Risk Factors in Breast Cancer

Submitted by Dr. Andreas Lambrianides
General Surgeon
Brisbane, Australia
 
Breast cancer is the most common malignancy of women in the United States, and the mortality rate is second only to lung cancer as a cause of death among women. Currently seven percent of American women are expected to develop breast cancer by the age of 70. One third of these will die of their disease.
 
All women presenting with breast problems should be assessed as to whether they are at normal or increased risk of developing breast cancer. Having assessed the risk, appropriate advice should be given for the prevention and early detection of the disease.
 
With increasing public awareness, and new information about the genetics of breast cancer becoming available, risk factor assessment is becoming progressively more important. Risk factors may be described in terms of risk expressed as relative risk (RR) or absolute risk (AR). Relative risk expresses as a ratio, the risk of a person with a particular variable, compare with the risk for the general population without the risk factor.
Absolute risk expresses the percentage chance of that person developing the disease in a given period of time.
 
In general, the absolute risks of developing breast cancer are:
20 - 40 0.5%
35 - 55 2.5%
50 - 70 4.7%
65 - 85 5.5%
A number of risk factors have been identified, but the ones of greatest importance are, a possible family history, a history of biopsy proven invasive or in situ (non invasive) carcinoma, or a history of atypical hyperplasia ( an increase in the number of cells in an organ or tissue that have some but not all the features of carcinoma in situ. There are various degrees of cellular and architectural atypia).
Risk factors can be grouped according to the relative risk.
Major increase in risk (RR > 4.0)
1. Strong family history of carcinoma of the breast
2. Atypical hyperplasia on biopsy
3. Past history of invasive carcinoma
4. Past history of ductal or lobular carcinoma in situ
 
Moderate increase in risk (RR 2.0 - 4.0)
1. Nulliparity (not having given birth to a child)
2. The first birth after the age of thirty five
 
Minor increase in risk (RR < 2.0)
1. Early menarche (early commencement of menstrual cycles)
2. Late menopause
3. Proliferate benign disease without atypia
Women with a first-degree relative with breast carcinoma have a life time RR of 1.5 - 2.0 times that of a woman without a family history. In women with two first-degree relatives this RR increases 4.6 times. The risk of developing breast carcinoma is higher when relatives developed the disease before the age of fifty or when the disease affected both breasts. A careful documentation is necessary in the presence of a family history in order to assess the possibility of a breast carcinoma gene present.
 
A patient with a previous history of invasive or non-invasive carcinoma has an increased risk of developing further carcinoma during her lifetime. An overall RR of 2.4 has been reported with a higher risk RR 9.9 in those women whose breast carcinoma was diagnosed before the age of 50. The risk is also greater if the initial carcinoma was of lobular type (a morphologic form of mammary carcinoma that probably arises from the terminal ductules of the breast lobule). One third of women with a high-grade ductal carcinoma in situ have been shown to develop further disease in that breast, half of which is invasive carcinoma. Lobular carcinoma in situ is associated with a long term 20 - 30 % risk of invasive breast carcinoma.
 
The risk of developing breast carcinoma is increased in women with a biopsy that shows atypical ductale hyperplasia, and this is further increased in the presence of a family history. Atypical hyperplasia is diagnosed when the criteria for ductal carcinoma in situ are present but are not present in full flower.
Uniform population of cells.
Smooth geometric spaces between the cells.
Hyperchromatic nuclei.
Atypical ductal hyperplasia has some of the above features but lacks the full measure of these major criteria. Any case having one or the other of the first two major criteria with the second present in only suggestive form would be diagnostic of atypical ductal hyperplasia. From this it can be seen that atypical hyperplasia is a reliable marker of increased risk of breast carcinoma. Ten years after diagnosis, the risk of carcinoma is increased five fold in women without a family history and eleven fold in those with a family history. The risk is significantly greater in pre-menopausal women (RR 5.9) than post- menopausal (RR2.3) women.
 
The strongest association with an increased risk of developing breast cancer, is a family history, specifically breast cancer in a first degree relative (mother, sister, daughter).
 
The high-risk genes are not common, and are responsible for about 5% of all breast cancers.
 
