37 Breast Cancer: Prevention, Screening, Diagnosis, and Treatment Robert L. Barbieri Breast cancer is the most common cancer of women in developed countries. After lung cancer, it is the second most common cause of cancer death in women. Through to 90 years of age, the lifetime risk of breast cancer is about 12%. Ninety-five percent of all invasive breast cancers are diagnosed in women greater than 45 years of age. For women with a family history of breast cancer, the personal risk for breast cancer is approximately doubled. The rate of breast cancer is highest in developed countries and lowest in developing countries. Breast cancer rates tend to be negatively correlated with cervical cancer rates. In other words, the higher the rate of breast cancer in a geographic region, the lower the rate of cervical cancer. Breast cancer occurs about 100 times more frequently in women than men, indicating the importance of estrogen in the etiology of breast cancer. In postmenopausal women, obesity is associated with a modest increase in the risk of breast cancer, possibly through excessive extra-ovarian aromatization of androgens to estrogen and increased circulating peptide growth factors such as IGFI. Regular physical activity is associated with a modest reduction in the risk of developing breast cancer. Alcohol consumption of two or more glasses per day increases the risk of breast cancer. Family history is an important risk factor for breast cancer. For women with one first-degree relative with breast cancer, the increase in risk is about twofold. With two affected first-degree relatives, the increase in risk is about threefold. Exposure to chest irradiation, especially before age 45 years, is a strong risk factor for breast cancer. Younger age at menarche and later age at menopause are both associated with an increased risk of breast cancer. Bilateral oophorectomy before 40 years of age reduces the risk of breast cancer by 50%. Nulliparous women are at a 50% increased risk of developing breast cancer. Women who give birth at a young age are at decreased risk of breast cancer. Immediately following pregnancy there is a slight increased risk of breast cancer, but in the 10 years following pregnancy there is a reduced risk of developing breast cancer. Breast-feeding is strongly associated with a reduction in the risk of breast cancer. Abortion is not associated with breast cancer risk. Changes in reproductive patterns may account, in part, for the increased risk of breast cancer in developed countries. In past centuries, the average woman had six births during her lifetime and breast-fed for 24 months per child. Currently, the average woman has two births and breast-feeds for 3 months per child. It is estimated that if women in developed countries reverted to the birth and breast-feeding patterns of previous centuries, the rate of breast cancer in the population would be reduced by at least 50%. Many studies report that endogenous estrogen concentration in postmenopausal women is associated with breast cancer risk (Evidence Box 37.1). The greater the serum level of estradiol and two precursors to estradiol, estrone sulfate and dehydroepiandrosterone sulfate, the greater the risk of estrogen and progesterone receptor-positive breast cancer. Reproductive steroids do not impact the risk of estrogen and progesterone receptor-negative negative breast cancer. In premenopausal women it is difficult to assess the relationship between reproductive steroids and breast cancer risk because of the constantly changing levels of hormones throughout the cycle. The best current data does suggest that in premenopausal women increased estrogen levels are associated with an increased risk of breast cancer. The best available current data indicates that estrogen— progestin contraceptives are not associated with an increased risk of breast cancer. There is widespread concern that estrogen—progestin hormone therapy in postmenopausal women may be associated with an increased risk of cancer. In the Women’s Health Initiative, treatment with conjugated equine estrogen 0.625 mg plus medroxyprogesterone actetate 2.5 mg daily was associated with a hazard ratio of 1.2 for breast cancer compared with placebo. In contrast, in the same study, treatment with conjugated estrogen 0.625 mg alone and without a progestin was not associated with an increased risk of breast cancer. These results, plus previous observational findings, suggest that it is the combination of both estrogen plus progestin that is associated with the greatest increase in the risk of breast cancer in postmenopausal women. Mutations in many genes, including BRCA1, BRCA2, p53, PTEN, and STK11, are associated with a very high risk of breast cancer. The biological mechanisms that link mutations of BRCA1 and BRCA2 with breast and ovarian cancer are discussed in Chapter 45. Among women with a critical BRCA1 mutation, about 50% will develop breast cancer. In families with a high penetrance of breast cancer, the risk of developing breast cancer is greater than 80% by age 70 years. Tests to screen for BRCA mutations are commercially available. These tests are very expensive because there are many mutations in the BRCA genes that may cause cancer. The population that should be tested has not been definitively defined. Testing should only be performed if the results will aid in the medical or surgical treatment of affected individuals and their family members. Criteria for testing include: 1) two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or less; 2) three or more first- or second-degree relatives with breast cancer with no reference to the age of diagnosis; 3) in first- or second-degree relatives, a combination of both breast and ovarian cancer or a single relative with both ovarian and breast cancer, or two or more relatives with ovarian cancer; 4) a