Breast cancer is the most common cancer affecting women in the US and is the second leading cause of cancer death. The lifetime risk of breast cancer for a woman is 12.7% (about 1 in 8), and the median age of diagnosis and of death are 61 and 69 years, respectively. Breast cancer mortality rates have significantly decreased during the past 50 years due to early detection and improvements in treatment. The current 5-year survival rate is 90%, substantially improved from 75% in 1975.
Risk Factors
The most used model to determine breast cancer risk is the Gail model. This uses an individual's current age, age at menarche, age at first live birth, the number of first-degree relatives with breast cancer, and the number and results of past breast biopsies to estimate the probability of breast cancer over time. Its accuracy is limited because it omits a detailed family history of breast and ovarian cancers and underestimates the risk in African American individuals and overestimates the risk in Asian American individuals. This model should not be used in individuals who have a personal history of breast cancer or in those who are known gene mutation carriers.
Age and female sex are the primary risk factors for breast cancer. Approximately 95% of breast cancers occur in women over age 40 years.
Hormone exposure. Early menarche (<12 years), late natural menopause (>55 years), older age at first full-term pregnancy, and fewer pregnancies increase an individual's risk of developing breast cancer. Breastfeeding is associated with a lower risk. In addition, moderate alcohol use, which is related to an increase in estrogen, carries a higher risk. Finally, the role of exogenous estrogen use in the development of breast cancer remains controversial. Long-term OCP use (>10 years) and current hormone therapy use are associated with a nonsignificant increased risk.
Diet and lifestyle. Significant differences in the incidence of breast cancer in different geographic and cultural areas have long raised the suspicion of dietary risk factors. High-fat diets have been implicated, but data are insufficient. Lifestyle activities with protective effects include physical activity, weight control, and abstaining from tobacco use.
Personal history. Women with a history of a known deleterious gene mutation or breast cancer are at a 0.5% to 1% risk per year of developing cancer in the contralateral breast in addition to the risk of recurrence in the treated breast. Most recurrences occur within the first 5 years after diagnosis. A personal history of dense breasts or a prior breast biopsy revealing atypical hyperplasia or lobular carcinoma in situ (LCIS) also yields an increased risk, as does prior radiation therapy (RT) to the chest wall.
Family history and genetic predisposition. Family history confers an increased risk for breast cancer, specifically with a history of breast cancer in the premenopausal state in a first-degree relative, a male, bilateral disease, or a family history of breast, ovarian, or other hereditary breast and ovarian syndrome-associated cancers (eg, prostate, pancreatic cancer).
Specific Hereditary Cancer Syndromes
Recognition of certain familial patterns and appropriate referral for patients who may have a genetic predisposition to cancer is critical for the diagnosis and management of potential hereditary cancer syndromes.
Two distinct populations should be considered for genetic testing: (1) individuals with a cancer diagnosis and (2) unaffected individuals with a strong family history of cancer or with an identified mutation in a blood relative. It is preferable to test a cancer-affected family member first. Unfortunately, this is not always possible. Testing usually involves a broad and comprehensive panel of cancer-related genes.
Criteria for genetic evaluation have been largely agreed on by multiple entities and are outlined in current consensus guidelines. Table 35-1 details the features suggestive of hereditary cancer.
|
BRCA1 and BRCA2
BRCA1 and BRCA2 are tumor suppressor genes and are inherited in an autosomal dominant fashion. Inheriting BRCA1/2 confers a 40% to 70% lifetime risk of breast cancer; these cases account for <10% of all diagnoses. In addition, BRCA1 confers a 40% risk of ovarian cancer and BRCA2 a 20% risk for ovarian cancer (see Chapter 54). Both mutations are more common in the Ashkenazi Jewish population (1 in 40). Individuals with these mutations have a 35% to 43% chance of developing a second primary breast cancer within the first 10 years of the first diagnosis. There is also a strong association between BRCA mutations and the diagnosis of triple-negative (ER, PR, Her2neu) breast cancer.
