What are three factors that affect breast cancer penetrance?
What are three factors that affect breast cancer penetrance? (Penetrance is defined as the likelihood of cancer when a cancer predisposing mutation is present). Will award points to the person who answers the question most accurately. Thanks!
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- Many family members with Hx. of Br. Ca. - Few family members with Hx. of Br. Ca. - Polymorphisms in certain otherwise 'protective' genes
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Family History as a Risk Factor for Breast Cancer In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative or a second-degree relative with breast cancer.[3-6] The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.[7] In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).[7] Risk increases with the number of affected relatives and age at diagnosis.[4,5,7] Refer to the Penetrance of Mutations section for a discussion of familial risk for women from families with BRCA1/2 mutations who themselves test negative for the family mutation. Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics: Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression. Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters. Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations; of Cowden syndrome due to PTEN mutations; and with mutations in CHEK2 .[9] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (MEN1) (OMIM).[9] Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities. The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following: Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk). Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual). Cases of male breast cancer. Possible increased risk of other selected cancers and benign features for males and females. (Refer to the Major Genes section of this summary for more information.) There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers with those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are unlikely to be of mucinous or borderline histopathology. [Refer to the Pathology/Prognosis of Breast Cancer and Pathology/Prognosis of Ovarian Cancer sections for more information.] Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[10,11] Other Risk Factors for Breast Cancer Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) These factors are considered in more detail in numerous reviews,[12,13] including among BRCA1/BRCA2 mutation carriers.[14] Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (More information about their effects in BRCA1/BRCA2 mutation carriers can be found in the section on Interventions later in this document.) Age Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[15] In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases. Reproductive and menstrual history Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.[14,16] Oral contraceptives Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer.[17] Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.[18-20] Hormone Replacement Therapy Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause.[21] The Women's Health Initiative (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[22,23] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P <.001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom.[24] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[25] The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[26-30,21] The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[23] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[21,31] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[32] Radiation exposure Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear. Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations,[33-36] and in association with germline ATM and TP53 mutations.[37,38] Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutat
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Symptoms The first sign of breast cancer is often a painless lump. But early breast cancer is often found on a mammogram before a lump can be felt. Other symptoms of breast cancer may not appear until the cancer is more advanced. These include: •A thickening in the breast or armpit. •A change in the size or shape of the breast. •Changes in the skin of the breast, such as a dimple or skin that looks like an orange peel. •A change in the nipple, such as scaling of the skin or a nipple that turns in. •A green or bloody fluid that comes from the nipple. •A change in the color or feel of the skin around the nipple (areola). About 1% of breast cancer occurs in men. Although most men diagnosed with breast cancer are older than 65, the disease can appear in younger men. For this reason, any breast lump in an adult male is considered abnormal.7 Inflammatory breast cancer is a specific type of breast cancer that involves the skin of the breast. It occurs when breast cancer cells form "nests" and block the lymphatic drainage from the skin of the breast. Symptoms include redness, tenderness, and warmth. Thickening of the skin of the breast (an orange-peel appearance), rapid breast enlargement, and ridging of the skin of the breast may also be present. Some women may also develop a lump in the breast. For more information, see the topic Inflammatory Breast Cancer. What Happens Breast cancer occurs when cells in the breast grow abnormally. As the breast cancer grows, it can spread to nearby tissues and lymph nodes. Advanced breast cancer can affect the bones, liver, and brain. Fortunately, when found at an early stage, breast cancer is highly curable. Your doctor will learn more about how your breast cancer may behave when the cancer cells are examined under the microscope. This is called classification. It tells your doctor how rapidly the cancer cells are growing and dividing and where they may have started in the breast tissue. Tests for hormone receptors and other markers are also done. All of this information will help you and your doctor make decisions about treatment. The stage indicates how far the cancer has spread within the breast, to nearby tissues, and to other organs. Your doctor will determine the stage of your breast cancer by gathering information from other tests, such as axillary lymph node surgery, blood tests, bone scans, and X-rays. The stage of your cancer is one of the most important pieces of information that will help guide your treatment options What Increases Your Risk Although the exact cause of breast cancer is not known, most experts agree that there are several factors that increase your risk of breast cancer. Top risk factors linked to breast cancer Aging. Your risk of breast cancer increases as you get older. By age group, breast cancer is diagnosed in:2 •4 out of 1,000 women in their 30s. •15 out of 1,000 women in their 40s. •26 out of 1,000 women in their 