Introduction
Breast cancer is the most frequently occurring cancer among women in the United States, excluding skin cancers like basal and squamous cell carcinomas. It ranks as the second leading cause of cancer-related deaths in women. In the year 2016, there were about 246,660 new cases of breast cancer, accounting for 29% of all newly diagnosed cancers in women. Tragically, it also resulted in 40,450 deaths, making up 14% of cancer-related deaths in the female population.
Around 1998, the incidence and mortality rates for breast cancer reached their highest levels, with 145 cases and 32 deaths per 100,000 women. However, thanks to advancements in screening techniques, preventive measures, and the modification of risk factors, there has been a modest decline in breast cancer incidence, dropping to approximately 123 cases per 100,000 women. Additionally, earlier detection and improved treatments have led to a decrease in breast cancer mortality, with rates now standing at 22 cases per 100,000 women.
It's worth noting that breast cancer is more commonly diagnosed in Caucasian women, with an incidence rate of 128 cases per 100,000 women, compared to African-American women, who have an incidence rate of 124 cases per 100,000 women. However, when it comes to breast cancer-related deaths, African-American women face a higher rate of 31 deaths per 100,000 women, compared to Caucasian women, who experience 22 deaths per 100,000
**Breast Cancer Risk Factors**
Several factors contribute to the risk of developing breast cancer. These include gender (with females being at higher risk), age, benign breast conditions, exposure to ionizing radiation, family history of breast cancer, mutations in inherited cancer-related genes, race/ethnicity, dietary choices, alcohol consumption, and estrogen exposure.
- **Age and Gender**: Among these factors, age and gender are the most significant. Breast cancer risk increases with age, with half of all breast cancer cases being diagnosed after the age of 61. While breast cancer can affect men, it's extremely rare, accounting for only 1% of breast cancer cases in the United States.
- **Radiation Exposure**: Exposure to therapeutic chest radiation at a young age, typically used to treat conditions like lymphoma, is linked to an elevated risk of breast cancer. This has led to the need for early and more intensive breast cancer screening for individuals who received such radiation.
- **Family History**: A family history of breast cancer is another risk factor, but it's a bit complex. A woman's risk of developing breast cancer increases if she has a first-degree relative (like a mother or sister) who had breast cancer. This risk is even higher if the relative was diagnosed at a younger age or if multiple first-degree relatives were affected. However, only 15% to 20% of women with breast cancer have a family history of the disease.
- **Inherited Gene Mutations**: About 5% to 10% of breast cancer cases are linked to inherited gene mutations. Genes like BRCA1, BRCA2, TP53 (associated with Li-Fraumeni syndrome), and others are examples. Women with BRCA1 or BRCA2 mutations, for instance, can have a much higher lifetime risk of breast cancer, often around 80%. These mutations also increase the risk of ovarian and other cancers.
- **Body Weight**: Weight plays a role in breast cancer risk. Being overweight or obese after menopause is associated with an increased risk, with a body mass index (BMI) of 28 kg/m^2 or higher being linked to about a 25% greater risk compared to those with lower BMIs. The exact mechanism is debated, but it may involve higher levels of estrogen in the body due to fat tissue converting androgens into estrogen.
- **Hormone Use**: Menopausal hormone therapy (MHT) containing estrogen and progesterone can increase breast cancer risk. Studies like the Women's Health Initiative found that prolonged use of these therapies can lead to a greater risk of breast cancer. The risk may persist even after discontinuation.
- **Alcohol Consumption**: Alcohol intake is a known risk factor for breast cancer. For every 10 grams of alcohol consumed daily (equivalent to a 4-ounce glass of wine), there's a 10% increase in breast cancer risk.
Understanding these risk factors can help individuals and healthcare providers make informed decisions regarding screening, prevention, and lifestyle choices to reduce the risk of breast cancer.
**Preventing Breast Cancer**
There are several factors that can help reduce the risk of developing breast cancer:
- **Minimizing Hormone Therapy**: If you're going through menopause and considering hormone therapy (MHT), try to use it for the shortest time necessary. Prolonged MHT use can increase breast cancer risk.
- **Maintaining a Healthy Weight**: Avoid gaining excess weight as an adult, especially after menopause. Being overweight can increase your risk of breast cancer.
- **Regular Physical Activity**: Engage in regular physical exercise. It can help lower your breast cancer risk.
- **Limiting Alcohol**: Try to limit alcohol consumption. Drinking too much alcohol is linked to an increased risk of breast cancer.
- **Early Motherhood and Breastfeeding**: Having your first child at a younger age and breastfeeding for at least 6 months can reduce the risk of breast cancer.