BRCA mutations account for most cases of HBOC (hereditary breast and ovarian cancer) and are associated with an increased lifetime risk of multiple other cancers, including pancreatic cancer, melanoma, and prostate cancer. A summary of cancer risks associated with BRCA mutations are shown in Table 35-2.
Surveillance to reduce breast cancer in those with BRCA mutations involves clinical breast exams and breast imaging as shown in Table 35-3.
| Gene | Genetic Syndrome | Surveillance and Age to Initiate | Risk Reduction and Age to Consider |
|---|---|---|---|
| BRCA1 | HBOC | Every 6 mo/annual TVUS and CA-125 (ages 30–35 y) Breast awareness (age 18 y) Clinical breast exam q 6–12mo (age 25 y) Annual breast MRI (ages 25–29 y) Annual mammogram alternating q6mo with MRI (age 30 y) | RRSO (ages 35–40 y) Offer RR mastectomy Consider RR medical therapy (OCPs, tamoxifen, raloxifene, aromatase inhibitors) |
| BRCA2 | HBOC | Same as BRCA1 | RRSO (ages 40–45 y) |
| Offer RR mastectomy | |||
| Consider RR medical therapy | |||
| PTEN | Cowden syndrome | Consider annual TVUS + EMB (ages 30–35 y) Breast awareness (age 18 y) Clinical breast exam q6–12mo (age 25 y) Annual breast MRI (ages 30–35 y) Annual mammogram alternating q6mo with MRI (ages 30–35 y) | Discuss RR hysterectomy when childbearing complete Discuss RR mastectomy |
| STK11 | PJS | Annual pelvic exam + pap smear (ages 18–20 y) Consider annual TVUS Clinical breast exam q6mo (age 25 y) Annual breast MRI (age 25 y) Annual mammogram alternative q6mo with MRI (age 25 y) | Discuss RR mastectomy |
| TP53 | LF | Breast awareness (age 18 y) Clinical breast exam q6–12mo (ages 20–25 y) Annual breast MRI (ages 20–25 y) Annual mammogram alternative q6mo with MRI (ages 20–25 y) | Discuss RR mastectomy |
CA-125, cancer antigen 125; EMB, endometrial biopsy; HBOC, hereditary breast and ovarian cancer syndrome; LF, Li–Fraumeni syndrome; LS, Lynch syndrome; MRI, magnetic resonance imaging; OCPs, oral contraceptives; PJS, Peutz–Jeghers syndrome; PPAP, polymerase proofreading–associated polyposis; RR, risk-reducing; RRSO, risk-reducing salpingo-oophorectomy; TVUS, transvaginal ultrasound.
Risk-reducing strategies include chemoprophylaxis with tamoxifen, raloxifene, or aromatase inhibitors and surgical risk reduction with risk-reducing bilateral mastectomy (90% reduction in risk of breast cancer) and risk-reducing salpingo-oophorectomy (50% reduction in risk of ovarian cancer). See Table 35-3.
Cowden Syndrome
Cowden syndrome is caused by a germline mutation in the PTEN gene and is inherited in an autosomal dominant fashion. Cowden syndrome is associated with multiple cancers, most commonly breast cancer and endometrial cancer with a 25% to 50% and 28% lifetime risk, respectively. Other associated cancers include thyroid (most commonly follicular, 3% to 10% risk), colon, and renal cancers.
Risk-reducing strategies include hysterectomy at the completion of childbearing and mastectomy on an individualized basis. See Table 35-3.
Peutz–Jeghers Syndrome
Mutations in the STK11/LKB1 gene, which are inherited in an autosomal dominant fashion, increase the risk of breast cancers, ovarian (sex cord stromal tumors), and cervical (adenoma malignum) by approximately 50%, 20%, and 10% lifetime risk, respectively.
Recommendations for risk reduction are individualized, and risk-reducing mastectomy can be considered. See Table 35-3.
Li–Fraumeni Syndrome
Li–Fraumeni syndrome is defined by inherited mutations in the TP53 gene, a critical tumor-suppressor gene regulating repair of DNA damage.
Individuals with these mutations are at an increased risk for multiple cancers, frequently in childhood, with the highest risk being that of breast cancer with up to a 60% lifetime risk, with disease often presenting in the third decade of life.
