Chapter 71: Breast Cancer
INCIDENCE AND EPIDEMIOLOGY
The most common tumor in women; 266,120 women in the United States were diagnosed in 2019 and 40,920 died with breast cancer. Men also get breast cancer; F:M is 150:1. Breast cancer is hormone-dependent. Women with late menarche, early menopause, and first full-term pregnancy by age 18 years have a significantly reduced risk. The average American woman has about a one in nine lifetime risk of developing breast cancer. Dietary fat is a controversial risk factor. Oral contraceptives have little, if any, effect on risk and lower the risk of endometrial and ovarian cancer. Voluntary interruption of pregnancy does not increase risk. Estrogen replacement therapy may slightly increase the risk, but the beneficial effects of estrogen on quality of life, bone mineral density, and decreased risk of colorectal cancer appear to be somewhat outnumbered by increases in cardiovascular and thrombotic diseases. Women who received therapeutic radiation before age 30 years are at increased risk. Breast cancer risk is increased when a sister and mother also had the disease.
Perhaps 8–10% of breast cancer is familial. BRCA-1 mutations account for about 5%. BRCA-1 maps to chromosome 17q21 and appears to be involved in transcription-coupled DNA repair. Ashkenazi Jewish women have a 1% chance of having a common mutation (deletion of adenine and guanine at position 185). The BRCA-1 syndrome includes an increased risk of ovarian cancer in women and prostate cancer in men. BRCA-2 on chromosome 11 may account for 2–3% of breast cancer. Mutations are associated with an increased risk of breast cancer in men and women. Germ-line mutations in p53 (Li-Fraumeni syndrome) are very rare, but breast cancer, sarcomas, and other malignancies occur in such families. Germ-line mutations in PALB2, hCHK2, and PTEN may account for some familial breast cancer. Sporadic breast cancers show many genetic alterations, including overexpression of HER2/neu in 25% of cases, p53 mutations in 40%, and loss of heterozygosity at other loci.
Genetic analysis has defined distinct subsets of breast cancers (see below). Tests for expression of panels of genes have been developed that can predict clinical behavior and be used to determine type and duration of therapy.
Breast cancer is usually diagnosed by biopsy of a nodule detected by mammogram or by palpation. Women should be strongly encouraged to examine their breasts monthly. In premenopausal women, questionable or nonsuspicious (small) masses should be reexamined in 2–4 weeks. A mass in a premenopausal woman that persists throughout her cycle and any mass in a postmenopausal woman should be aspirated. If the mass is a cyst filled with nonbloody fluid that goes away with aspiration, the pt is returned to routine screening. If the cyst aspiration leaves a residual mass or reveals bloody fluid, the pt should have a mammogram and excisional biopsy. If the mass is solid, the pt should undergo a mammogram and excisional biopsy. Screening mammograms performed every other year beginning at age 50 years have been shown to save lives. The controversy regarding screening mammograms beginning at age 40 years relates to the following facts: (1) the disease is much less common in the 40- to 49-year age group, and screening is generally less successful for less common problems; (2) workup of mammographic abnormalities in the 40- to 49-year age group less commonly diagnoses cancer; and (3) about 50% of women who are screened annually during their forties have an abnormality at some point that requires a diagnostic procedure (usually a biopsy), yet very few evaluations reveal cancer. However, many believe in the value of screening mammography beginning at age 40 years. After 13–15 years of follow-up, women who start screening at age 40 years have a small survival benefit. Women with familial breast cancer more often have false-negative mammograms. MRI is a better screening tool in these women. Women with dense breasts (>50% fibroglandular tissue) are said to be at increased risk (1.2- to 2-fold), but it is not clear that they require increased surveillance.
CLINICAL AND MOLECULAR STAGING
Therapy and prognosis are dictated by stage of disease (Table 71-1). Unless the breast mass is large or fixed to the chest wall, staging of the ipsilateral axilla is performed at the time of lumpectomy (see below). Within pts of a given stage, individual characteristics of the tumor may influence prognosis: expression of estrogen receptor improves prognosis, while overexpression of HER2/neu, mutations in p53, high growth fraction, and aneuploidy worsen the prognosis. Molecular profiling has identified genetically distinct subsets including luminal A and B (estrogen receptor positive), normal breast-like, HER2-amplified, and basal (or triple-negative based on no expression of hormone receptors or overexpression of HER2). These subsets differ in prognosis. Breast cancer can spread almost anywhere but commonly goes to bone, lungs, liver, soft tissue, and brain.
