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Overview
Breast cancer is the second most common cancer in the US and the most common cancer among women. One in 8 women will be diagnosed with breast cancer in her lifetime. According to the American Cancer Society, in 2012, the number of new cases of breast cancer is estimated to be 226,870, which represents 29% of all cancer diagnoses in women. Of all breast cancers diagnosed in women, over three-quarters are diagnosed in postmenopausal women and one-quarter in premenopausal women. Only 6% of those first diagnosed with breast cancer have metastatic disease. The 5-year survival rate for local breast cancer is now 99%, whereas the 5-year survival for metastatic breast cancer is 23%.1 According to the American Cancer Society, deaths from breast cancer have fallen by 30% over the past 2 decades.2 It is unclear what has caused this improvement, but it may be an artifact of the increased number of early stage diagnoses, which have favorable prognoses upon treatment.
Risk Factors
There is no universal cause of breast cancer, but there are numerous contributing factors associated with this diagnosis. Women are at 100 times greater risk than men. The chance of getting breast cancer increases with age. Inherited genetic mutations, specifically mutation of the BRCA1 and BRCA2 repair genes, play a role in about 5% to 10% of breast cancer cases. Gene mutations, specifically of the genes BRCA1, BRCA2, and p53, are associated with a 40% to 85% lifetime risk of developing breast cancer. Women with a mother, daughter, or sister with breast cancer are twice as likely to contract the disease as women with no close relatives with breast cancer.
Other factors that increase the risk include exposure to radiation and early menarche. Women who have taken birth control pills at any time during the previous 10 years are thought to have a slightly higher risk of breast cancer than those who have not. On the other hand, previous pregnancy and having breast-fed are both thought to lower breast cancer risk slightly. Using hormone replacement therapy (HRT; estrogen and progestin) to treat symptoms of menopause increases the risk of breast cancer. Alcohol use, obesity, and a sedentary lifestyle also increase risk. In fact, in a 2012 meta-analysis, 10% of all incident breast cancers are attributed to inactivity.3 Other potential risk factors include smoking; eating charred red meat regularly; and exposure to pesticides, PCBs, and other pollutants.
Pathophysiology
Breast cancer, like all cancers, represents an accumulation of increasingly dysfunctional genetic mutations, epigenetic mutations, altered signal transduction, altered cellular metabolism, and disrupted stromal integrity. The ultimate culmination of these influences is architectural and functional cellular abnormalities, such as loss of differentiation, genetic instability, and severely altered cellular metabolism. As a result of these aberrations, malignant cells behave erratically, driven by unregulated proliferation and angiogenic genes. There is a complex interplay between the tissue stroma and the cells within. A full discussion of this is beyond the scope of this article; however, one component of the stroma that is particularly relevant to breast cell malignancy deserves further discussion; namely, hormonal influence, particularly that of estrogen and progesterone.
The majority of breast cancers are estrogen receptor positive, meaning that they overexpress estrogen receptors on their cell surfaces and use these receptors to drive cell proliferation. The estrogen receptor plays a particularly important role in the pathophysiology of the majority of breast cancers. When bound by estrogen, the intracellular domain of the alpha subtype of the estrogen receptor dissociates from heat shock proteins; undergoes conformational changes, phosphorylation, and dimerization; and translocates to the nucleus, where it binds to, and inactivates, transcription repressor genes. Seventy percent of estrogen-related genes are downregulated by estrogen and include transcriptional repressors and antiproliferative and pro-apoptotic genes. In addition, activated estrogen receptors in turn trigger other kinase signal transduction pathways (phosphatidyl-inositol-3-OH kinase, or PI3K, Jun NH2-terminal kinases, or JNKs, stress activated protein kinases, or SAPKs, and insulin growth factor-1, or IGF-1), leading to increased proliferation, angiogenesis and decreased apoptosis.4,5 A prospective case-control study matched 277 women who developed invasive breast cancer against 423 postmenopausal control subjects without breast cancer. All women were postmenopausal and had never used hormone therapy. The serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). More extensive 2-hydroxylation of parent estrogens was associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols was associated with higher risk of postmenopausal breast cancer.6
