What Is deCODE BreastCancer™?
The deCODE BreastCancer™ test is a novel, DNA-based reference laboratory test for the first common genetic risk factors to be identified that contribute to a substantial proportion of female breast cancers in the general population. The validity of these 7 variants as risk factors for the common forms of breast cancer has been demonstrated in large, multinational discovery and replication studies involving nearly 100,000 breast cancer patients and healthy control subjects.
The risk quotients at each of the 7 markers, measured in DNA isolated from the inner cheek or blood sample, are multiplied together to define risks from 0.4- to 4.0-fold relative to the general population. It is estimated that these 7 markers together account for 60% of breast cancer (population attributable risk). About 5% of women have a 2-fold risk on average for breast cancer compared to the general population and about 1% have a 3-fold risk according to the test results only. This translates for white women to a lifetime risk of 24% and 36%, respectively, versus the average risk of 12%. These common genetic variants do not explain risk due to family history of breast cancer as numerous studies have shown that the risk is independent of family history. Therefore, the test is useful for both the 70 to 80% of the population that does not have a family history of breast cancer as well as those who have a positive family history for breast cancer. The test also predicts the likelihood of the cancer being estrogen receptor- (ER-) positive, if it occurs. It is thought that tamoxifen only has effects on ER- positive tumors.
Why take deCODE BreastCancer™?
There are 3 reasons for using the deCODE BreastCancer™ test for defining a patient’s genetic risk for breast cancer.
1) According to the American Cancer Society (ACS), high-risk women with a 20% lifetime risk (or a relative risk of 1.65 based on the deCODE BreastCancer™ test) should have a yearly breast MRI added to their usual yearly mammography beginning at age 40. MRI is better at detecting early tumors than standard mammography, but is only recommended for higher-risk women. The ACS also recommends that physicians consider breast MRI for patients who have a modestly high risk for breast cancer based on lifetime risks of 15 to 20% (relative risks of 1.25 to 1.65).
2) According to the American Society of Clinical Oncology (ASCO), higher-risk women (defined as greater than 1.66% 5-year risk) should consider with their physicians whether to use tamoxifen (or similar drugs that also block the effects of estrogen which can drive small tumors into larger tumors) as a preventive measure. The average 55-year-old woman has a 1.2% risk of developing breast cancer over the next 5 years. If her deCODE BreastCancer™ test result showed a genetic risk of 1.4, her total 5-year risk of 1.7 would make her a candidate for preventive therapy, whereas based on conventional risk factors, she would be considered to have an average risk.
3) Patients who have a strong family history of early-onset breast cancer in multiple first-degree relatives are often tested for mutations in the BRCA1 and BRCA2 genes. Several of the genetic variants used in the deCODE BreastCancer™ test increase the lifetime risk for breast cancer in women positive for the BRCA1 or BRCA2 gene mutations. The test is also useful in parallel with BRCA1 and BRCA2 testing since it may reinforce that patients who are negative for BRCA1 and BRCA2 may still be at increased risk for later-onset breast cancer.
Background
Breast cancer is by far the most common cancer in women worldwide. Current global incidence is in excess of 1,151,000 new cases diagnosed each year. Breast cancer incidence is highest in developed countries, particularly among populations of Northern European ethnic origin, and is increasing. In the United States, the annual age-standardized incidence rate is approximately 125 cases per 100,000, more than 3 times the world average. Rates in Northern European countries are similarly high. In 2008 it is estimated that 184,450 new cases of invasive breast cancer will be diagnosed in the United States and 40,930 people will die from the disease. To this figure must be added the 67,770 ductal- and lobular-carcinoma in-situ diagnoses expected in 2008. From an individual perspective, the lifetime probability of developing breast cancer is 12.3% in US women (ie, 1 in 8 women will develop breast cancer during their lives). As with most cancers, early detection and appropriate treatment are important factors. Overall, the 5-year survival rate for breast cancer in the United States is 89%. However, in individuals presenting with regionally invasive or metastatic disease, the rate declines to 84% and 27%, respectively.
Increasingly, emphasis is falling on identifying individuals who are at high risk for breast cancer. Such individuals can be managed by more intensive screening, preventative chemotherapies, hormonal therapies, and, in cases of individuals at extremely high risk, prophylactic surgery. Large-scale screening programs constitute a huge economic burden on health services, while preventative therapies have associated risks and quality-of-life consequences. The overall goal of breast cancer risk assessment is to provide a rational framework for the development of personalized medical management strategies for all women, with the aim of increasing survival and quality of life in high-risk women while minimizing costs, unnecessary interventions, and anxiety in women at lower risk.
deCODE BreastCancer™
The deCODE BreastCancer™ test determines the genotypes for 7 known single-nucleotide polymorphisms (SNPs) that have been linked to genetic predisposition to female breast cancer. The variants are located on chromosomes 2q35 (rs13387042), 5p12 (rs4415084, near the MRPS30 gene), 5q11 (rs889312, near the MAP3K1 gene), 8q24 (rs13281615), 10q26 (rs1219648, near the FGFR2 gene), 11p15 (rs3817198, near the LSP1 gene), and 16q12 (rs3803662, near the TNRC9/TOX3 gene). Based on an individual’s genotypes for these SNP markers, lifetime genetic risk of being diagnosed with breast cancer can be determined and related to the general risk of breast cancer in the population.
The deCODE BreastCancer™ test reports the subject’s measured genetic risk of breast cancer relative to the average population and the lifetime risk of being diagnosed with breast cancer. The relative risk of breast cancer determined by the test can vary from 0.45 for subjects who are homozygous (2 copies) for the protective variants at all 7 markers, to 3.77 for subjects who are homozygous for risk variants at all markers. About 42% of the female population has genotype combinations of the tested markers that confer an increased relative risk (>1) of breast cancer. Ten percent of women in the general population have genotypes that confer more than a 40% increase in the relative risk of breast cancer, about 5% would be considered high risk with a 1.66-fold or greater risk (corresponding to a lifetime risk of 20% or greater), and approximately 1% of women have an average 3-fold risk (37% lifetime risk).
The risk distribution in the general population and the proportion of the population with decreased (<1) and increased (>1) risks according to the test are given in the figure below.
deCODE BreastCancer™ and estrogen-receptor status of tumors
Variants of 5 out of the 7 SNP markers (on 2q35, 5p12, 8q24, 10q26, and 16q12) have been shown to confer increased breast cancer risks that are preferential for ER- positive (ER+) tumors (ie, each risk variant increases the risk of being diagnosed with an ER+ tumor to a greater extent than it increases the risk of being diagnosed with an ER- negative [ER-] tumor). Therefore, given that an individual is diagnosed with breast cancer, the probability that the tumor will be ER+ or ER- will vary depending on their genotypes of these 5 markers. The deCODE BreastCancer™ test reports the conditional probability that the tumor will be ER+ or ER-based on the subject’s genotype, given that the subject is diagnosed with breast cancer. The probabilities of ER+ breast cancer are determined by the test range of from 55.6% for subjects who are homozygous for non-risk variants at all 5 markers, to 91.3% for subjects who are homozygous for risk variants at all 5 markers.
deCODE BreastCancer™ and heritable breast cancer and breast cancer syndromes
The deCODE BreastCancer™ test does not assess risk from rare, high-penetrance mutations in genes such as BRCA1, BRCA2, TP53, and PTEN that confer high risks of familial, early onset breast cancer. These genes are involved in only a very small fraction of breast cancer cases arising in the general population. 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.