ABOUT THE BREAST CANCER RISK SCREENING (BCRA) TOOL

 

 

INTRODUCTION 1

GAIL MODEL 3

PEDIGREE ASSESSMENT TOOL 3

INTERPRETING THE REULTS OF THE RISK SCREENING TOOL 5

LIMITATIONS OF THE GAIL MODEL AND PAT 6

PEDIGREE ASSESSMENT TOOL (PAT) The following limitations of the PAT have been identified. 6

REVIEW OF LITERATURE 7

 

 

 

INTRODUCTION

 

The Saint Anthony Breast Cancer Risk Screening Tool was designed for use by non-specialists to assist in providing breast cancer risk assessment in a primary care setting.  The tool is intended to be used as a risk screening tool and is not intended to take the place of formal cancer risk assessment by a qualified healthcare professional.  The purpose of this tool is to rapidly identify women in a primary care setting who may be at increased risk for developing breast cancer so that further evaluation can be performed in order to comprehensively assess risk and develop an individualized, risk-adapted disease prevention and screening strategy.   For some women at increased risk, lifestyle modifications, risk avoidance and more frequent clinical breast exams may suffice, while others may also benefit from chemoprevention with a selective estrogen receptor modulator (SERM) such as tamoxifen or raloxifene.  Finally, women at the highest end of the risk spectrum who are at risk for hereditary breast cancer syndromes may be appropriate candidates for genetic counseling and consideration of DNA testing for germline mutations in the BRCA1 and BRCA2 genes.  Women in this category may also benefit from more intensive surveillance programs, including the use of newer imaging modalities such as breast MRI.   In some cases, consideration of risk-reducing surgeries (bilateral mastectomy and bilateral salpingo-oophorectomy) is also appropriate.  Thus, women in this category benefit from both genetic counseling and cancer risk counseling.  (See the National Cancer Institute’s website for additional information on breast cancer risk-reduction at:

http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page4.)

 

The goal of this risk screening tool is not only to identify women at increased breast cancer risk, but also to stratify the increased risk population along the risk continuum and to perform a triage function to assist in determining appropriate candidates for referral to genetic counselors and specialized cancer risk clinics. 

 

The risk of developing breast cancer for any given woman is determined by the complex interplay between a variety of factors, including genetic influences, environmental exposures, reproductive and hormonal factors, the presence of benign proliferative breast disease and mammographic density, as well as dietary and other factors.  A substantial portion of the adult female population is at moderately increased breast cancer risk (lifetime risk in the range of 15%-30%) due to various combinations of the above risk factors.  Estimates as to the size of this moderately increased risk group vary widely due to differences in criteria used to define “increased risk” and differences between study populations.  It is important to note that while genetic influences are often operative in elevating breast cancer risk, only a small subgroup of  women have a true hereditary breast cancer syndrome.   Approximately 2% of women in a screening mammography population in one study had a family history suggesting the possibility of a hereditary breast cancer syndrome.  However, it is important to identify women in this category because their lifetime breast cancer risk may be as high as 50-80%, and many of these women are also at substantially increased risk for ovarian cancer.

 

A breast cancer risk screening strategy must identify two distinct populations of women at increased breast cancer risk; moderately increased risk individuals who are unlikely to have a true hereditary cancer syndrome, and individuals at high risk for hereditary breast cancer.  Women in the moderate risk category benefit from cancer risk counseling and are potentially candidates for  implementation of a program of increased cancer screening, risk avoidance and possibly chemoprevention with a SERM, but do not require genetic counseling or DNA testing for germline mutations.   On the other hand, women at high risk for hereditary breast cancer syndromes benefit from referral to a genetic counselor and/or specialized cancer risk clinic with expertise in genetic counseling for cancer susceptibility, DNA testing, cancer risk counseling and management of high risk individuals.   The Saint Anthony Breast Cancer Risk Screening Tool employs two separate models in an attempt to identify women at all levels on the risk spectrum; the modified version of the Gail model- which accounts for both familial and non-familial risk factors- for identifying women at moderately increased risk and a pedigree assessment tool (PAT), which identifies the small subgroup of women at risk for hereditary breast cancer syndromes.

