risk in certain groups, such as obese patients.

                                                                                                

National Cancer Institute Model:  The NCI risk assessment tool is essentially a simplified Gail Model that also factors in race.  Race is a factor in determining breast cancer risk but is excluded when determining eligibility for clinical trials.  This tool is probably the most popular risk assessment tool available to the public as an on-line, interactive risk calculator.  The on-line quiz is a shorter, nine-point questionnaire that includes multiple factors, giving a woman her future five-year risk of breast cancer and her lifetime risk of breast cancer.

                                                                                             

The NCI tool does not account for a lot of risk factors that can be modified.  For this reason, it is difficult to use this test as a motivation tool to show people how lifestyle can alter their risk of breast cancer.  It also cannot be used in breast cancer survivors, in patients with DCIS, LCIS, or people who carry one of the BRCA genes.

BRCAPRO model:  This is a statistical model available as a computer program that uses two different algorithms to evaluate family history and helps a doctor determine the likelihood of finding either a BRCA1 mutation or a BRCA2 mutation in a family.  The results of this can be used to determine if BRCA testing is indicated.  This is very useful in light of the high cost of BRCA testing ($3,000).  None of the nonhereditary risk factors can yet be incorporated into the model, however.  In a comparison of four different methods for estimating breast cancer risk in patients with a family history of breast cancer, the BRCAPRO model was the least accurate.  It predicted only 49% of the breast cancers that actually occurred in the screened group of patients with a family history of breast cancer.

Harvard Center for Cancer Prevention Risk Assessment Tool:  This is another breast cancer risk assessment tool that includes more lifestyle factors than the NCI or Gail Model tools.  It has not been studied as extensively as the Gail Model or the simplified NCI model, but it is promising in that it includes many lifestyle factors that people can do to modify their risk of developing cancer.  It is also an on-line questionnaire that can be used by both women and men to estimate their breast cancer risk.

Making all this practical

 

          Now after a thorough and confusing discussion of all these statistical models, it’s time to make all this information practical.  What is the best way to help a patient accurately assess her risk of breast cancer and if possible, show her what positive factors are reducing her risk and what negative factors can be changed to reduce her risk?  If possible, it would also be great to show the patient the value and indications for testing, imaging, chemoprevention, and in some cases surgery.  A discussion of the practical aspect of each of these is addressed in a Q & A format below:

Q: What (free) online programs can be used to help a patient assess their risk of breast cancer?

A: Several of the risk assessment tools mentioned above can be accessed for free by the public. Here are the tests and their websites:

   

1. Your Disease Risk – English version: http://www.diseaseriskindex.harvard.edu

This is a great interactive questionnaire that calculates five-year and lifetime risk of breast cancer developed by the Harvard Center for Cancer Prevention and made public online in 2000.  In 2005, they launched the Spanish version of the site, “Cuidar de su Salud”.  The risk calculator includes lifestyle factors such as weight, dietary vegetables, alcohol intake, as well as Jewish ethnicity.  It does not include other ethnicities, however, and is not accurate for BRCA mutation carriers or breast cancer survivors.  Despite these issues, this is by far the best free online risk calculator since it is very interactive and gives you a personalized description of your risk in the form of a colored bar graph, which they can electronically manipulate to experience “virtual” risk reduction.  The bar graph is a seven-level scale that compares users to a typical man or woman your age.  Users learn where to focus their prevention efforts and how to make lifestyle changes by “clicking on” personalized strategies.  With each click, the bar graph shrinks, and the user watches his/her predicted risk drop.  This is a great concept to motivate people to participate and comply with lifestyle modification measures.

2. The NCI Risk Assessment Tool -regular web: http://www.cancer.gov/bcrisktool

     This is the easy to use, on-line questionnaire based on a modified Gail model that also includes ethnicity.  It does not factor in a personal history of breast cancer, DCIS, or LCIS.  It does not account for other factors such as BRCA status, hormonal replacement therapy, lifestyle factors, breast feeding, menopause, or mammographic density.  Despite these issues, it is a very useful tool that gives a woman her five-year and lifetime risk of breast cancer.  It is the only risk assessment tool that can be used via mobile handheld devices (any type).  A version of this can be downloaded for PDAs with Windows Pocket PC operating system as well.

Q:  What programs can be used to help a doctor make decisions about ordering a breast MRI?

  

A:  The American Cancer Society has developed some very good guidelines for breast cancer screening with MRI.  It should be emphasized that MRI is an adjunct to mammography, not a replacement.  

1. A Cancer Journal for Clinicians – http://caonline.amcancersoc.org/cgi/content/full/57/2/75 2. BRCPRO - ver.4.3 available @ http://www4.utsouthwestern.edu/breasthealth/cagene/default.asp

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