|Primary Tumor (T)|
|T0||No evidence of primary tumor|
|TIS||Carcinoma in situ|
|T1||Tumor ≤2 cm|
|T1a||Tumor >0.1 cm but ≤0.5 cm|
|T1b||Tumor >0.5 but ≤1 cm|
|T1c||Tumor >1 cm but ≤2 cm|
|T2||Tumor >2 cm but ≤5 cm|
|T3||Tumor >5 cm|
|T4||Extension to chest wall, inflammation, satellite lesions, ulcerations|
|Regional Lymph Nodes (N)|
|PN0(i–)||No regional lymph node metastasis histologically, negative IHC|
|PN0(i+)||No regional lymph node metastasis histologically, positive IHC, no IHC cluster >0.2 mm|
|PN0(mol–)||No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)|
|PN0(mol+)||No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)|
|PN1||Metastasis in one to three axillary lymph nodes, or in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent|
|PN1mi||Micrometastasis (>0.2 mm, none >2 mm)|
|PN1a||Metastasis in one to three axillary lymph nodes|
|PN1b||Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparenta|
|PN1c||Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent.a (If associated with greater than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden.)|
|pN2||Metastasis in four to nine axillary lymph nodes, or in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node metastasis|
|pN3||Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparenta ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral subcarinal lymph nodes|
|Distant Metastasis (M)|
|M0||No distant metastasis|
|M1||Distant metastasis (includes spread to ipsilateral supraclavicular nodes)|
|Stage IIIB||T4||Any N||M0|
|Stage IIIC||Any T||N3||M0|
|Stage IV||Any T||Any N||M1|
Treatment: Breast Cancer
Five-year survival rate by stage is shown in Table 71-2. Treatment varies with stage of disease and expression of hormone receptors and HER2.
Ductal carcinoma in situ is noninvasive tumor present in the breast ducts. Treatment of choice is wide excision with breast radiation therapy. In one study, adjuvant tamoxifen further reduced the risk of recurrence.
Invasive breast cancer can be classified as operable, locally advanced, and metastatic. In operable breast cancer, the outcome of primary therapy is the same with modified radical mastectomy or lumpectomy followed by breast radiation therapy. Axillary dissection may be replaced with sentinel node biopsy to evaluate node involvement. The sentinel node is identified by injecting a dye in the tumor site at surgery; the first node in which dye appears is the sentinel node. Women with tumors <1 cm and negative axillary nodes require no additional therapy beyond their primary lumpectomy and breast radiation. Adjuvant combination chemotherapy for 6 months appears to benefit premenopausal women with positive lymph nodes, pre- and postmenopausal women with negative lymph nodes but with large tumors or poor prognostic features, and postmenopausal women with positive lymph nodes whose tumors do not express estrogen receptors. Estrogen receptor–positive tumors >1 cm with or without involvement of lymph nodes are treated with aromatase inhibitors. Women who began treatment with tamoxifen before aromatase inhibitors were approved should switch to an aromatase inhibitor after 5 years of tamoxifen and continue for another 5 years.
Adjuvant chemotherapy is added to hormonal therapy in estrogen receptor–positive, node-positive women and is used without hormonal therapy in estrogen receptor–negative node-positive women, whether they are pre- or postmenopausal. Various regimens have been used. The most effective regimen appears to be four cycles of doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, IV on day 1 of each 3-week cycle followed by four cycles of paclitaxel, 175 mg/m2, by 3-h infusion on day 1 of each 3-week cycle. In women with HER2+ tumors, trastuzumab augments the ability of chemotherapy to prevent recurrence. The activity of other combinations is being explored. In premenopausal women, ovarian ablation (e.g., with the luteinizing hormone–releasing hormone [LHRH] inhibitor goserelin) may be as effective as adjuvant chemotherapy.
Tamoxifen adjuvant therapy (20 mg/d for 5 years) or an aromatase inhibitor (anastrozole, letrozole, exemestane) is used for postmenopausal women with tumors expressing estrogen receptors whose nodes are positive or whose nodes are negative but with large tumors or poor prognostic features. Breast cancer will recur in about half of pts with localized disease. High-dose adjuvant therapy with marrow support does not appear to benefit even women with high risk of recurrence. In pts with tumors expressing Her2, use of adjuvant trastuzumab with chemotherapy reduces risk of recurrence by at least 50%.
Pts with locally advanced breast cancer benefit from neoadjuvant combination chemotherapy (e.g., CAF: cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and 5-fluorouracil 500 mg/m2 all given IV on days 1 and 8 of a monthly cycle for 6 cycles) followed by surgery plus breast radiation therapy.
Treatment for metastatic disease depends on estrogen receptor status and treatment philosophy. No therapy is known to cure pts with metastatic disease. Randomized trials do not show that the use of high-dose therapy with hematopoietic stem cell support improves survival. Median survival is about 22 months with conventional treatment: aromatase inhibitors for estrogen receptor–positive tumors and combination chemotherapy for receptor-negative tumors. Pts whose tumors express HER2/neu have higher response rates by adding trastuzumab (anti-HER2/neu) to chemotherapy. Trastuzumab emtansine is a drug conjugate that targets HER2-expressing cells and has antitumor activity. Some advocate sequential use of active single agents in the setting of metastatic disease. Active agents in anthracycline- and taxane-resistant disease include capecitabine, vinorelbine, gemcitabine, irinotecan, and platinum agents. Pts progressing on adjuvant tamoxifen may benefit from an aromatase inhibitor such as letrozole or anastrozole. Half of pts who respond to one endocrine therapy will respond to another. Bisphosphonates reduce skeletal complications and may promote antitumor effects of other therapy. Radiation therapy is useful for palliation of symptoms.
|STAGE||5-YEAR SURVIVAL (PERCENTAGE OF PTS)|
Women with breast cancer have a 0.5% per year risk of developing a second breast cancer. Women at increased risk of breast cancer can reduce their risk by 49% by taking tamoxifen or an aromatase inhibitor for 5 years. Women with BRCA-1 mutations can reduce the risk by 90% with simple mastectomy.