 

 

GAIL MODEL

 

The modified version of the model of Gail, et al. is widely used for calculating individualized risk estimates for invasive breast cancer.  The Gail model 1 calculates a woman’s absolute risk of developing invasive breast cancer over defined intervals of time, with both a short-term (five year) and lifetime (thirty year) risk estimate provided.  The estimates are based on a multivariate logistic regression model which was derived from follow-up of a cohort of white women in the United States undergoing annual screening mammography as part of the Breast Cancer Detection Demonstration Project (BCDDP).  Multivariate relative risk estimates were derived from the BCDDP cohort for five variables:  age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of breast biopsies and the presence of atypical hyperplasia on a breast biopsy.  Absolute risk estimates were derived by combining individual relative risk estimates associated with the five variables with age-specific breast cancer rates from the BCDDP cohort.  Subsequently the model was modified 2 by replacing BCDDP age-specific rates with rates of invasive breast cancer from the Surveillance, Epidemiology, and End Results Program (SEER) of the National Cancer Institute from 1983-1987.  The modified version of the Gail model also provides separate estimates for white and black woman.   The modified version of the Gail model (henceforth simply referred to as “the Gail model”) was used by investigators at the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine eligibility for the P-1 breast cancer chemoprevention trial.  The FDA-approved indication of tamoxifen as a breast cancer chemoprevention agent is based on a Gail model estimate ( predicted 5 year risk of developing invasive breast cancer > 1.66%)4.  Furthermore, the Gail model has many features that make it an excellent candidate for use as a risk screening tool employed at the primary care level:  it has been validated in several different datasets3, all required risk factor data is easily obtained from participants, it incorporates both familial and non-familial risk factors, it provides both five-year and lifetime risk estimates expressed as cumulative absolute risk rather than relative risk, and  a computer software program has been developed to perform the calculations.  The computer source code for the original algorithm that has been incorporated into this tool was kindly provided by Mitchell Gail, M.D., Ph.D., Chief of Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute.  The Saint Anthony Breast Cancer Risk Screening Tool considers any woman with a 5 year Gail estimate of 1.7% or higher, or a lifetime estimate of 15% or higher to be in the increased risk category.  

See the section “Limitations of the Gail model and PAT” below for a discussion of the limitations of this tool.

 

 

PEDIGREE ASSESSMENT TOOL

 

The pedigree assessment tool (PAT) was developed by investigators at the OSF Saint Anthony Medical Center to identify women in a primary care setting with family cancer histories suggesting a hereditary breast cancer syndrome, including, but not limited to, potential BRCA gene mutation carriers 5.  For more information on hereditary breast cancer syndromes go to the National Cancer Institute website at: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional

I.      The PAT is a simple point scoring system which assigns point values for each case of breast or ovarian cancer within a family (table 1 below).  The actual numeric values assigned for each case of breast or ovarian cancer were arbitrarily selected, but they are weighted so that more points are assigned for cases with features associated with a higher probability that a BRCA mutation is present:  early age of breast cancer diagnosis, ovarian cancer in the family, male breast cancer in the family and Ashkenazi (eastern European) Jewish ancestry.   A PAT score is calculated for both the maternal and paternal lineage by adding together the point assignments for each case of breast or ovarian cancer in each genetic lineage.  The final PAT score assigned to the participant is the higher of the maternal and paternal PAT scores. 

 

 

TABLE 1

Pedigree Assessment Tool Scoring System

 

Diagnosis

Points assigned

Breast cancer at age 50 or higher

3

Breast cancer prior to age 50

4

Ovarian cancer at any age

5

Male breast cancer at any age

8

Ashkenazi Jewish heritage

4

 

 

The pedigree assessment tool (PAT) score is calculated by adding the points assigned to every family member with a breast or ovarian cancer diagnosis, including 2nd and 3rd degree relatives.  A separate score is calculated for both the maternal and paternal lineage and the higher of the 2 scores is assigned to the participant.  For example, a woman with the following family history would have a maternal PAT score of 7 and a paternal PAT score of 12:  sister diagnosed with breast cancer at age 43 (4 points), maternal aunt diagnosed with breast cancer at age 72 (3 points), paternal aunt diagnosed with ovarian cancer at age 62 (5 points) and paternal grandmother with breast cancer at age 59 (3 points).  In this example, the sister is counted in both the maternal and paternal PAT score since she belongs to both genetic lineages.  Likewise, a participant herself, and any of her siblings, children, grandchildren, and nieces/nephews affected with breast or ovarian cancer are included in both the maternal and paternal point total.

