Abstract The purpose of this paper is to examine the role genetics play related to hereditary breast cancer and the options available for risk reduction and prevention. Four published articles, two medical databases and a genetic focused website were examined during the process of this research. Breast cancer is one of the leading causes of death amongst women and heredity is second only to age amongst risk factors. This paper will show how genetic mutations are linked to hereditary breast cancer and the degree of risk they pose on carriers of these mutations.
This paper will also examine the process by which affected individuals should be tested for the mutations, who should be tested and options available for cancer prevention and early detection are available. General statistics regarding the mutations, various preventative actions and screening methods will also be disclosed throughout the course of the paper. Hereditary Breast Cancer: The Implications of Genetic Mutations Documented awareness of breast cancer dates back as far as 1600 BC in Egyptian writings. The idea that breast cancer is linked to heredity was first looked at in the late 1800’s.
In 1866 a famous French surgeon by the name of Paul Broca came out with the “Broca” report showing that breast cancer can be inherited through families passing from one generation to another (Van der Groep, Van der Wall, & Van Diest, 2011, sec. B). He identified this by constructing a pedigree of his wife’s family after she was diagnosed with breast cancer. Presently, a family history of breast cancer is one of the highest risks for developing breast cancer, second only to age. The purpose of this paper is to examine the role genetics play related to hereditary breast cancer and the options available for risk reduction and prevention.
Women with a family history of breast cancer have a significant twofold higher lifetime risk of developing breast cancer than those who do not. Although genetic mutation is a definite factor amongst familial breast cancer, it is not the only link since there are families with breast cancers without germline mutations. According to Isaacs, Fletcher, & Peshkin (2011), “familial cancers may be associated with chance clustering of sporadic cancer cases within families, genetic variation in lower penetrance genes, a shared environment, or a combination of these factors” (sec.3).
The majority of hereditary breast cancers are linked to two genes, BRCA1 and BRCA2. These genes were first discovered in in 1994 and 1995 respectively and pose a risk of developing breast cancer in women up to 87% by the age of 70 if they carry a mutation in either one of these genes (Metcalf et al. , 2007, p. 208). Men who have an abnormal BRCA2 gene are approximately 80 times more likely to develop breast cancer than men who don’t, which is about 8% by age 80 (“Genetics,” 2012, sec. 2).
Hereditary genetic mutations account for approximately 10% of all breast cancer, most commonly being BRCA1 and BRCA2 mutations. What are BRCA1 and BRCA2 genes and who has them? BRCA1 and BRCA2 are tumor suppressor genes and everyone has them. Since they are tumor suppressor genes they play an important role in maintaining gene integrity, they repair damaged DNA, and serve as checkpoints in cell cycles which allows for repairs to be made before mitosis occurs (Isaacs et al. , 2011). The problem and the increased risk for cancer occur when there is a mutation in one or both of these genes.
Isaacs et al. , (2011) said the following: Germ line mutations in BRCA1 and BRCA2 result in mutation carriers having loss of one of their wild type alleles and thus they have only one rather than two functional alleles of these genes in their cells. This leads to an increase in genomic instability and tumorigenesis. Tumors in carriers tend to demonstrate loss of the other wild type allele either through loss of heterozygosity or other somatic mutation. The reason why BRCA1 and BRCA2 mutations predispose mainly to breast and ovarian cancers is unclear.
At least some data suggest that intact BRCA1 inhibits ligand-independent transcriptional activation of the estrogen receptor-alpha and that functional inactivation could lead to altered hormonal regulation of mammary and ovarian epithelial proliferation (para. 6). The prevalence of BRCA1 and BRCA2 mutations have been shown to vary in certain geographical areas and ethnic groups, especially among small ancestral groups that may have been geographically or culturally isolated, as seen in the high prevalence of BRCA mutations amongst the Ashkenazi Jewish population (Isaacs, et al., 2011).
The histology of BRCA1 associated breast cancers are associated primarily with invasive ductal adenocarcinomas and have histopathological characteristics including: they are poorly differentiated, have a high mitotic count, show a high frequency of necrotic areas and a remarkable degree of lymphoplasmocytic infiltration and lymphovascular invasion (Van der Groep et al. , 2011, sec. 4).
Van der Groep (2011) went on to explain that “BRCA1 associated breast cancers are classified as basal and the gene expression profile of BRCA1 tumors involves genes that were found to have functions in proliferation, angiogenesis, cell motility, cell adhesion, transcription and DNA repair” (sec. 4). BRCA1 associated breast cancer has a higher frequency of lung and brain metastasis and a prognosis that studies have found to be similar to worse as compared with sporadic breast cancers in age-matched patients (Van der Groep et al., 2011).