For individuals with BRCA1/2 gene mutations, taking proactive steps like prophylactic mastectomy (removing the breasts) and prophylactic oophorectomy (removing the ovaries) can significantly reduce the risk of breast cancer.
**Medications for Prevention**
- **Selective Estrogen Receptor Modulators (SERMs)**: Medications like tamoxifen and raloxifene, when taken for a specified period (usually 5 years), can reduce the risk of invasive breast cancer by 50%. However, they do not necessarily improve overall survival. Tamoxifen does have some side effects, including a slightly increased risk of uterine cancer and blood clot formation. Tamoxifen has been studied for both premenopausal and postmenopausal women, while raloxifene has been mainly evaluated in postmenopausal women.
- **Aromatase Inhibitors (AIs)**: Medications like exemestane and anastrozole are also effective in preventing breast cancer in postmenopausal women. However, they are associated with side effects such as an increased risk of osteoporosis. The choice between SERMs and AIs depends on various factors, including bone health.
It's important to note that while AIs are as effective as SERMs, only SERMs are currently approved by the US Food and Drug Administration (FDA) for primary breast cancer prevention.
**Breast Cancer Screening**
Regular screening is vital for detecting breast cancer early:
- **Mammography**: Getting a mammogram every one or two years can help detect early-stage breast cancers before symptoms appear. The effectiveness varies by age, with a significant benefit seen in women aged 50 to 69. Most facilities use digital mammography, and some offer tomosynthesis (3D mammography), although its superiority over standard digital mammograms is uncertain. Possible downsides of screening include discomfort, false-positive results, radiation exposure, and overdiagnosis (detecting cancers that may not cause harm).
- **When to Start and Stop**: Experts recommend discussing mammography starting around age 40 with personalized risk assessment. Routine screening typically begins at age 45 or 50, depending on guidelines. For women in their 40s, the benefits are somewhat lower due to a lower risk of breast cancer and a higher risk of false positives. Decisions on when to stop screening should be tailored to individual circumstances, with some groups recommending screening as long as a woman's life expectancy exceeds ten years.
- **Breast Self-Exams**: Routine breast self-examinations are no longer advised. Instead, women should be aware of any breast changes and discuss them with their healthcare provider.
- **Additional Tests**: Ultrasound may be used to follow up on abnormal clinical findings or mammograms. MRI is more sensitive than mammography but is not routinely used for screening. It may be considered for high-risk individuals, such as those with certain gene mutations or a history of therapeutic chest radiation during childhood.
Regular screening is essential for early detection, which can improve breast cancer outcomes. The right screening plan should be discussed with a healthcare provider, considering individual risk factors.
**Understanding Breast Cancer Staging and Treatment**
Breast tissue is composed of epithelial elements (like ducts) and stromal elements (such as fatty and fibrous tissues). Over 95% of breast cancers develop from epithelial cells, making them carcinomas. These breast carcinomas can be either in situ (confined within ducts or lobules) or invasive (spreading into surrounding breast tissue and possibly to other parts of the body). In situ carcinomas include ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Invasive breast cancers encompass various histologic types, with invasive ductal carcinoma (IDC) being the most common, accounting for about 75% of cases.
Several factors affect breast cancer prognosis and treatment decisions, including the cancer's grade, stage, hormone-receptor status, and HER2 status. Grade describes the microscopic features of the cancer and is categorized as well-differentiated (grade 1), moderately differentiated (grade 2), or poorly differentiated (grade 3). Stage is based on tumor size (T), extent of lymph node involvement (N), and presence of distant metastases (M). Stage 0 refers to noninvasive cancer (e.g., DCIS or LCIS), while invasive cancers are classified as stage I, II, or III, depending on their size and extent of spread. Stage IV indicates cancer that has spread to distant sites.
Inflammatory breast cancer (IBC) is an aggressive type, presenting with warm, thickened skin and a peau d'orange appearance over the breast. Unlike other breast cancers, IBC often lacks a palpable mass. It usually requires intensive treatment, including neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation therapy.
**Stage 0 Breast Cancer (Carcinoma in Situ)**
DCIS is a noninvasive cancer confined within the breast ducts, and it has become more common with the increased use of mammography. It accounts for about a quarter of newly diagnosed breast cancers. Surgical treatment options for DCIS include lumpectomy (removing the tumor while preserving the breast) or mastectomy (removing the whole breast). Lumpectomy followed by radiation therapy is the standard, reducing the risk of local recurrence by 50%. While axillary lymph node biopsy is unnecessary for pure DCIS, hormone therapy, such as tamoxifen or aromatase inhibitors (AIs), may be recommended after surgery to reduce future breast cancer risk.
