MD2B - Breast Cancer

Introduction

Breast cancer is the most common cancer in women, accounting for 15% of newly diagnosed cases. It is the second leading cause of cancer-related mortality among women in industrialized countries. In the U.S., the lifetime risk of breast cancer is approximately 1 in 8, calculated up to age 85. Significant improvements in breast cancer outcomes are due to advancements in screening technology, better access to healthcare, and increased life expectancy [1-2]. Treatment and prognosis depend on multiple factors, including a woman’s baseline risk, tumor characteristics, lymph node status, and hormone receptor status.

Epidemiology and Etiology

• The incidence of breast cancer in the U.S. is approximately 300,000 cases annually, with less than 1% (about 1,700 cases) occurring in men. More than 70% of cases are diagnosed in women aged 55 and older
• Breast cancer causes more than 40,000 deaths annually in the United States [3]
• The etiology of breast cancer remains unknown in many patients
• Hereditary mutations such as BRCA-1 and BRCA-2 account for 3-10% of cases [4]
  • BRCA 1 mutation: 60-80% lifetime risk
  • BRCA 2 mutation: 40-50% lifetime risk
• Risk factors include the following, with the first six being most important:
  • Female gender, (female-to-male ratio: 125:1)
  • Age, with sharp increases every 5 years between ages 30 and 50 [5]
  • Previous diagnosis of breast cancer, especially if the prior cancer was invasive
  • Family history, especially in multiple first-degree relatives diagnosed at a young age (Relative risk if the disease is in: mother = 1.8, sister = 2.5, both = 5.6)
  • Benign breast disease, if proliferative or atypical hyperplasia on biopsy
  • Endogenous endocrine factors, (e.g. early menarche <12 years, late menopause >50 years, no pregnancies, and first pregnancy after age 30 [5]
  • Exogenous hormone use such as estrogen replacement
  • Race and ethnicity, with incidence highest in Caucasians whereas adjusted mortality is highest in African-Americans
  • Prior radiation exposure, especially in Hodgkin's disease survivors

Prevention

• Maintaining a healthy, active lifestyle which includes a low-fat diet and limiting alcohol consumption, can help reduce the risk of breast cancer
• Taking tamoxifen or raloxifene can reduce the risk of developing breast cancer in high-risk women by about 50% or 38%, respectively [6]

Screening Guidelines

• There is no universally agreed-upon age for which women should begin breast cancer screening
• Self-breast exams are no longer recommended. Patients are encouraged to have “breast awareness” meaning they should be familiar with their breasts and report any changes to their primary provider [7-8]
• The American Cancer Society (ACS) recommends annual mammograms for women aged 45-54. For women aged 55 years and older, mammograms can be done every other year, depending on personal preference
• Women at increased risk (e.g., family history, BRCA carriers, prior breast cancer), in consultation with their physicians, should consider starting mammography screening earlier. This may also include additional screening with breast ultrasound, MRI or more frequent exams [7]
• Women with a first degree relative with breast cancer should begin screening 10 years earlier than the age at which that relative was diagnosed [7-8]

Clinical Presentation

• History: Often asymptomatic, but may present with symptoms such as nipple discharge, a lump or thickening in the breast (commonly the upper outer quadrant) or underarm, change in breast size or shape and skin changes. In advanced cases, symptoms may include dimpling, retraction, redness or scaling of the skin or nipple
• Physical Exam: A meticulous breast and axillary exam should be performed, with attention to pulmonary and musculoskeletal systems looking for signs of metastatic disease
• Lab studies: complete blood count and basic chemistries
• Radiologic studies: Diagnostic mammogram and ultrasound to rule out multicentricity, define the extent of the tumor, and identify chest wall or skin involvement; Breast MRI may also be performed for findings not well visualized on mammogram or for women with dense breasts [8]
  • CXR; bone scan, CT scan, and/or PET CT scan may be performed in patients with symptoms or advanced disease.
• Diagnostic studies: Core needle biopsy with needle localization
• Special studies: Estrogen/progesterone receptor status and HER2 status [8-9]

