BREAST CANCER

BREAST CANCER - Alexandra Sherman, BA
BASICS
DESCRIPTION
• Malignant neoplasm in the breast
• Classified as carcinoma in situ (CIS) or invasive; 70% of all breast cancers possess a component of invasion.
• Age-specific incidence of breast cancer increases sharply until menopause and continues to increase at a slower rate in the geriatric population.
ALERT
Geriatric Considerations
Higher percentage of estrogen receptor-positive tumors (80%) in the geriatric population; correlates with improved disease free survival.
Pregnancy Considerations
• Breast cancer occurs infrequently during pregnancy (2.8%).
• Delay in diagnosis is common, and most series report poorer survival related to advanced stage at diagnosis.
GENERAL PREVENTION
• Mammography to screen for disease
- The U.S. Preventive Services Task Force recommends a mammography with or without clinical breast examination every 1-2 years for women >40.
- The American Cancer Society recommends mammography and a clinical breast examination every year after age 40 and a clinical breast examination every 3 years for ages 20-39.
- The ACOG and AMA recommend mammogram every 1-2 years and an annual clinical breast examination starting at age 40 and then annual mammograms at age 50.
- Albeit controversial, mammography may reduce mortality by 30% in women 50-69; the reduction in mortality is less impressive for women 50 or >70 years.
• Tamoxifen reduces invasive and noninvasive breast cancers by 50% in high-risk women but has significant risk of thromboembolic events and uterine cancer.
- Recently reported results from the STAR trial showed that raloxifene (Evista) was as effective as tamoxifen in preventing invasive breast cancer in postmenopausal women but was associated with less risk for DVT (NNT = 455), pulmonary emboli, and uterine cancer (NNT=370).
EPIDEMIOLOGY
• Breast cancer is the most common malignancy in women in North America.
• Predominant age: 30-80 with peak age 45-65; 77% of cases occur in women >50
• Predominant sex: Female > Male (1% occurs in males)
Incidence
The American Cancer Society estimates that 212,930 new cases will be diagnosed in 2005, with 40,870 deaths (including 460 men).
Prevalence
One in 7 women will develop breast cancer within her lifetime.
RISK FACTORS
• Increased risk occurs in 1st-degree relatives (relative risk 1.7- 2.5), with bilateral disease in premenopausal relatives (relative risk = 10.5), or bilateral disease in postmenopausal relatives (relative risk = 5.0).
• Hormonal risk factors include early menarche, late menopause, nulliparity, 1st full-term pregnancy after age 30, postmenopausal HRT.
• Women with a history of breast cancer or previous breast biopsies revealing atypical changes are at increased risk (5-10 times) for subsequent cancer.
• Exogenous estrogen use, especially in conjunction with progestins, increases risk.
- Premenopausal oral contraceptives have not been shown to increase risk.
• Radiation exposure has been associated with an increased risk of breast cancer.
Genetics
• 10-20% of the patients have a significant family history of breast cancer.
• Women who inherit a mutated BRCA1, a tumor suppressor gene, have a 60-80% lifetime risk of breast cancer and a 33% risk of ovarian cancer. BRCA2 is associated with increased risk of breast cancer in men and women.
- Family history suggestive of breast cancer susceptibility genes include multiple 1st-degree and 2nd-degree relatives with early breast cancer diagnosis and the presence of ovarian cancer.
- 1 in 400 U.S. women carry a germ-line mutation for BRCA1.
• Her-2,neu is an oncogene whose overexpression plays a role in 25-30% of breast cancers; Her-2,neu confers a poor prognosis and has treatment implications.
ASSOCIATED CONDITIONS
Organ disease at metastatic sites


DIAGNOSIS
SIGNS AND SYMPTOMS
• Palpable mass (55%)
• Abnormal mammogram without a palpable mass (35%)
• Color, size (enlargement or shrinkage), or shape changes
• Lymphedema (peau d'orange)
• Dimpling
• Nipple retraction, tenderness, or pain
• Axillary mass
• Bone pain (rare)
• Discharge (bloody discharge is more ominous)
History
Any personal or family history of breast cancer, previous breast biopsy, or recent changes in breasts
TESTS
Bone scan, CT, or ultrasound of abdomen if widespread or recurrent disease is suspected
Lab
Initial lab tests include CBC, liver function tests, chest radiograph, bilateral mammography  ultrasound, estrogen and progesterone receptor determination, FISH for her-2,neu status and S-phase determination. Consider MRI.
Imaging
• Mammography (sensitivity = 50-80% depending on analog versus digital, age, menstrual status, and breast density; positive predictive value = 5-20%)
- Most common abnormalities: Irregular mass, spiculated density, microcalcifications (35%), or architectural distortion.
• Ultrasound may confirm whether a suspicious lump is solid or cystic and help define its size and extent.
Diagnostic Procedures/Surgery
• Nonpalpable lesions: Core biopsy or open excisional biopsy
• Palpable abnormality: Fine-needle aspiration or core-needle biopsy.
Pathological Findings
• Noninvasive cancers: Intraductal (DCIS) or intralobular (LCIS) (carcinoma in situ)
- Intraductal cancers: Micropapillary, cribriform, solid, or comedo. The comedo growth pattern is considered more aggressive.
• Invasive cancers
- Ductal NOS (70%), lobular (5%), Paget disease (2%), inflammatory and miscellaneous (metaplastic, neuroendocrine, or squamous cell carcinomas [1%])
- Patients with invasive intraductal histologies with medullary (6%), colloid/mucinous (3%), tubular, papillary, and adenoid cystic (2%) subtypes have improved survival.