BRCA1 (Breast cancer one gene), also linked to ovarian cancer, was the first breast cancer gene to be isolated. The second breast cancer gene BRCA2 was localized in 1994 and isolated in 1995. The other well-studied tumor gene is located on chromosome 17p13.1 and is the single most common target for genetic alteration in human tumors. A little over 50% of human tumors contain mutations in this gene. Homozygous (Homo = same) is when both genes in the pair (genes occur in pairs) are the same. Loss of the p53 gene is found in virtually every type of cancer, including lung, colon and breast, which are the three leading causes of cancer deaths. In most cases the inactivating mutation affecting both p53 allele (different versions of the same gene that code for the same trait) are diagnosed in somatic cells (non reproductive cells). Inheritance of one mutant allele predisposes individuals to develop malignant tumors because only one additional “hit” is needed to inactivate the second normal allele. Such individuals said to have the Li - Fraumeni syndrome have a 25 fold greater chance of developing a malignant tumor by the age of fifty compared with the general population. It is estimated that germ line mutations in p53 account for 1% of breast cancers among women, in whom the tumor is detected before the age of forty years. P53 senses DNA damage by unknown mechanisms and assists in DNA repair by causing G1 arrest and inducing DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to undergo apoptosis (commit suicide). In view of these activities, p53 has been called the policeman of the genome. With homozygous loss of p53 DNA damage goes un-repaired, mutations become fixed and malignancy occurs.
 
BRCA1 is located on a small locus (position) on chromosome 17q12-21 in a large number of families in whom breast cancer develops at an early age. Mutations in BRCA1 and BRCA2 account for 80% of the familial cases. Mutations of BRCA1 and BRCA2 are rarely found in sporadic breast cancer; therefore neither of the two BRCA genes in contrast to p53 is associated in the development of sporadic (non familial) form of breast cancer.
 
The functions of the BRCA genes are not fully defined. Protein products are localized to the nucleus and are believed to be involved in transcriptional regulation.
 
It is thought that mutations in the BRCA1 gene account for 8% of breast cancers before the age of 30, 5% of cancers before the age 50 and 1% of those after age 50 years. Women with BRCA1 mutations are estimated to have a lifetime risk of breast cancer of 20% by forty years, 51% by fifty years and 81% by seventy years. Women with BRCA1 mutations are also at a greater lifetime risk of ovarian breast cancer, which has been estimated to range from 20 to 60 %.
 
The same mutations in the BRCA genes behave in a different manner in different populations. In the Ashkenazi Jews, the risk is lower at 56% by the age of 70 years.
 
Women with breast cancer and a BRCA1 mutation have a 64% risk of developing breast cancer in the opposite breast and a 44 - 63% risk of ovarian cancer.
 
Mutations in BRCA2 gene which is located on chromosome 13q are incriminated in some 70% cases of breast cancer that are not secondary to mutations in the BRCA1 gene. Similar to the situation with BRCA1, women with BRCA2 mutations also exhibit an increase risk of ovarian carcinoma.
 
Male breast cancer in families is uncommon with BRCA1 Mutations. BRCA2 mutations account for six percent of men with breast cancer.
 
It is now possible to test for the presence of gene mutations, BRCA1, BRCA2 and p53. The test should not be performed without detailed discussions before and after the test in order that patients undergoing the procedures have a clear understanding of the implications of a positive or negative outcome.
 
Current testing will only detect 70% of mutations for BRCA1 and some of those detected may not be clinically significant so false positive and false negative results are possible. Identifying a specific BRCA mutation is not a simple task and the complexity should not be underestimated. Because of the complexities involved and the difficulty of interpreting results, gene testing is not available in every day clinical practice and the test should be undertaken through a department of medical genetics.
 
The possibility of finding a breast cancer gene mutation is greater in women from families with both ovarian and breast carcinoma, and when the breast cancer was diagnosed prior to the age of fifty-five years. Inheritance may be via maternal or paternal lines, and generations may be bypassed as a result of a carrier who is not affected.
 
Once a patient becomes confirmed as having a high-risk gene mutation, the aim is to:
Surveillance for prevention and early detection of breast cancer.
Possibility of prophylactic mastectomy.
                            Surveillance should include:
Monthly breast self examinations commencing in early adult life (18 - 21)
Twice yearly breast clinical examinations
Annual mammography beginning at the age of 25 - 35 years.
Annual pelvic examination and trans vaginal ultra sound beginning at the age of 25 -   35 years
Annual serum CA-125 levels (tumor marker for ovarian carcinoma)
Consider chemoprophylaxis with tamoxifen in suitable patients
 
The option of prophylactic mastectomy remains controversial. Patients should be told that prophylactic mastectomy does not remove all breast tissue therefore a persistent risk remains. Theoretical models predict a life gain from 2.9 - 5.3 years. Finally the psychological problems should be considered in a patient with a prophylactic mastectomy, which could disrupt social harmony.
 
The value of the procedure is of unproven value and should not be considered likely.

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