first-degree relative with bilateral breast cancer; 5) history of breast cancer in a male relative. Quantitative tools for predicting the risk of breast cancer include the Gail model, Breast Cancer Risk Assessment, Claus, and Tyrer-Cuzick tools. The Gail model is the most widely utilized and uses seven factors to predict risk: current age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of prior breast biopsies, the presence of atypical hyperplasia on biopsy, and race. The calculator is available at: http://www. cancer.gov/bcrisktool/ Using the Gail model, for women 35–59 years of age, a 5-year risk of at least 1.66% is considered to be “at increased risk” and such women are considered suitable for hormonal chemoprevention (see below). A similar calculator, the Breast Cancer Risk Assessment (BCRA) tool, is based on the Gail model but contains more recently available population data. This model is suitable for use by women of different races and ethnicities. This calculator is available at: http://bcra.nci.nih.gov/ brc/q1.htm As new breast cancer risk factors are identified, such as breast density at mammography, available risk calculators are being constantly updated and refined. Numerous clinical trials have demonstrated that treatment with a selective estrogen receptor modulator such as tamoxifen or raloxifene reduces the risk of invasive and noninvasive breast cancer in women at increased risk. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) the entry criteria were: 1) women 60 years of age or older; 2) women between 35 and 59 years of age with a 5-year risk for breast cancer of at least 1.66% as predicted by the Gail model; or 3) women greater than 35 years of age and a personal history of lobular carcinoma in situ (LCIS) (see Chapter 36, The Breast and Benign Breast Disease). Women (N = 13 388) meeting these entry criteria were randomized to tamoxifen 20 mg daily orally or placebo. The study was discontinued after a median of 48 months of treatment, but many women who were randomized to tamoxifen continued to take the treatment. The cumulative incidence of invasive breast cancer was 4.3% in the placebo group and 2.5% in the tamoxifen group. In the women who entered the study with LCIS, 1.2% in the placebo group and 0.6% in the tamoxifen group developed invasive cancer. All of the risk reduction was due to a decrease in the number of estrogen receptor-positive tumors. The risk reduction was 36% for women <50 years old and 51% for women =60 years. Tamoxifen treatment did not have an impact on survival. The risks associated with tamoxifen therapy included endometrial cancer (risk ratio 3.3), pulmonary emboli (risk ratio 1.5), and stroke (risk ratio 2.2). During the study 53 cases of endometrial cancer were diagnosed in the tamoxifen group and 17 cases in the placebo group. Raloxifene is also approved for hormonal chemoprevention of breast cancer. It has different properties from tamoxifen as outlined in Evidence Box 37.2. The aromatase inhibitors anastrozole and letrozole are under active study to assess their utility in the prevention of breast cancer. For women carrying a mutation in the BRCA1 or BRCA2 genes, prophylactic bilateral total mastectomy is associated with a 90% reduction in the risk of developing breast cancer. The significant impact of bilateral mastectomy on quality of life has limited the widespread acceptance of this approach to risk reduction. In carriers of mutations in the BRCA1 or BRCA2 genes prophylactic bilateral salpingo-oophorectomy (BSO) reduces the risk of both breast and ovarian cancers. In one retrospective study BSO was associated with a 95% reduction in the risk of ovarian cancer and a 50% reduction in the risk of breast cancer. BSO is typically planned for a woman at a time after completion of her family, but before the youngest age of onset of breast and ovarian cancer in her family. Screening refers to the wide-scale diagnostic testing of a population at average risk of a disease. For a population at very high risk of a disease, “early disease detection” is probably a better term for the diagnostic tests that are performed. Screening is inherently associated with significant costs, many false-positive tests, and may induce anxiety in the population being screened. The costs of screening must be balanced against the potential benefits. There is very little evidence that teaching patients to perform breast self-examination significantly impacts the rate of breast cancer death. However, women who perform a very thorough breast self-examination may detect breast tumors at an earlier stage than women who do not perform self-examination or only perform a cursory self-examination. Breast physical examination by a clinician can detect about 50% of breast cancers. Mammography detects about 90% of breast cancers. In some instances a breast cancer not detected at mammography can be palpated on clinical examination. In countries where it is widely available, mammography plays a more important role than physical examination for the detection of breast cancer. In developing countries where mammography is not widely available, clinical breast examination is of significant value in screening for breast cancer. Screening mammography is recommended annually for all women greater than 40 years of age. In one comprehensive meta-analysis of clinical trials, annual mammography reduced the risk of breast cancer mortality by 22 % in women =50 years and 15 %
Epidemiology
Reproductive Risk Factors
Reproductive Hormones
Oral Contraceptives
Postmenopausal Hormone Therapy
Breast Cancer Genetics
Prevention
Quantitative Assessment of Risk
Hormone Prevention
Risk-Reducing Bilateral Mastectomy
Risk-Reducing Bilateral Salpingo-oophorectomy
Screening
Breast Self-Examination
Physical Examination by a Clinician
Mammography
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