Risk-reducing mastectomy is recommended. See Table 35-3.
Screening and Prevention
Screening consists of clinical breast exams and screening mammography (Table 35-4). The breast self-exam is no longer recommended in average-risk individuals as there is a risk of harm from false-positive test results and a lack of evidence of benefit. Breast self-awareness, however, is encouraged so patients can discuss changes with their provider. Breast exams are best for detecting tumors >2 cm in size. The National Breast and Cervical Cancer Early Detection Program found that breast exams detect approximately 5% of cancers not visible on mammography. Concerning features for cancer include single, hard, immobile, irregular margins, and >2 cm. Most cancerous masses are painless, but 10% of patients present with breast discomfort. Symptoms associated with cancer include nipple discharge, rash or ulceration, diffuse breast erythema, adenopathy, or symptoms associated with metastatic disease (bone pain, shortness of breath, neurologic symptoms).
| Application | Sensitivity/Efficacy | Limitations | Guidelinesa | |
|---|---|---|---|---|
| Mammography | Detects microcalcifications, abnormal shadowing, or soft tissue distortion | Sensitivity: 74–95% Specificity: 89–99% Sensitivity is decreased in women under age 50 y and in women with dense breasts Reduces risk of cancer-related mortality by 16–35% | Less sensitive for faster growing tumors (young women) Breast density Hormone therapy Breast implants | USPSTF: age ≥50–74 y, q2y ACOG: Offer at age 40 y; no later than age 50 y, q1–2 y to age 75 y ACS: Offer age 40–45 y; recommend for ages 45–54 y, q1y; recommend for age >55 y, q1–2 y till life expectancy <10 y |
| Clinical breast exam | Inspect, palpate while supine and sitting, include axillary and supraclavicular lymph nodes, nipple and areola Recommended 6–10 min | Sensitivity 54% Specificity 94% Detects approximately 5% of cancers missed by mammography | Examiner dependent Less specific than mammography—higher rate of biopsy for benign disease Limited by obesity | USPSTF: insufficient evidence to recommend for or against ACOG: Offer q1–3 y for ages 25–39 y, then annually for age >40 y ACS: not recommend |
| Breast self-Examination | Monthly exams, during approximately 10th day of cycle | Sensitivity 20–30% Very few randomized trails Failed to show benefit in rate of diagnosis, cancer death, or tumor size | Examiner dependent Higher rate of biopsy for benign disease Evidence of utility limited | USPSTF: does not support teaching self-breast exams ACOG: not recommended; supports self-breast awareness ACS: not recommended |
aData from breast cancer risk assessment and screening in average-risk women. Practice Bulletin No. 179. American College of Obstetricians and Gynecologists Committee on Practice BulletinsGynecology. Obstet Gynecol. 2017;130(1):e1–e16. (Reaffirmed 2021)
ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; USPSTF, US Preventive Services Task Force; y, year; q, every.
Screening Mammography
Mammography is the primary screening modality as it reduces breast cancer mortality in average-risk individuals. Breast cancers detected by mammography tend to be smaller and have more favorable histologic and biologic features. Limitations to mammography include patient age, dense breast tissue, use of hormone replacement therapy, breast implants, rate of tumor growth, and evaluation of any disease extending beyond the margins of the breast. Approximately 5% to 15% of cancers are not apparent on mammography.
Screening mammography is for individuals with no signs or symptoms of breast disease and consists of bilateral two-view images. It can potentially detect lesions as small as 1 mm. Digital mammography (colloquially known as 3D mammography) is more effective than film mammography, especially for patients <60 years old or with dense breasts.
Diagnostic mammography is performed after the discovery of an abnormality found on exam or screening mammography. It presents various views (∼8 to 12) to further characterize abnormalities.
Alternate Screening Modalities
MRI is more sensitive but less specific and more expensive than mammography in the detection of breast cancers. An MRI screening is recommended for patients with >20% lifetime risk of developing breast cancer and includes those with known BRCA mutations, first-degree relatives of those with BRCA mutations who have not undergone genetic testing, a history of chest RT between ages 10 and 30, patients with hereditary cancer syndromes, or a first-degree relative with one of those syndromes. MRI screening is not recommended for average-risk patients.