The progesterone receptor is gaining increasing recognition for its growth-promoting role in breast cancer. Breast cancer cells that express the progesterone receptor have higher rates of proliferation. Progesterone receptor positive breast cancer cells also have a higher uptake of glucose and demonstrate increased rates of glycolysis and lipogenesis, suggesting that progesterone facilitates the ability of PR+ tumors to utilize any available fuel source for survival and growth.7 Progesterone has been further implicated as an important factor in breast carcinogenesis from clinical studies on women receiving hormonal replacement therapy (HRT) and risk of developing breast cancer. Among women who experience new-onset breast tenderness with the initiation of the HRT (conjugated equine estrogens [CEE] and medroxyprogesterone) there is an increased risk of invasive breast cancer (HR 1.33, 95% CI 1.02–1.72). However, this increase is not seen with CEE alone (HR 0.98, 95% CI 0.62–1.53).8 This finding has been demonstrated in other clinical trials as well with estrogen plus progestin resulting in significantly increased abnormal mammograms, a result not found in women using CEE alone for up to 5 years.9
The clinical implications from the studies on hormones and breast cancer are still emerging. Nonetheless, it appears that a combination of increased estrogen, progesterone, and insulin (upregulates IGF-1) and overexpression of estrogen receptors subtype alpha, progesterone receptors, and IGF-1 receptors create a potent set-up for breast cancer growth. Lifestyle factors that predispose women to this scenario include obesity, insulin resistance, and impaired hormone metabolism; that is, single nucleotide polymorphisms in cytochrome P enzymes such as cyp1B1, cyp3A4, and catechol-O-methyltransferase (COMT). These predispositions become important components of prevention.
Diagnosis
In its early stages, breast cancer is typically not painful; the first symptom may be an obvious lump in the breast tissue. The presence of a lump is typically noticed before any additional symptoms occur; however, some breast tumors develop in areas of the breast that cannot be felt. As breast tumors enlarge, symptoms can include breast discharge, nipple inversion, dimpling of the skin of the breast, and fatigue. In later stages, possible symptoms include changes in the size, shape, or color of the breast, nipple, or skin surrounding the nipple, as well as discharge or bleeding. Breast tumors are typically detected by screening mammograms, breast self-examination, or an examination by a health-care practitioner.
Mammography increases the likelihood of early detection, In fact, the introduction of screening mammography in the US has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women.10 Over this same time period, the rate at which women present with advanced cancer has decreased by 8%, representing an absolute decrease of 8 cases per 100,000 women per year. Mammography has evoked considerable controversy as a screening tool due to the fact that its implementation has only marginally reduced the death rate from breast cancer. Because only approximately 6% of the additional early stage cancers that mammography detects are predicted to progress to advanced disease, the advent of widespread screening with mammography has lead to an estimated overdiagnosis of 1.3 million women in the US in the past 30 years, or approximately 70,000 women each year.11 As a result, there is much debate regarding if, when, and how often women should start getting regular mammograms. The current US guidelines for average risk women state that women should not start getting mammograms until they are 50 years old and then should continue to receive them every two years. Proposals to reduce the use of mammography have met with significant public defiance; thus, these guidelines remain in place, although not without scrutiny. Ultimately, the decision about when to begin screening mammograms is one that needs to be made by both the woman and her health-care provider based on individual risk factors and index of concern.
If cancer is suspected after mammography or palpation, more imaging tests, such as an ultrasound or breast MRI, will be done. Of note, breast thermography, which assesses temperature differentials in the tissue, can be considered as an adjunctive screening test. However, the body of evidence does not support the use of thermography as a stand-alone diagnostic tool, and in fact its use as such generates a high rate of false positives and false negatives.12 If the imaging is not conclusive, a patient may be a candidate for breast-specific gamma imaging (BSGI), a molecularly based scan useful in detecting ductal carcinoma in situ and lobular carcinoma. If cancer is still a concern after these imaging studies, the person should undergo a biopsy, the only definitive diagnostic method for breast cancer. Most patients will undergo a fine-needle biopsy to extract cells for analysis. Some patients will undergo a core needle biopsy, which removes more of the tissue. Pathological review of the removed tissue determines whether the tumor is ductal or lobular carcinoma. Infiltrating or invasive ductal cancer is the most common type of breast cancer, comprising 70% to 80% of all breast cancers. Additionally, the tumor will be evaluated for its grade of differentiation, proliferative activity, and status in regard to estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER-2neu). All of these factors have significant implications in terms of prognosis and treatment options.