 

A woman with bilateral breast cancer is assigned a point total equal to 2 times (2x) the score corresponding to her age at the time of her initial breast cancer diagnosis.  For example, a woman diagnosed with breast cancer initially at age 47 who develops a contralateral breast cancer at age 60 is assigned 8 points (2 x 4), while a woman diagnosed at ages 57 and 62 would be assigned 6 points (2x3).  Note that this is a modification from the original scoring system as reported in paper from Hoskins, et al  (reference 5 below).  A woman with both breast and ovarian cancer is assigned the sum of the appropriate breast cancer score (3 or 4 points depending on age at breast cancer diagnosis) plus 5 points for the ovarian cancer.  Four points are added to the final total if the family is of Ashkenazi Jewish ancestry.  For example, for a participant with a maternal PAT score of 4 and a paternal PAT score of 6, if there is Jewish ancestry in the maternal lineage, the final maternal PAT score is 8 (4+4) and the paternal score remains 6.  If both parents were of Jewish ancestry the maternal PAT score would be 8 and the paternal PAT score would be 10 (6+4).

 

The PAT was designed to identify women at high risk for hereditary breast cancer, including potential BRCA1 and BRCA2 mutation carriers.  In particular, it was designed to identify women at high risk for a hereditary breast cancer syndrome who would be appropriate candidates to refer for genetic counseling and consideration of DNA testing of the BRCA1 and BRCA2 genes, by virtue of a 10% or higher probability that a BRCA1 or BRCA2 mutation is present within their family.  It was also designed to identify individuals who are unlikely to harbor BRCA mutations, but are at increased breast cancer risk due either to polygenic susceptibility or susceptibility due to high penetrance genes other than BRCA1 and BRCA2, since these women also benefit from cancer risk counseling and implementation of a cancer risk-reduction program.  To test the ability of the PAT to accurately identify this cohort of women, a validation study was performed by analyzing the family history of 3,906 women without a personal history of breast cancer who presented for a screening mammogram at a community hospital 5.    This analysis identified a PAT score of 8 as the optimal threshold value for assigning women to the high risk cohort (10% or higher probability that a BRCA mutation is present within the family).  At a cutoff score of 8, the PAT performed with a sensitivity of 100%, specificity of 93% and positive predictive value of 63%.   .  The Saint Anthony Breast Cancer Risk Screening Tool considers any woman with a PAT score > 8 at high risk for a hereditary breast cancer syndrome.  See the section “Limitations of the Gail model and PAT” below for a discussion of the limitations of this tool.

 

 

INTERPRETING THE REULTS OF THE RISK SCREENING TOOL

 

The Saint Anthony Breast Cancer Risk Screening Tool identifies women at increased breast cancer risk and for triage purposes divides them into 2 categories.

 

Moderately increased risk:  women with a 5 year Gail estimate of  > 1.7%, and/or a lifetime estimate of  > 15%, and/or a PAT score of 6-7. 

Women in this category typically have lifetime breast cancer risk in the range of 15%-35%.  Many women in this population have a family history of breast cancer, but they are unlikely to harbor mutations in highly penetrant, autosomal- dominantly inherited cancer susceptibility genes.  Accordingly, evaluation by a healthcare professional with expertise in genetic counseling is generally unnecessary, although they still benefit from evaluation by healthcare professionals with expertise in formal cancer risk assessment and cancer risk counseling in order to develop and implement a risk-adapted, cancer risk-reduction plan. 

 

High risk for hereditary breast cancer syndrome:  PAT score > 8 and any Gail estimate.  Women in this category typically have a lifetime breast cancer risk between 40-85%, and many are also at increased risk for ovarian cancer.  Many women in this group have a family cancer history indicating a high probability that a mutation is present in a highly penetrant, autosomal- dominantly inherited cancer susceptibility gene such as BRCA1 or BRCA2.  Accordingly, evaluation by a healthcare professional with expertise in genetic counseling for cancer susceptibility is an important component of cancer risk counseling in this situation.  Other women in this category are unlikely to harbor mutations in BRCA1 or BRCA2,  but are still at high risk for breast cancer due either to polygenic susceptibility from lower penetrance genes or due to high penetrance genes other than BRCA1 or BRCA2.  All women in this category benefit from genetic counseling to determine if DNA testing is appropriate and from cancer risk counseling to discuss options for cancer risk-reduction and increased breast cancer surveillance.

 

 

LIMITATIONS OF THE GAIL MODEL AND PAT

 

 

GAIL MODEL   The following limitations of the Gail model have been identified.