The histology of BRCA2 associated breast cancers are associated primarily with invasive ductal carcinomas and are noted to be poorly differentiated with high mitotic rates, increased nuclear pleiomorphism, and have a high proportion of continuous pushing margins (Van der Groep et al. , 2011). One main difference between BRCA1 and BRCA2 is that in BRCA1 there is a low expression of the estrogen receptor (ER) and a low expression of the progesterone receptor (PR), and in BRCA2 there is a more frequent expression of ER and PR.
According to Van der Groep (2011), “In women with BRCA2 associated breast cancer, bone and soft tissue metastasis are observed more frequently likely associated with their more frequent ER positivity” (sec. 5). Another genetic mutation that deserves some attention is Li-Fraumeni syndrome, an inherited disorder manifested by a wide range of malignancies occurring with an early age of onset. It is an autosomal dominant disorder, where by individuals that are affected have inherited one abnormal copy of the TP53 gene and the second allele of TP53 is either deleted or mutated.
Tumor protein p53 delays cell cycle progression, allowing for DNA repair and apoptosis; if is mutated then cells with damaged DNA can survive and proliferate, leading to malignant transformation (Van der Groep et al. , 2011). In a study conducted of 525 patients, 17% were positive for the TP53 mutation (Van der Groep et al. , 2011). In all cases where a TP53 mutation was identified there was either a family history or the patient themselves had one of four “core” malignancies which included breast cancer, sarcoma, adrenalcortical carcinoma, or brain tumor prior to age 50, with an average age of 21 in women and 28 in men (Van der Groep et al.
, 2011). A startling 141 cancers were diagnosed out of 82 patients with mutations, with breast cancer occurring in 44 of those patients (Van der Groep et al. , 2011). The lifetime risk of cancer for women with the TP53 mutation is nearly 100% as compared to 73% in men. According to Van der Groep (2011), “Women with Li-Fraumeni syndrome are at a markedly increased risk of developing premenopausal breast cancer. In one series the median age at diagnosis was 33 years; in another report approximately one-third occurred prior to age 30” (sec.9).
Genetic testing, involving a blood test, is an option available to individuals that have a family history of breast cancer. Before undergoing genetic testing, the individual must receive genetic counseling to ensure a full understanding of the pros and cons of genetic testing, which enables the person to provide informed written consent. The individual then must decide if genetic testing is right for them.
It is also important for the physician to assess the patient’ s emotional state as well as their ability to process the information they might receive regarding a possible positive or negative DNA mutation test result (Lynch, Silva, Snyder, & Lynch, 2008, p. 11). According to Lynch et al. (2008), “The entire impact upon hereditary cancer syndrome diagnosis and its ultimate management starts with our strong emphasis on a well-orchestrated family history” (p. 12). Cost for genetic testing can be very high; although some insurance companies will cover the cost for patient’s deemed to be a high risk.
Metcalf et al. (2007) ascertained the following information: It is known that women with a BRCA1/2 mutation have one of the highest known risks for the development of breast cancer. However, there are several options available to reduce the risk of developing breast cancer. These include chemoprevention (including tamoxifen), prophylactic surgery (mastectomy or oophorectomy). None of these options offer women a 100% breast cancer risk reduction, and each preventative option has risks and benefits, both medical and psychological.
These circumstances make decisions about breast cancer prevention difficult to make (p. 208). Metcalf et al. ’s study involved creating a decision making tool to serve as an aid to women in making their decision regarding preventive options. Women in the study reported that they need more information in order to make an informed decision. The decision aid used a pre and post test and gave detained information about various options along with information on how they may expect to feel emotionally related to each of those options (Metcalf et al., 2007).
Although this was a very limited study, it does potentially have some significant implications, according to Metcalf, et al. (2007) “We observed decreased levels of decisional conflict suggestive of implementation of decisions, and an increase in the number of women that were leaning towards a breast cancer prevention option” (p. 216). Metcalf et al. (2007) concluded, “with use of the decision aid, more women will elect for a cancer prevention option, and ultimately fewer women will develop and/or die of hereditary breast cancer” (p. 216).
Metcalf’s conclusion might be slightly egocentric, but the findings are rather interesting and certainly persuasive that the more information given, the more likely a comfortable decision will be made possibly in a shorter time frame, which for some could make the difference of life and death. In another study discussed by Silva et al. they too found a lack of knowledge about clinical implications of mutant genes is an important issue to be addressed; their findings showed that clinicians performed inappropriate risk assessments contributing to patients’ emotional distress (Silva et al., 2008, p. 15).