DIFFERENTIAL DIAGNOSIS
• Benign breast disorders, such as abscesses, hematomas, fibroadenomas, fibrocystic change, ductal or lobular hyperplasia, or sclerosing adenosis
• Malignant breast diseases, including sarcomas, lymphomas, or metastatic disease to breast
TREATMENT
Patients treated by a team consisting of a medical oncologist, a surgeon, and a radiation oncologist
GENERAL MEASURES
• Early breast cancer treatment (stage I/II)
- Lumpectomy (wide excision with breast conservation), sentinel node biopsy, hormonal therapy, and radiotherapy is the treatment of choice.
- Combination chemotherapy is also indicated, because most patients have subclinical metastases.
• Treatment of locally advanced breast cancer (stage III)
- Usually multidisciplinary treatment consisting of mastectomy, axillary dissection, radiation, and chemotherapy  tamoxifen
• Treatment of advanced or recurrent disease (stage IV)
- Surgical resection if possible, plus chemotherapy, radiation, hormonal therapy.
Activity
As tolerated.
SPECIAL THERAPY
Radiotherapy
• Postlumpectomy radiation is the mainstay of adjuvant local therapy and has been shown to decrease local recurrence compared to lumpectomy and hormonal therapy alone (1)[A].
• The indications for postmastectomy radiation therapy to the chest wall include patients with 4 positive lymph nodes, the presence of extracapsular extension, and tumor stage of T3 or more.
MEDICATION (DRUGS)
• Combination chemotherapy (most common regimens: CMF, AC or AC + Taxol) reduces the risk of recurrence and improves overall survival in women with tumors >1cm and positive nodes.
- Chemotherapy, notably AC + Taxol improves overall survival by 16.7% in ER- women compared to 4% in ER+ women (2)[B].
• Adjuvant tamoxifen (Nolvadex) (20 mg/d) reduces the risk of recurrence and death for women of all ages by 5-11%, especially in postmenopausal, ER/PR+ women.
• An aromatase-inhibitor, anastrazole (Arimidex) (1 mg/d) may be more effective (NNT = 40 recurrent disease) and better tolerated (NNT = 166 endometrial cancer, NNT = 125 DVT) in ER/PR+, postmenopausal women with localized disease than tamoxifen, although it does increase risk of musculoskeletal problems (NNH = 30 fracture) compared to tamoxifen (3)[A].
• Trastuzumab (Herceptin) (4 mg/kg loading dose, 2 mg/kg maintenance infusion) improves mortality by 1/3 when combined with chemotherapy for early stage HER-2,neu+ breast cancer (4)[A].
• Contraindications: Strict hematologic, renal, hepatic, and cardiac guidelines must be followed for the administration of cytotoxic chemotherapy. Arimidex should not be given to pregnant women.
• Adverse events: See manufacturer' literature. Herceptin associated with CHF.
• Precautions: Monitor for infections and infusion reactions in chemotherapy patients. See "Complications" section for discussion of tamoxifen.
• Significant possible interactions: Drug interactions are common and depend on combinations used. Refer to manufacturer's literature.
First Line
All drugs mentioned above may be used as first-line treatments.
SURGERY
Breast-conserving surgery is appropriate for most breast cancers, because no difference in long-term survival is noted when comparing mastectomy to breast conservation (5)[A]. Axillary node dissection is indicated with all invasive tumors and large noninvasive ones. Identification and biopsy of sentinel nodes may be preferred over axillary dissection because of its lower morbidity rate, but is only appropriate for patients with early-stage breast cancer with clinically negative axillary nodes.
FOLLOW-UP
PROGNOSIS
• 5-year survival
- Stage 0 (noninvasive): 100%
- Stage I (2 cm, no spread): 98%
- Stage II (>2 cm, or spread to axillary lymph nodes): 76-88%
- Stage III (>5 cm or fixed nodes, metastatic disease to the skin, inflammatory changes, chest wall extension, or supraclavicular lymph nodes): 49-56%
- Stage IV (distant metastatic disease): 16%
• The status of the axillary lymph nodes is the most important indicator for disease relapse.
- If any axillary nodes are positive, 60-70% risk of relapse within 5 years.
- If all axillary nodes are negative, 70-80% chance of a long-term cure
COMPLICATIONS
• Postoperative: Lymphedema (5% in modified radical mastectomy), seroma, wound infection, and limited shoulder motion
• Chemotherapy: Nausea, vomiting, alopecia, leukopenia, bladder irritation, stomatitis, fatigue, and menstrual abnormalities
• Tamoxifen: Hot flushes, menstrual irregularities including menopause, vaginal discharge, hypercalcemia, skin rashes, endometrial carcinoma, DVTs, CVAs and interactions with warfarin, erythromycin, cyclosporin, nifedipine, and diltiazem.
• Irradiation: Skin reaction, fatigue, fibrosis (1%), brachial plexopathy (1%), rib fracture (1%), arm edema, pulmonary fibrosis (1%), and rarely 2nd breast malignancy
PATIENT MONITORING
• Up to 60% of patients with invasive disease will relapse within 5 years despite initial therapy.
- Diagnosis of relapse does not impact survival.
• Surveillance for recurrent disease should include physical examination every 4-6 months for 5 years, then yearly. Mammography and routine chemistries should be done annually. Women on tamoxifen should have annual pelvic exams.
• The workup of a suspected recurrence should include CBC, liver function tests, chest radiograph, bone scan, a CT of the affected area, mammogram, and/or a biopsy.
REFERENCES
1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. NEJM 2002;347:1233-1241.
2. Berry D, Cirrincione C, Henderson C, et al. Estrogen receptor status and outcomes of modern chemotherapy for patients with node positive breast cancer. JAMA 2006;295:1658-1667.
3. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365(9453):60-62.
4. Romond E, Perez E, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable her-2 positive breast cancer. NEJM 2005;353:1673-1684.
5. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. NEJM 2002;347:1227-1232.