Chemoprevention
Chemoprevention includes treatment with the selective ER modulators (SERMs) tamoxifen and raloxifene, usually for a duration of 5 years. Appropriate candidates for prophylactic endocrine therapy include individuals ages >35 with a history of LCIS, DCIS, or atypical ductal or lobular hyperplasia; individuals ages 35 to 59 with a Gail model risk of breast cancer ≥1.66% over 5 years; or those with known BRCA mutations who do not undergo risk-reducing mastectomy.
Tamoxifen has estrogenic effects on uterus and bone but antagonistic effects on the breast. Prophylactic use of tamoxifen reduces the risk for ER-positive breast cancer in patients without previous breast cancer but does not impact overall survival. It has been shown to decrease breast cancer risk in BRCA2 carriers but not BRCA1 carriers, likely due to the low prevalence of ER-positive breast cancers in patients with BRCA1 mutations.
Raloxifene has estrogenic effects on lipids and bone but antagonistic effects on the uterus and breast. It reduces the incidence of ER-positive breast cancer in postmenopausal patients but, like tamoxifen, has no effect on survival. It is slightly less effective than tamoxifen in preventing breast cancer but has lower risks of endometrial cancer/hyperplasia and venous thromboembolism. Its use has not been studied in premenopausal patients.
Aromatase inhibitors. Only anastrozole and exemestane have been evaluated in the setting of primary prevention of breast cancer and showed similar results. There was a 50% reduction in number of invasive breast cancers in high-risk patients, although with significantly more musculoskeletal side effects in addition to the antiestrogenic side effects of vaginal dryness, vasomotor symptoms, and hypertension (as seen with SERMs) when compared with placebo.
Surgical Prevention
Surgical prevention can be considered in two groups of individuals: (1) patients positive for BRCA1 or BRCA2 and (2) patients with a strong family history suggestive of hereditary breast cancer but negative for BRCA1 or BRCA2. Surgical prevention includes contralateral mastectomy, risk-reducing bilateral mastectomy, and bilateral salpingo-oophorectomy (BSO). Risk-reducing bilateral mastectomies have been shown to reduce the risk of breast cancer by 90%. This is increased to 95% if combined with a BSO.
Presentation and Diagnosis
Any breast complaint potentially signifies malignancy, warranting an evaluation. Review history and symptoms and identify risk factors for breast cancer. With or without concerning exam features (ie, a hard, fixed, irregular mass), an age-appropriate breast imaging workup is warranted. Guidance for which imaging study is indicated can be found from the American College of Radiology (ACR) Appropriateness Criteria, an online resource updated by the American College of Radiology. Imaging results based on the breast imaging reporting and data system (BIRADS) classification system will guide management recommendations regarding the need for biopsy or continued observation.
For individuals <30 years old with palpable mass, breast ultrasound is the initial preferred imaging modality. Ultrasound also can be used as an adjunctive screening tool in patients with dense or cystic breasts or those with breast implants. Suspicious features include solid masses with ill-defined borders, acoustic shadowing, or complex cystic lesions.
For individuals >30 years old with a palpable mass, diagnostic mammography is the recommended initial imaging study, usually followed by breast ultrasound for further characterization of concerning lesions. Diagnostic mammography also is performed when screening mammography of an asymptomatic individual is ambiguous or concerning. Findings suspicious for cancer include increased density, irregular margins, spiculation, clusters of microcalcifications, asymmetric density or parenchymal distortion, or a new abnormality compared with prior mammograms.
Suspicious radiologic findings require breast biopsy for tissue sampling and histologic evaluation with possible future surgical consultation. Tissue sampling methods include fine-needle aspiration, core-needle biopsy, or excisional biopsy. For cystic lesions yielding bloody fluid on aspiration or a mass that persists after aspiration, excisional biopsy or surgical consultation is indicated. Fluid cytology is no longer recommended given low sensitivity and specificity for detecting malignant cells.