50s. •37 out of 1,000 women in their 60s. Being female. Although breast cancer can occur in men, most breast cancer is found in women. Conditions that increase the risk of developing breast cancer Personal history of breast cancer. Women who have had breast cancer in one breast have an increased chance of having another breast cancer. The breast cancer can come back in the same breast, in the opposite breast, or in other areas of the body, such as the lungs, liver, brain, or bones. Family history. A woman's risk of breast cancer increases if her mother, sister, daughter, or two or more other close relatives, such as cousins, have a history of breast cancer, especially if they were diagnosed with breast cancer before age 50. •Women who inherit specific changes (genetic mutations) in the BRCA1 and BRCA2 genes are much more likely to have breast cancer. They are also more likely to have colon or ovarian cancer. But most women who have a family history of breast cancer do not have changes in BRCA genes. •Mutations in the BRCA1 and BRCA2 genes are more common in certain ethnic groups, such as Ashkenazi Jews.9 •Genetic tests are available to determine whether you have the genetic mutations long before any cancer appears. In families where many women have had breast or ovarian cancer, genetic testing can show whether a woman has specific genetic changes known to greatly increase the risk of breast cancer. Doctors may suggest ways to try to prevent or delay breast cancer or to improve the detection of breast cancer in women who have the genetic mutations. For more information, see: Should I have a gene test for breast cancer? Breast changes. Women who have atypical hyperplasia, ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS) or who have had two or more breast biopsies for other noncancerous conditions are more likely to have breast cancer. Other factors that increase the risk of breast cancer Race. In the United States, breast cancer occurs more frequently in white women than in black, Hispanic, or Asian women. But black women are more likely to get breast cancer at a younger age and are also more likely to die of breast cancer.10 This may be linked in part to genetic differences—an aggressive type of breast cancer called basal-like tumor seems most likely to affect young African-American women. Lower survival rates among black women may also be linked to lower quality health care.11 Radiation therapy. Women whose breasts were exposed to significant amounts of radiation at a young age, especially those who were treated for Hodgkin's lymphoma, have an increased risk for developing breast cancer. Studies show that the younger a woman was when she received her treatment, the higher her risk for developing breast cancer later in life.10 Late or no childbearing. Women who had their first child after the age of 30 have a greater chance of developing breast cancer than women who had their children at a younger age. Women who never had children have an increased risk for developing breast cancer. Not breast-feeding. Women who don't breast-feed have a higher risk of breast cancer than those who breast-feed. The more months of breast-feeding, the lower the breast cancer risk. Hormones. Female hormones play a part in some types of breast cancer. •The use of hormone therapy after menopause for more than 4 years causes an increased risk of developing breast cancer. This increased risk occurs with current use of hormones and returns to normal over time after hormones are stopped.1 •Beginning menstruation before age 12 and beginning menopause later than age 55 increase a woman's risk of breast cancer. The years when you have a menstrual cycle are your high-estrogen years. Experts think that the longer you have higher estrogen, the more risk you have for breast cancer.4 •Having extra body fat and drinking alcohol both lead to higher levels of estrogen in the body. Especially after menopause, when your estrogen levels are naturally low, this raises your breast cancer risk.4 For more information about your personal risk level, go to www.cancer.gov/bcrisktool. Prevention You cannot control some things that put you at risk for breast cancer, such as your age and being female. But you can make personal choices that lower your risk of breast cancer. If you are at high risk for getting breast cancer, your doctor may also offer you certain medical treatments that can help prevent breast cancer. Female hormones Hormones change the way cells within the breast grow and divide. The years when you have a menstrual cycle are your high-estrogen years. Experts think that the longer you have higher estrogen, the more risk you have for breast cancer.4 This includes taking hormones after menopause.1, 26 •Avoid long-term, high-dose hormones after menopause. If you use hormone therapy for menopause symptoms, use a low dose for as short a time as possible. This includes estrogen-progestin and estrogen-testosterone.1, 3 Using estrogen by itself may slightly raise breast cancer risk.1 •Breast-feed. Breast-feeding may lower your breast cancer risk. The benefit appears to be greatest in women who breast-fed for longer than 12 months or who breast-fed several children.27 •Strive for a healthy weight. Extra fat cells make extra estrogen, which raises your breast cancer risk.4 Getting regular exercise and watching what you eat can help. Having a full-term pregnancy before age 30 also lowers your breast cancer risk.10 Healthy food and exercise •Eat a healthy diet with plenty of fruits, vegetables, and whole grains. A low-fat diet with limited red meat may lower your breast cancer risk.28, 29, 30 •Be active. Try to get 30 to 60 minutes of exercise at least 5 days a week.5 Staying active may lower your breast cancer risk.31 •Drink no more than one alcoholic drink a day.4 Using alcohol leads to extra estrogen in the body, which raises your breast cancer risk.10 "Anti-estrogen" medicine If you are at high risk for breast cancer, talk to your doctor about taking medicine that helps prevent it. This is sometimes called hormone therapy for breast cancer. It blocks the effects of hormones on breast cancer cells. •Tamoxifen is a medicine that blocks the effect of estrogen on breast cancer cells and normal breast cells. Among high-risk women, tamoxifen lowers their risk of breast cancer about the same as raloxifene does.32 But this medicine may also increase other risks, such as for endometrial cancer, stroke, and blood clots in veins and in the lungs. •Raloxifene is widely used to prevent and treat osteoporosis. It works like estrogen on bone, but it works like an "anti-estrogen" on breast tissue.33 Among high-risk women, raloxifene lowers their breast cancer risk about the same as tamoxifen does. Compared to tamoxifen, raloxifene's endometrial cancer risk is lower.32
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