deCODE BreastCancer™ - Empowering Prevention
Early diagnosis and primary prevention are crucial to breast cancer control. The deCODE BreastCancer™ test is an important and significant additional risk factor identifier that should be taken into account when deciding on optimal strategies for the screening and prevention of breast cancer.
Current recommendations and suggested screening strategies for early breast cancer detection are based on the premises of defining women who have normal risk (the average population risk) and those who are at significantly increased risk. Of greatest impact for definition of the latter group (by the number of women) are the age and the family history (for further reference, see: www.cancer.org). In addition to women who have the clear risk factors for previous radiation therapy to the chest, lobular carcinoma in situ (LCIS)/atypical hyperplasia, ductal carcinoma in situ (DCIS), or have previously been diagnosed with breast cancer, the ACS and the National Comprehensive Cancer Network (NCCN) algorithms aim at identifying individuals who are at higher risk by their family history and other clinical parameters. On the one hand, these algorithms attempt to identify women who belong to families where heritable cancer gene mutations are segregating as indicated by DNA testing and/or the number of cases in the family, age of onset, other cancers (especially ovarian cancer), and/or the presence of 2 breast cancer primaries. On the other hand, they aim at detecting women >35 years of age who have a risk of over 1.75% of developing breast cancer in the next 5 years by the risk factors used in the Modified Gail Model (BSCR-B) (http://www.cancer.gov/bcrisktool/) or other models like the Claus model (Claus et al, 1991).
The deCODE BreastCancer™ test may be used for risk modification in all of the above 3 main categories, ie, the normal risk group, the suggestive/confirmed heritable breast cancer cases and the modeled risk cases, since its genetic risk results seem, to a great extent, be to independent of the parameters used in these risk models, most importantly the age and the family history. Additionally, 3 of the deCODE BreastCancer™ markers have been shown to modify the risk of breast cancer in patients who are known carriers of high-penetrance mutations in the BRCA1 and/or BRCA2 genes, ie, affecting the penetrance of these mutations.
The normal-risk group
The basic lifetime risk of developing breast cancer is estimated to be 12.3% in the United States. About 4% of all white women will have a combined genetic risk of 1.66 or higher according to the deCODE BreastCancer™ test, which moves them into the 20% or higher lifetime risk category defined by the ACS. Additional, 15% of all white women have deCODE BreastCancer™ risk results in the range of 1.25 to 1.66, which constitutes a moderately increased risk as defined by the ACS (15 to 20% overall lifetime risk).
Increased risk by risk modeling
As stated previously, having just 1 first-degree relative with breast cancer doubles the risk, bringing the lifetime risk to 24.6%. Family history is at the center and, in general, of the greatest significance in the most commonly used risk calculating models. The most acknowledged are the Gail model (http://www.cancer.gov/bcrisktool/), the Claus model (Claus et al, 1991), the BRACAPRO model (Parmigiani et al, 1998) and the Cuzick–Tyrer model (Mann et al, 2006). None of these are perfect and each has its specific limitations as demonstrated in the relatively poor concordance of, for example, the Gail and the Claus models. The greatest discrepancies in risk prediction are seen in individuals with nulliparity (no pregnancies), multiple benign breast biopsies, or with a strong paternal or first-degree family history (McGuigan et al, 1996; McTiernan et al, 2001). The Gail model only takes into account the number of first-degree relatives, thereby underestimating risk in the 50% of families with cancer in the paternal lineage. It also does not account for the age of onset of breast cancer. The Claus model does not include any of the nonhereditary risk factors. The BRACAPRO model provides estimates for the likelihood of finding either a BRCA1 mutation or a BRCA2 mutation in a family but allows for neither non-hereditary factors nor other “genetic” elements to be included, thereby underestimating the risk in breast-cancer-only families. The Cuzick–Tyrer model integrates family history, surrogate measures of endogenous estrogen exposure, and benign breast disease in a comprehensive fashion, and in addition to producing a readout of BRCA1/2, allows for the presence of multiple genes of differing penetrance. The Gail, Claus, and BRCAPRO models all underestimate risk, particularly in women with a single first-degree relative affected with breast cancer. This is thought to imply that the effect of a single affected first-degree relative is higher than may have been previously thought and the Gail model is likely to underestimate risk in this group as it does not take into account the age at onset of breast cancer.
None of the available risk models do or can take into account the deCODE BreastCancer™ risk alleles in their calculations. The Cuzick–Tyrer model already is taking into account the possible presence and effect of multiple genes of differing penetrance. Therefore, the modeled risk derived from this tool should not be multiplied by the deCODE BreastCancer™ results since the effect of the risk variants may already be accounted for to an unknown, albeit imperfect degree. This also applies to the emerging BOADICEA model (Antoniou et al, 2008), which has the potential to be updated for accommodation of the deCODE BreastCancer™ risk alleles.
Because of the limitations of the available computerized risk models, many find manual risk estimation to be one of the best ways to assess risk by considering the strongest risk factor (Evans and Howell, 2007), which, in many assessment clinics, is family history. Manual breast cancer risk assessment is largely based on the published Claus risk tables (Claus et al, 1994) and use of data in clear-cut BRCA1/2 families from penetrance data for breast cancer (Antoniou et al, 2003). If first-line risk can be assessed on this basis, then adjustments can be made for other factors (Evans et al, 2002 and 2005) and a good manual assessment will alert the assessor to any spurious readout from a computer model.