For lesions radiographically detected but nonpalpable, image-guided biopsy is performed. Techniques include needle localization, excisional biopsy, and stereotactic core biopsy and are performed with the assistance of a breast radiologist.
Premalignant Breast Lesions
LCIS is a nonpalpable, noninvasive lesion arising from the lobules. LCIS is more common in premenopausal patients and is often an incidental finding on biopsy. It is often multicentric and bilateral. While its direct presence is not a precursor to breast cancer, it is a marker identifying individuals with a 10% to 20% risk of developing invasive cancer in either breast in the next 15 years. Initiating risk-reducing therapies including tamoxifen, raloxifene, aromatase inhibitors, or risk-reducing mastectomy should be strongly considered to decrease the risk of developing subsequent breast cancer.
Malignant Breast Lesions
Breast cancer most commonly arises in the upper outer quadrant of the breast, taking an average of 5 years to become palpable. It arises in the terminal duct lobular unit of the breast and can be invasive or noninvasive (in situ). The growth pattern is described as comedo or noncomedo (solid, cribriform, micropapillary, and papillary).
DCIS refers to a proliferation of cancer cells within the ducts without invasion through the basement membrane into the surrounding stroma. Histologically, DCIS can be divided into multiple subtypes: solid, micropapillary, cribriform, and comedo. DCIS is graded as low, intermediate, or high based on how abnormal the cancer cells microscopically appear. DCIS is an early, noninfiltrating form of breast cancer with minimal risk of metastasis and an excellent prognosis with surgical therapy alone with or without RT. The goal of treatment of DCIS is to prevent the development of invasive breast cancer.
Invasive cancer. The two most common types of invasive cancers are lobular and ductal. Infiltrating lobular carcinoma is a variant associated with microscopic lobular architecture. These carcinomas account for 10% to 15% of invasive breast cancers, are often multifocal, have a higher incidence of bilaterality, and are less evident on mammography. Infiltrating ductal carcinoma accounts for 60% to 75% of all tumors. These cancers account for a group of tumors classified by cell type, architecture, and pattern of spread. These include mucinous, tubular, and medullary carcinomas.
Staging and Prognostic Factors
The tumor-node-metastasis (TNM) staging system for breast cancer from the American Joint Committee on Cancer uses tumor size, axillary node status (incorporating sentinel nodes), and metastasis status.
Expression of estrogen and progesterone receptors (ER, PR) in tumor tissue is associated with a better prognosis and can be targeted with systemic therapy.
HER2/neu is a gene encoding transmembrane receptor for growth factors, thus regulating cellular growth and differentiation. Overexpression of this oncogene leads to a more aggressive subtype of breast cancer, which tends to be high grade, poorly differentiated, have lymph node involvement, and have increased resistance to chemotherapy.
Assigning breast cancer stage is complex. In 2018, American Joint Committee on Cancer updated the TNM staging system to also include tumor grade, ER/PR status, HER2 status, and oncotype DX score (a genomic test that analyzes the activity of a group of genes that can influence tumor growth and response to treatment).
Prognosis varies based on the stage of the disease (Table 35-5).
aAdapted from Surveillance, Epidemiology, and End Results Program. Cancer stat facts: female breast cancer. Surveillance, Epidemiology, and End Results Program Web site. Accessed November 24, 2023. https://seer.cancer.gov/statfacts/html/breast.html
bStaging definitions: localized = confined to primary site; regional = spread to regional lymph nodes; distant = cancer has metastasized; unknown = unstaged.
cBased on women diagnosed with breast cancer between 2013 and 2019.
SEER, Surveillance; Epidemiology, End Results.
Treatment
Early detection is key to improved survival rates (see Table 35-5). In general, clinical stages I and II, and certain patients with clinical stage III disease (T3N0), are considered early stages of breast cancer. These patients are generally treated with surgery to the breast and regional lymph nodes with or without RT. Systemic therapy may be offered based on primary tumor characteristics (eg, size, grade, hormonal, or HER2 receptor status) and lymph node involvement. Treatment for locally advanced breast cancers includes multimodal therapy and utilizes a multidisciplinary approach between surgical oncology, radiation oncology, and medical oncology, and this collaboration has been associated with a reduction in breast cancer mortality.
