MD2B - Breast Cancer

Introduction

Breast canceris the most common cancer in women, accounting for 32% of newly diagnosed cases. It is the second leading cause of cancer mortality among women in industrialized countries. In fact, the lifetime risk of breast cancer in US women is currently estimated to be as high as 1 in 8, calculated up to an age of 85 years. The changing epidemiology is thought to reflect both increased detection over the years secondary to improved technology and access to health care, as well as increased longevity in industrialized nations. There are a host of well-established risk factors that have emerged through multiple epidemiological studies. Treatment strategies and prognosis are dependent on these factors, as described below.

Epidemiology and Etiology

• Incidence of over 210,000 cases yearly in the United States, with about 1,700 cases (<1%) occurring in men, and over 70% occurring in women age 50 or older.
• Mortality of greater than 40,000 deaths in the United States yearly [1].
• Etiology remains unknown in the majority of patients.
• Hereditary mutations (BRCA-1 and BRCA-2) comprise 3-10% of cases.
• Risk factors include the following, with the first six being most important:
• • Sex , female:male of 125:1
  • Age, with steep increases every 5 years between ages 30 and 50 [2]
  • Prior breast cancer, especially of the invasive (vs. in situ) type
  • Family history , especially in multiple first-degree relatives at young ages (relative risk if the disease is in: mother = 1.8, sister = 2.5, both = 5.6)
  • Benign breast disease, only if proliferative or atypical hyperplasia on biopsy
  • Endogenous endocrine factors , including early menarche <12 years, late menopause >50 years, no pregnancies, and first pregnancy after age 30 [2]
  • Exogenous hormones , including estrogen replacement and birth control
  • Race and ethnicity , with incidence highest in Caucasians, adjusted mortality highest in African-Americans
  • Previous radiation exposure , especially in Hodgkin's disease survivors
  • High-fat diets and alcohol consumption =2 drinks/day

Prevention

• Lifestyle: avoid long-term hormone replacement therapy, have children before age 30, breastfeed, avoid weight gain through exercise and low-fat diets, limit alcohol consumption.
• Pharmacologic: taking tamoxifen for five years can reduce the risk of developing breast cancer by about 50% in high risk women.
• Potential protective effects from vitamins A, C and E, and phytoestrogens (naturally occurring estrogens that are in high numbers in soy).

Screening of Patients with Few or No Known Risk Factors

• ACS Cancer Detection Guidelines
• • Complete annual physical and clinical breast exams every three years for women in their 20s and 30s and every year for women age 40 and over
  • Monthly breast self-exams beginning at age 20
  • Yearly bilateral mammograms starting at age 40
  • Women at increased risk (e.g., family history, genetic tendency, prior breast cancer), in consultation with their physicians, should consider starting mammography screening earlier, breast ultrasound or MRI, more frequent exams

Clinical Presentation

• History : Often asymptomatic, could present with nipple discharge, a lump or thickening in the breast or underarm, change in the size or shape of the breast, dimpling, retraction, redness or scaling of the skin or nipple in advanced disease.
• Physical Exam : Meticulous breast and axillary exam, with attention to pulmonary and musculoskeletal systems for signs of metastatic disease.
• Lab studies: CBC and basic chemistries.
• Radiologic studies : Diagnostic mammogram s to rule out multicentricity, define the extent of tumor, and identify chest wall or skin involvement; ultrasound, especially in younger women with dense breasts; CXR; bone scan s and CT scan in patients with symptoms or advanced disease.
• Diagnostic studies : core needle biopsy with needle localization has replaced excisional biopsy as the procedure of choice for all palpable masses; FNA is a quicker and easier procedure but has a higher false negative rate and is less able to distinguish between in situ and invasive cancer [3].
• Special studies : Estrogen/progesterone receptor status, histologic/nuclear grade, S-phase fraction, Her-2/neu, +/- p53 and cathepsin-D [4].

Natural Course and Pathology

• Often has a long and unpredictable course.
• Staging: both a clinical and a pathological assessment.
• • Clinical staging includes careful physical examination of the breasts, nipples, chest wall and axillary nodes, as well as a thorough search for bony and other metastatic involvement.
  • Pathologic staging is essential, as clinical staging is often considered inaccurate and axillary node involvement is the strongest prognostic indicator for survival [5].
  • Pathologic staging follows the American Joint Committee on Cancer's Pathological Staging System (TNM).
• Prognostic factors include:
• • Axillary lymph node involvement: Single most influential predictor of cancer recurrence and survival, dependent on the absolute number of positive nodes.
  • Tumor size: Second most important predictor of outcome.
  • Estrogen and progesterone receptor status: From 50-80% of cancers are ER positive. Patients with these tumors have increased survival following adjuvant therapy, especially if the patient is also PR positive.
  • Histology : Medullary and mucinous cancers have the best prognosis, scirrhous cancers have variable outcomes, and inflammatory cases demonstrate the worst survival.
  • Nuclear grade: More important in node-negative patients, with low-grade, well-differentiated tumors faring best.
  • Ploidy and S-phase fraction: Determined by flow cytometry, with low DNA index and low S-phase fraction portending better prognoses.
  • Her-2/neu oncogene: Amplification of the HER2 gene and/or overexpression of the HER2 protein, which are associated with more aggressive tumor behavior, occur in 15-25% of breast cancers. Trastuzumab, a recombinant monoclonal antibody against HER2, when given with adjuvant chemotherapy, has recently been shown to decrease recurrence and improve disease-free survival in HER2 positive patients [6].
  • Cathepsin D: Associated with high recurrence risk and poor survival [4].