Conventional Treatment
Conventional treatment for breast cancer relies heavily on surgery, often followed by radiation therapy. Chemotherapy and hormone therapy are used in cases of high-risk early-stage and metastatic breast cancer. Surgery is used in almost all cases, with the goal of removing all cancerous tissue and obtaining a clean surgical margin. Surgery encompasses lumpectomy and mastectomy, both of which are typically accompanied with removal of ipsilateral sentinel nodes. Sentinel lymph nodes are the first to receive drainage from the tumor and most likely to harbor metastatic disease. Some women opt for mastectomy or are advised to obtain this surgery due to the multifocal nature of their tumor, characteristics of their breast tissue or shape, or concerns with radiation therapy that accompanies lumpectomy. Mastectomy (removal of the breast) or modified radical mastectomy (removal of the breast and axillary lymph nodes) may avoid the recommendation for postsurgical radiation, but can increase the risk of lymphedema and may lead to additional surgery with breast reconstruction.
Local or regional breast cancer surgical specimens are often evaluated using the Oncotype DX test, a multigene assay test. The results of the Oncotype DX generate a score which predicts the probability of recurrence and therefore the predicted benefit derived from chemotherapy. Used in conjunction with the standard staging, grading, and tumor marker analyses, this assay may help determine the most appropriate treatment strategy. Presently, studies indicate that this assay is most appropriate for those with newly diagnosed stage I or II node-negative, estrogen receptor positive breast cancer, who will be treated with tamoxifen.
In cases of stage 0 breast cancer (carcinoma in situ) and tumors less than 1 centimeter in diameter, lumpectomy and close follow-up is one treatment choice. However, even in these early-stage breast cancers, local radiation treatment will typically be recommended in order to prevent local recurrence. In a study with 818 women, disease-free survival at eight years was 75% for those who underwent lumpectomy plus radiation therapy, versus 62% for those who underwent lumpectomy alone.13 However, radiation therapy does not lower the risk of recurrence in the opposite breast or elsewhere in the body.
Patients with stage I (local, not in the lymph nodes) through stage III (has spread to the regional lymph nodes) breast cancer require a multimodal approach to treatment. The treatment strategy is determined based on tumor characteristics, Oncotype DX results, and patient characteristics. Following surgery, likely additional treatments include:
- radiation therapy to the affected breast
- radiation therapy to the affected breast plus the lymph nodes and/or chest wall
- chemotherapy (typically includes cyclophosphamide and paclitaxel +/− doxorubicin). Note: Women with HER-2/neu-positive tumors will benefit from adriamycin, whereas women with HER-2/neu-negative tumors will not. Women under the age of 50 with node-positive, ER-positive, PR-positive, and HER-2/neu-positive tumors obtain the most benefit from chemotherapy.
- hormonal therapy (selective estrogen receptor modulator [SERM], typically tamoxifen, for premenopausal women or an aromatase inhibitor [AI] for postmenopausal women). The expected survival benefit from hormonal therapy (SERM or AI) can be estimated for each patient. An individual's absolute risk reduction can range from significant to minor and this expected benefit should be weighed against the experienced adverse effects of the medication.
Women with metastatic breast cancer will usually receive chemotherapy along with hormonal therapy and trastuzumab (Herceptin) if their tumor is HER-2/neu-positive (about 25% of breast cancers). There are several chemotherapy agents used for metastatic breast cancer, including doxorubicin, cyclophosphamide, fluorouracil, methotrexate, epirubicin, carboplatin, paclitaxel, and docetaxel. Adverse toxicity from chemotherapy is expected, and integrative management of these symptoms is important.
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