 

Several known breast cancer risk factors are not accounted for by this model. This includes, but is not limited to exogenous hormone exposure (post-menopausal hormone replacement therapy), alcohol consumption, post-menopausal weight gain, lack of physical exercise, mammographic breast density, ionizing radiation exposure, and possibly dietary factors.  Finally, other unidentified factors may affect risk and are not accounted for by this tool.

Breast cancer risk is underestimated in carriers of highly penetrant breast cancer susceptibility genes such as BRCA1 and BRCA2.

Risk calculations are most accurate for women undergoing routine screening mammography.

Most of the data used to estimate risk are from white women who participated in a study of screening mammography. The risk of developing breast cancer for black women may be underestimated. The risk estimates for women from certain ethnic groups (including black and Hispanic) are subject to greater uncertainty than those for white women. Risk calculations for Native American, Alaskan Native, Asian, and Pacific Islander women are based on the rates for white women and may not be accurate

The risk prediction does not allow one to say precisely which women will develop breast cancer. The distribution of risk estimates for women who develop breast cancer overlaps the estimates of risk for women who do not.  Some women who develop breast cancer do not have increased scores on a Gail model estimation, and many women with increased Gail estimates will never develop breast cancer.

 

 

PEDIGREE ASSESSMENT TOOL (PAT) The following limitations of the PAT have been identified.

 

The assessment is based on patient self-reporting of family cancer history.   Studies have shown that patient self-reporting of family cancer history is not always accurate.  Incorrect reporting of family history information could substantially alter the results obtained with this tool.

Rare genetic syndromes may be overlooked by this tool.  Rare genetic syndromes that increase breast cancer, such as the Li-Fraumeni syndrome and Cowden’s syndrome, have unique family history features that are not accounted for by the PAT.

Individuals with a low PAT score will on occasion come from a family with a BRCA1 or BRCA2 mutation.  The tool is designed to detect women from families with a  > 10% probability that a BRCA1 or BRCA2 mutation is present.  For example, families with 2 cases of breast cancer, one diagnosed under age 50 and the second diagnosed after age 50, have an approximately 5% probability of harboring a BRCA1 or BRCA2 mutation.  The PAT will score these families as “low probability” of a hereditary breast cancer syndrome (PAT score = 7) and the summary statement interpreting the PAT score will state that “it is unlikely that a hereditary breast cancer syndrome is present”.  It is important to recognize that “low probability” for a hereditary breast cancer syndrome (i.e. < 10%) does not mean “no probability”.

Not all women with a high PAT score  ( > 8 ) have a high probability of harboring a BRCA1 or BRCA2 mutation.   The tool was designed to identify women whose family cancer history indicates a > 10% probability that a BRCA1 or BRCA2  mutation is present.  In the validation study of the PAT 5, a PAT score of > 8 was associated with a positive predictive value of 63%.  In other words, in a screening mammography population consisting of primarily non-Jewish, Caucasian women,  2/3 of women with a PAT score of >8 had a family cancer history indicating a > 10% probability that a BRCA mutation is present.  Approximately 1/3 women with a PAT score > 8 had a BRCA mutation probability of < 10%.  For example, non-Jewish families with 3 cases of breast cancer all diagnosed after age 50 and no ovarian cancer or male breast cancer will have a PAT score = 9, but a BRCA mutation probability of only 6% according to one model.  However, it is important to note that although the BRCA mutation probability is low in this situation, that does not mean low risk of breast cancer.  It is clear that genetic influences other than BRCA1 and BRCA2 may be operative in families with multiple cases of breast cancer but no ovarian cancer.  Women in these families are often at substantially increased breast cancer risk and still benefit from genetic counseling and cancer risk counseling, even though DNA testing for BRCA mutations is generally not beneficial.  

 

 

 

REVIEW OF LITERATURE

1.     Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Shairer C, Mulvihill JJ: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81(24):1879-86, 1989. [PubMed Abstract]

2.     Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK, Benichou J, Wieand HS: Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 91(18):1541-8, 1999. [PubMed Abstract]

3.     Rockhill B, Spiegelman D, Byrne C, Hunter DJ, Colditz GA: Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93(5):358-66, 2001. [PubMed Abstract]

4.     Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, Vogel V: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 91(21):1829-46, 1999. [PubMed Abstract]

5.     Hoskins KF, Zwaagstra A, Ranz M.  Validation of a tool for   identifying women at high risk for hereditary breast cancer in  population-based screening.  Cancer 107(8): 1769-76, 2006.  [PubMed Abstract]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16967460&query_hl=3&itool=pubmed_docsum



 

Last edited: 10/31/2006

 

Back to the Main Page