Treatment

Noninvasive cancer

Ductal carcinoma in situ (DCIS)

• High potential for progression to invasive cancer.
• Treated effectively with lumpectomy followed by radiation (especially given for higher nuclear grade, comedo necrosis), with only extensive or multifocal DCIS warranting simple mastectomy.
• Lymph node dissection is not indicated

Lobular carcinoma in situ (LCIS)

• A 30% risk of subsequent invasive cancer in either breast over a 15-20 year period following diagnosis [7].
• Most patients undergo continued regular screening for breast cancer with no specific treatment after a diagnosis of LCIS.
• Bilateral mastectomy is not currently indicated and largely dependent on patient preference.
• Tamoxifen has been shown to reduce the risk of developing breast cancer in LCIS patients by 56% [8].

Invasive cancer: Early stage vs. locally advanced

• Surgical treatment : Purpose is to reduce the tumor burden to a number of viable cells amenable to destruction by chemotherapy or host-factors.
• • Total mastectomy vs. breast preservation with wide excision (lumpectomy) and post-operative radiation; both treatment approaches have been shown to result in equivalent survival rates, as demonstrated in the groundbreaking B-04 and B-06 trials.
  • All patients, with the exception of elderly patients who have favorable prognostic factors and who are not chemotherapy candidates, undergo ipsilateral lymph node evaluation.
  • • Sentinel lymph node biopsy may initially be performed to determine if a formal axillary lymph node dissection is required.
• Radiation therapy : Adjunct to surgery, with the intention to prevent local and regional recurrence that occurs more often in patients with locally advanced disease.
• • All patients who receive breast conservation therapy with wide local excision should receive post-operative adjuvant radiation therapy.
  • Radiation is also recommended following mastectomy in patients who have large tumors, multiple lymph node involvement, or close/positive margins after the surgery.
• Chemotherapy: Standard adjuvant post-operative therapy for many patients.
• • Indicated for women with locally advanced disease at high risk for locoregional recurrence large tumors, many involved lymph nodes, close/positive surgical margins).
  • Combining radiotherapy with chemotherapy after modified radical mastectomy has been shown to decrease the rates of locoregional and systemic relapse and reduce breast cancer mortality [9].
  • • While the use of concomitant chemotherapy and radiation therapy in early-stage women treated with breast-conserving surgery is not recommended due to increased side effects, the ideal sequence of systemic therapy and radiation therapy remains debated [10].
  • The Early Breast Cancer Trialist's Collaborative (EBCTC) group showed a superiority of combination regimens to single agents, with cyclophosphamide, methotrexate, and 5-FU (CMF) being more effective than either methotrexate or 5-FU alone in node-negative patients [11].
  • • AC (doxorubicin and cyclophosphamide) is an effective alternative regiment.
  • No apparent survival advantage to preoperative (neoadjuvant) chemotherapy as compared with postoperative chemotherapy; However, neoadjuvant therapy can be used to shrink larger tumors to allow for more effective surgery, primary chemotherapy has been shown to cause tumor regression in 60-90% of women [12], and anthracycline-based regimens show ed efficacy in node-positive cases.
• Hormonal therapy: Tamoxifen (a selective estrogen receptor modulator) was discovered in 1962 as potential contraceptive and fertility drug. It is well tolerated and has favorable cardiovascular effects, but it is associated with a modest increase in the risk of endometrial cancer. Ovarian ablation is comparable in efficacy to tamoxifen and chemotherapy in premenopausal women but is rarely used in the United States.
• • The EBCTC group demonstrated that the use of tamoxifen led to a reduction in the annual odds of recurrence by 25%, of death by 17%, and of contralateral breast cancer by 40% [13].
  • Tamoxifen is more effective in postmenopausal women and in ER positive patients.
  • Aromatase inhibitors (AIs) may alternatively be used in postmenopausal women as initial adjuvant therapy or following 2-5 years of tamoxifen therapy.
  • • Available AIs in the United States include anastrazole (Arimidex), exemestane (Aromasin), and letrozole (Femara).