LCIS is a noninvasive cancer arising from breast lobules. It's usually discovered incidentally during unrelated biopsies. LCIS itself doesn't require treatment, but it signals an increased risk of developing invasive breast cancer in either breast. Management options include surveillance or preventive medications like SERMs or AIs. Bilateral mastectomy isn't typically recommended.
**Stages I, II, and III Breast Cancer (Nonmetastatic)**
The goal for invasive breast cancer confined to the breast and/or axillary lymph nodes is cure. Surgical removal, either mastectomy or lumpectomy, is the primary treatment. Lumpectomy followed by radiation therapy is advised to reduce the risk of local recurrence. Axillary lymph node biopsy helps determine the prognosis and guide treatment. A sentinel node biopsy is preferred, allowing for less extensive axillary surgery if the sentinel nodes are clear. Hypofractionated radiation therapy may be an option for some women, shortening treatment duration.
The choice between mastectomy and lumpectomy depends on individual factors. Breast reconstruction is possible following mastectomy. Sentinel node biopsy and its results help decide whether additional axillary lymph node surgery is needed. While complications following complete dissection are uncommon, some women may experience chronic lymphedema.
Understanding the stage and characteristics of breast cancer is crucial for determining the appropriate treatment plan, ensuring the best possible outcome for each patient.
**Navigating Systemic Therapy for Breast Cancer**
In many cases, localized breast cancer can be effectively treated with surgery and radiation therapy. However, some patients remain at risk of developing metastatic disease even after these treatments. The likelihood of recurrence depends on factors like the stage and biological characteristics of the cancer, including its grade, hormone receptor status, and HER2 status. Unfortunately, blood tests and scans can't reliably predict who will experience recurrence.
The aim of adjuvant therapy is to lower the risk of cancer recurrence. This involves using systemic medications to target microscopic cancer cells that surgery or radiation might have missed. Decisions regarding adjuvant therapy depend on the risk of recurrence and the specific cancer type. Generally, the higher the risk, the more significant the potential benefit of adjuvant therapy.
Risk factors for metastatic breast cancer include larger tumor size, higher tumor grade, presence of lymphovascular invasion, hormone receptor-negative disease, and axillary node involvement. Additionally, gene expression analyses like the OncotypeDX recurrence score can help estimate the risk of recurrence for early-stage hormone-positive, HER2-negative breast cancer. This score provides insights into the likelihood of distant recurrence and the potential benefits of adding adjuvant chemotherapy to hormone therapy.
The choice of adjuvant therapy also hinges on the biological characteristics of the cancer. Hormone receptor-positive breast cancers (those with estrogen or progesterone receptors) can respond well to hormonal therapy. This treatment typically lasts 5 to 10 years, starting after surgery and, if applicable, chemotherapy. Tamoxifen is common for premenopausal women, often combined with ovarian suppression. Postmenopausal women may receive an aromatase inhibitor (AI) or a combination of tamoxifen and an AI. Adjuvant hormonal therapy can reduce the risk of death by about a third. Each therapy has its side effects: tamoxifen can increase the risk of thromboembolic disease and uterine cancer, while AIs may lead to musculoskeletal symptoms and osteoporosis.
Around 25% of breast cancers overexpress the HER2 protein. Patients with untreated HER2-positive breast cancer face a higher risk of recurrence. Trastuzumab, a monoclonal antibody, is used alongside adjuvant chemotherapy to target HER2-positive cancer cells. This combination significantly reduces the risk of recurrence and death. Trastuzumab may not be suitable for patients with preexisting heart failure, as about 2% to 3% of patients who receive it develop congestive heart failure. Monitoring the patient's heart function during treatment is recommended.
In the neoadjuvant setting (treatment before surgery) for higher-risk, HER2-positive breast cancer, pertuzumab is often added to the treatment regimen. Pertuzumab blocks the activation of the HER2 protein.
Regardless of hormone receptor or HER2 status, adjuvant chemotherapy is sometimes necessary for higher-risk tumors, reducing the risk of recurrence for all types of breast cancer. Adjuvant chemotherapy typically involves two or three medications with non-overlapping side effect profiles. Common drugs include cyclophosphamide, methotrexate, doxorubicin, paclitaxel, and docetaxel. Regimens with three chemotherapy medications offer greater benefits but come with increased toxicity.
Side effects and risks of chemotherapy can include fatigue, hair loss, nausea, diarrhea, infection, heart failure, and more. While chemotherapy isn't routinely recommended for certain types of breast cancer, it may be considered based on specific characteristics or gene expression profiling tests like OncotypeDX. Individualized treatment decisions are essential to balance potential benefits and risks.