Natural Course and Pathology

• For early-stage breast cancer 5-year survival rate in the United States is approximately 90%
• Staging: Both clinical and pathologic staging are essential in breast cancer management and guide treatment decision making
  • Clinical staging includes careful physical examination of the breasts, nipples, chest wall and axillary nodes. Imaging is performed to understand the extent of disease and biopsy provides pathologic confirmation of the diagnosis
  • Pathologic staging requires surgical removal and histologic examination of the tumor. Axillary lymph node biopsy or dissection is also needed in most cases.
  • Both clinical and pathologic staging follows the American Joint Committee on Cancer's Staging System (TNM).
    • T = Tumor size & extension into nearby structures
    • N = Nodal involvement
    • M = Distant metastasis (if present, the patient is considered stage IV)
• Prognostic factors include:
  • Axillary lymph node involvement is the single most influential predictor of cancer recurrence and survival, dependent on the absolute number of positive nodes [10]
  • Tumor size is the second most important predictor of outcome
  • Estrogen and progesterone receptor status: Approximately 50-80% of breast cancers are estrogen receptor (ER) positive. Patients with ER-positive tumors, particularly those who are also progesterone receptor (PR) positive, show improved survival rates following adjuvant therapy, such as hormonal treatments, which target these receptors  
  • Her-2/neu oncogene: Amplification of the HER2 gene or overexpression of the HER2 protein is observed in 15-25% of breast cancers and is associated with aggressive tumor behavior. Trastuzumab, a recombinant monoclonal antibody against HER2 may be given neoadjuvantly or adjuvantly in combination with chemotherapy when given with adjuvant chemotherapy, has been shown to decrease recurrence and improve disease-free survival in HER2 positive patients [9, 11]
• Histology: Favorable histologies include tubular, cribiform and mucinous
• Nuclear grade: Determined using the Nottingham combined histologic grade, which assesses various histologic characteristics. The grading system helps predict tumor behavior, with lower-grade tumors generally associated with better outcomes [8]
  • Grade 1: Low-grade (favorable)
  • Grade 2: Intermediate-grade (moderately favorable)
  • Grade 3: High-grade (unfavorable) 

Treatment

Noninvasive cancer

Ductal carcinoma in situ (DCIS)

• A precancerous entity with potential to progress to invasive cancer if left untreated. Regardless, the mortality rate from DCIS is extremely low
• Patients may be treated with lumpectomy +/- radiation or mastectomy
• Lymph node dissection is not indicated

Lobular carcinoma in situ (LCIS)

• Associated with an increased risk (30%) of developing invasive breast cancer in either breast over a 15–20-year period following diagnosis [12]
• Generally, excision should be considered for LCIS
• Bilateral mastectomy is not currently indicated and largely dependent on patient preference
• Tamoxifen and raloxifene have been shown to reduce the risk of developing breast cancer by 56% and 38%, respectively [13]. Raloxifene is sometimes preferred for patients due to its lower toxicity profile [6]

Invasive cancer

Surgery:

• Total mastectomy vs. breast preservation with wide excision (lumpectomy) followed by post-operative radiation.
• Both treatment approaches have been shown to result in equivalent survival rates, as demonstrated in the B-04 and B-06 trials [14-15]
• A sentinel lymph node biopsy should be performed in most patients [8]. Findings determine if the patient requires a full axillary node dissection

Radiation therapy:

• Given to patients in the adjuvant setting to prevent cancer recurrence
  • Most patients who receive breast conservation therapy with wide local excision (lumpectomy) should receive post-operative adjuvant radiation therapy. This treatment paradigm has been shown to decrease cancer recurrence at 10 years vs breast conservation surgery alone (35% vs. 19.3%, p<0.001). However, this effect is less pronounced in low-risk patients [16-17]
  • Radiation is recommended following mastectomy in patients who have higher risk factors for recurrence, such as large tumors, involvement of multiple lymph nodes, or absence of hormone receptors

Chemotherapy: 

• May be given in the neoadjuvant or adjuvant setting
• Generally indicated for patients with large tumors, HER2+ tumors, lymph node involvement, or high Oncotype scores
• There is no difference in patient outcomes whether chemotherapy is given in the neoadjuvant vs adjuvant setting [18]
  • Neoadjuvant chemotherapy may help downstage large tumors, making them smaller. This can enable patients to opt for a lumpectomy (breast-conserving surgery) rather than a mastectomy
• Many neoadjuvant chemotherapy regimens are available and depend on the receptor subtype and nodal status
  • AC-T (doxorubicin, cyclophosphamide and paclitaxel) is given to patients with triple negative (ER negative, PR negative, HER2 negative) breast cancers
  • TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) is given to patients with HER2+ tumor

Hormonal therapy: 

• Given adjuvantly to patients with hormone receptor-positive breast cancer. Found to reduce breast cancer recurrence and new primary breast cancers in the opposite breast
• The agent used depends on the patient’s menopausal status. Tamoxifen is given to premenopausal patients whereas an aromatase inhibitor is given to postmenopausal patients.
  • The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) demonstrated that the use of tamoxifen resulted in a 25% reduction in the odds of breast cancer recurrence, a 17% reduction in breast cancer-related mortality, and a 40% reduction in the risk of developing contralateral breast cancer [19]
  • Fulvestrant (Faslodex) is an antiestrogen agent used to block estrogen from binding to cancer cells, which normally stimulates growth. Fulvestrant has also been shown to target cancer cells for destruction.