Hereditary breast cancer
All of the above mentioned models seem to accurately predict risk in women with multiple relatives affected by breast cancer (that is, 2 first-degree relatives and 1 first-degree relative plus 2 other relatives). The deCODE BreastCancer™ test does not assess risk from rare, high-penetrance mutations in genes such as BRCA1, BRCA2, TP53, and PTEN, which confer high risk of familial, early-onset breast cancer. However, some of the variants in the deCODE BreastCancer™ test modify the risk of breast cancer in subjects who carry mutations in the BRCA1 and/or BRCA2 genes. The deCODE BreastCancer™ test reports a factor based on the relevant SNP genotypes by which the lifetime risk from the BRCA mutation should be multiplied in order to determine the overall lifetime genetic risk of breast cancer, given that the subject is diagnosed as a carrier of a high-penetrance BRCA1 or BRCA2 mutation.
The deCODE BreastCancer™ test in clinical practice
The deCODE BreastCancer™ test makes significant contribution to modifying basic or modeled risks since it is, to a great extent, independent of the individual factors currently used to estimate future breast cancer risk in individuals. Validations of the significance and magnitude of association for each of the 7 SNPs evaluated in the deCODE BreastCancer™ test are based on studies of 4.500 to 26.000 breast cancer cases and between 17.500 and 32.000 controls. deCODE and others have shown that the markers used are independent of immediate family history, breast density, menarche, age of first pregnancy, and nulliparity. The deCODE BreastCancer™ test results represent an independent, validated set of risk factors that is an important addition to the currently recognized risk factors for breast cancer.
Current recommendations for breast cancer screening and diagnosis are based on clinically validated studies of the effectiveness of screening interventions among women of predefined risk categories. These risk categories have been defined by conventional risk factors and their relative contribution, the strongest risk factors being age and close family history of breast cancer (almost 2-fold relative risk). The deCODE BreastCancer™ test provides new information on the genetic risk contribution of 7 highly significant DNA variants, risk information that seems to be an addition to the currently used risk assessment tools, but not a replacement. It seems to be particularly important for the group of women who will be moved up or down in risk category by multiplication of their basic or modeled risk by the deCODE BreastCancer TM results.
Subjects at higher risk of breast cancer may be considered for earlier start ages for clinical breast exams and mammographic screening, and/or enhancement of X-ray mammographic screening programs by including MRI assessments. The ACS recommends that women at high risk (>20% overall lifetime risk) of breast cancer should get an MRI and a mammogram every year. Women at moderately increased risk (15 to 20% overall lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their annual X-ray mammographic screening.
Subjects at higher risk of breast cancer, particularly estrogen receptor-positive breast cancer, may benefit from preventative hormonal therapy with a selective estrogen response modifier (SERM), such as tamoxifen, or similar agent. According to the ACS, most doctors consider that women aged 60 or over have a sufficiently high risk of breast cancer to be considered for tamoxifen therapy in a primary preventative mode. Women aged less than 60 may, if they have substantial genetic and nongenetic risk factors, also be considered for such preventative treatments. The breast cancer genetic risk assessment provided by the deCODE BreastCancer™ test can assist in clinical decision making under these circumstances. In addition to providing a general assessment of overall breast cancer risk, some of the SNP variants in the deCODE BreastCancer™ test have been shown to confer preferentially increased risks of estrogen receptor positive (ER+) breast cancer. The deCODE BreastCancer™ test report provides an assessment of the subject’s risk of ER+ vs. ER-breast cancer. SERMs are particularly effective at preventing ER+ forms of breast cancer. Therefore the ER+ breast cancer risks assessed by the deCODE BreastCancer™ test can provide an additional aid to clinical decision making when considering the likely benefits of SERM therapy in a preventative mode.
Some forms of hormone replacement therapy (HRT) have been reported to increase risks of ER+ breast cancer. In subjects who are being considered for HRT, the deCODE BreastCancer™ test and its inclusive ER+ vs. ER- risk assessment can provide an aid to clinical decision making when weighing up the potential risks and benefits of HRT.
The variants on 5q11, 10q26, and 16q12 have been shown to significantly affect the risk of breast cancer in subjects who are carriers of high-penetrance mutations in the BRCA2 gene. The variant on 16q12 has also been shown to significantly affect the risk of breast cancer in subjects who are carriers of high-penetrance mutations in the BRCA1 gene. Therefore, given that a subject is a carrier of a high-penetrance BRCA mutation, the lifetime probability that they will be diagnosed with breast cancer is modified by their genotypes for these SNP variants. The relative risks of the SNP variant genotypes interact in a multiplicative manner with the respective high-penetrance BRCA mutations. The deCODE BreastCancer™ test reports a factor based on the relevant SNP genotypes by which the lifetime risk from the BRCA mutation should be multiplied in order to determine the overall lifetime genetic risk of breast cancer, given that the subject is diagnosed as a carrier of a high-penetrance BRCA1 or BRCA2 mutation.
Patients who are identified as being at high risk of breast cancer may be considered for risk-reducing surgery, either bilateral mastectomy, oophorectomy, or both. Clearly, such drastic treatments are recommended only for patients who found to be at extremely high risk. Taken individually, no genotype in the deCODE BreastCancer™ test confers sufficiently high risk for risk reducing surgical interventions to be recommended. However, since some of the SNP variants in the deCODE BreastCancer™ test have been shown to modify the risk of breast cancer in patients who are known carriers of high-penetrance mutations in the BRCA1 and/or BRCA2 genes, the deCODE BreastCancer™ test can be used as an aid to clinical decision making in conjunction with a BRCA1 or BRCA2 genetic test.
The deCODE diagnostic laboratory
The deCODE BreastCancer™ test is performed in deCODE’s CLIA-registered laboratory. The test can only be ordered by qualified physicians and medical practitioners. If you are an individual interested in deCODE BreastCancer™, you can continue reviewing this site, and even download and print the test order forms to meet with your doctor and discuss the next steps.