Surgical or Local Treatment
Mastectomy involves the complete surgical removal of breast tissue. Mastectomy is recommended if the disease is multicentric, invades the skin and/or chest wall, has inflammatory features, or if negative margins cannot be achieved with breast preservation (eg, lumpectomy). Radical mastectomy includes removal of the breast, overlying skin, pectoralis major and minor with fascia, and the entire axillary contents. The modified radical mastectomy includes removal of the entire breast, only the fascia of the pectoralis major muscle, and only levels I and II of the axillary lymph nodes. A total or simple mastectomy removes the breast with the nipple-areolar complex but without lymph nodes. “Skin-sparing” mastectomy provides superior cosmetic results and may be appropriate for patients with DCIS; stages I, II, or III breast cancer; or for prophylactic mastectomy.
In breast-conserving therapy (BCT), a wide local excision or lumpectomy is performed to achieve a 1- to 2-mm negative margin. Adjuvant RT is required. Radiation is delivered to the entire breast with a possible boost dose to the lumpectomy bed. Trials comparing BCT + RT with mastectomy have demonstrated comparable survival rates.
Assessing axillary lymph node status is important in prognosis, staging, and treatment planning. Complications of axillary dissection include lymphedema (10% to 15%), pain, numbness, or weakness of the affected arm.
Evaluation of clinically suspicious axillary node(s) can be accomplished with ultrasound and fine-needle aspiration or core biopsy.
Sentinel lymph node biopsy (SLNB) is the preferred method for axillary node staging in the clinically negative axilla. The SLN is identified using radioactive tracer or dye injected into the periareolar region of the breast. When the isotope and dye are used in combination, the positive predictive value of SLNB approaches 100%.
RT, although most often administered as part of BCT, can also be used for other indications including after mastectomy when the malignant lesion is >5 cm, in the presence of local spread to regional lymph nodes, or if positive surgical margins.
Systemic Therapy
Systemic therapy given before surgery (neoadjuvant therapy) is often recommended for patients with locally advanced disease. Treatment after surgery (adjuvant therapy) is typically recommended for hormone receptor–positive breast cancer, positive lymph nodes, or other high-risk characteristics.
Hormonal therapy is the most frequently recommended adjuvant systemic therapy and is aimed at targeting ER- and/or PR-positive breast cancer.
Tamoxifen has been used most and results in a 26% annual reduction in the risk of recurrence and a 14% annual reduction in the risk of death from breast cancer. Tamoxifen is usually administered for at least 5 years. It is associated with a twofold increased risk of endometrial cancer and venous thromboembolic events (∼4 in 1000 cases). Abnormal uterine bleeding in any pre- or postmenopausal individual on tamoxifen should be assessed with endometrial sampling. However, routine imaging or sampling is not recommended for tamoxifen users.
Aromatase inhibitors (eg, letrozole, anastrozole, exemestane) are potent inhibitors of estrogen synthesis and are only recommended for postmenopausal patients. They have been shown to be more effective than tamoxifen in treating breast cancer, with virtually no risk of endometrial hyperplasia and a reduced risk of thromboembolic events when compared to tamoxifen. Side effects include osteoporosis, myalgias, elevated cholesterol, and joint pain. These agents are effective as first- or second-line agents in patients whose cancer has progressed during or after tamoxifen therapy.
Biologic therapy. Trastuzumab (Herceptin) is a genetically engineered monoclonal antibody to the HER2 protein. Its use concurrently with chemotherapy in HER2-positive breast cancers results in significant improvement in disease-free and overall survival. There is, however, an increased risk of congestive heart failure and decreased left ventricular ejection fraction in patients receiving trastuzumab, so routine cardiac monitoring is recommended. Cardiotoxicity can be reversible after discontinuation of trastuzumab.
Chemotherapy has been shown to improve overall survival and reduce the odds of death by 25% in selected patients. The decision to use cytotoxic chemotherapy depends on tumor histology, tumor size, nodal status, hormonal status, genomic profiling, and benefit–risk calculators. Examples of chemotherapy agents used include anthracyclines and taxanes.