It has been found in recent years that approximately 80% of women who underwent prophylactic mastectomies without having thorough risk assessments and genetic counseling later found out they were not BRCA carriers and not carry the same inordinate risk for those mutations (Silva et al. , 2008, p. 15). Silva et al. (2008), concluded “significant psychological problems are often seen in these individuals who test negative for a BRCA mutation years after undergoing prophylactic mastectomy for a putative but undefined or poorly quantitated risk” (p. 15).
Women who are carriers for BRCA1 and/or BRCA2 mutations who have had adequate risk assessment and genetic counseling who choose to have prophylactic breast surgery, reduce the risk of breast cancer as much as 97% (“Genetics,” 2012). The surgery removes nearly all of the breast tissue, so there are very few breast cells left behind that could develop into a cancer. Women with an abnormal BRCA1 or BRCA2 gene that have a prophylactic oophorectomy before menopause decrease their risk of breast cancer by approximately 50% because the ovaries are the main source of estrogen in a premenopausal woman’s body (“Genetics,” 2012).
Hormonal therapy is another option for women at high risk for breast cancer. Selective estrogen receptor modulators, such as Tamoifen and Evista have been shown to reduce the risk of developing hormone-receptor-positive breast cancer in women at high risk (“Genetics,” 2012). While tamoxifen has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal and premenopausal women, evista has been shown to be more effective in postmenopausal women (“Genetics,” 2012).
Unfortunately these medications are not effective in hormone-receptive-negative breast cancer. Radiologic screening and surveillance is another option some women choose to do rather than taking medications or having prophylactic surgery. Individuals at high risk who choose this option are encouraged to regular screenings including, thorough breast exams, breast ultrasound, mammography and breast MRI. The recommendation is every 6 months have at least one up to all four of these screenings done.
MRI testing is shown to yield 77% sensitivity, mammography is 36% sensitive, mammography plus a complete breast exam is 45 % sensitive, and MRI plus mammography plus ultrasound yields 95% sensitivity (Silva et al. , 2008, p. 16). In conclusion, while heredity is the second highest risk factor for breast cancer, only 10% of individuals affected carry mutated genes associated with the development of breast cancer. However it is those 10% carrying mutated genes that have such a high propensity of developing the disease.
Although each researcher varies slightly on their data and even their views on the pathogenesis of hereditary breast cancer and the genetic mutations involved, they all agree that if the mutated gene exits there is a high propensity for the development of breast cancer. The majority also agree that prophylactic surgery is the safest most risk-decreasing choice an individual can make if they carry a genetic mutation placing them at high risk. It has also been proven that frequent screenings and use of multiple screening tools and exams is the best way of keeping potential breast cancer under surveillance in hope to catch it in its earliest of stages.
It is important to remember that obtaining a detailed family history, performing a thorough risk assessment and a referral to genetic counseling to individuals found to be at high risk are the starting points in this very complex multidisciplinary approach to determining hereditary breast cancer syndromes, risks and prevention.
References Evans, G. (2011, September 26). Li-Fraumeni syndrome. Up To Date. Retrieved from http://www. uptodate. com/contents/li-fraumeni-syndrome? source=search_result Genetics. (2012, March 20). BreastCancer. org. Retrieved from http://www. breastcancer.org/risk/factors/genetics. jsp Isaacs, C. , Fletcher, S. W. , & Peshkin, B. N. (2011, February 15).
Genetic testing for hereditary breast and ovarian cancer syndrome. Up To Date. Retrieved from http://www. uptodate. com/contents/genetic-testing-for-hereditary-breast-and-ovarian-cancer-syndrome? source=see_link Lynch, H. , Silva, E. , Snyder, C. , & Lynch, J. (2008). Hereditary breast cancer: Part 1. diagnosing hereditary breast cancer syndromes. Hereditary Breast Cancer: Part 1. Diagnosing Hereditary Breast Cancer Syndromes, 14(1), 3-13.
Metcalf, K. A. , O’Connor, A. , Gershman, S. , Armel, S., Finch, A. , Demsky, R. , … Narod, S. A. (2007). Development and testing of a decision aid for breast cancer prevention for women with BRCA1 or BRCA2 mutation. Clinical Genetics, 72, 208-217. doi: 10. 1111/j. 1399-0004. 2007. 00859. x Silva, E. , Gatalica, Z. , Snyder, C. , Vranic, S. , Lynch, J. F. , & Lynch, H. T. (2008). Hereditary breast cancer: Part II. management of hereditary breast cancer: Implications of molecular genetics and pathology. Hereditary Breast Cancer: Part II. Management of Hereditary Breast Cancer: Implications of Molecular Genetics and Pathology.