Figure 2 Histopathology of invasive ductal carcinoma of breast
Source: Medscape.
With ER positive or PR positive breast cancer, hormone-blocking medications, such as tamoxifen, may be an option to slow the cancer’s growth. HR negative cancers do not respond to hormone-based therapy.
Breast Cancer and Stem Cells
Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until then, they are protected from cell suicide by several protein clusters and pathways. One of the protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently “on,” rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that cause cancer in combination with other mutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the “on” position, and the cancer cell does not commit suicide. Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.
Failure of immune surveillance, the removal of malignant cells throughout one’s life by the immune system
Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.
In the United States, 10–20% of patients with breast cancer and patients with ovarian cancer have a first- or second-degree relative with one of these diseases. The familial tendency to develop these cancers is called hereditary breast–ovarian cancer syndrome. The best known of these are the BRCA mutations. Some mutations associated with cancer, such as p53, BRCA1, and BRCA2, occur in mechanisms to correct errors in DNA. These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs. However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families. This is caused by unobserved risk factors. This implicates environmental and other causes as triggers for breast cancers. The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA double strand breaks. These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2. However, mutations in BRCA genes account for only 2–3% of all breast cancers. Levin et al. say that cancer may not be inevitable for all carriers of BRCA1 and BRCA2 mutations. About half of hereditary breast–ovarian cancer syndromes involve unknown genes.
GATA-3 directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.
Most breast cancers that arise in the setting of a germline mutation in BRCA1 are triple negative (i.e., they do not express any hormonal receptors like estrogen, progesterone, or HER2/neu receptors, hence triple negative). Patients with triple-negative breast cancer that is diagnosed at 60 years or younger undergo BRCA mutation testing regardless of family history. Some genetic susceptibility may play a minor role in most cases. Overall, however, genetics is believed to be the primary cause of 5–10% of all cases. In those with zero, one, or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1%, with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6%, respectively. In those with a first-degree relative with the disease, the risk of breast cancer between the ages of 40 and 50 is double that of the general population.
In less than 5% of cases, genetics plays a more significant role by causing a hereditary breast–ovarian cancer syndrome; this includes those who carry the BRCA1 and BRCA2 gene mutation. These mutations account for up to 90% of the total genetic influence, with a risk of breast cancer of 60–80% in those affected. Other significant mutations include p53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), STK11 (Peutz–Jeghers syndrome), CHEK2, ATM, BRIP1, and PALB2.
Because of the role of BRCA1 in DNA damage response and cell cycle checkpoint control, it is believed that BRCA1-associated breast cancer will be sensitive to certain DNA-damaging agents, such as platinum agents (carboplatin or cisplatin). In one clinical trial of BRCA1 mutation carriers presented at the 2011 Annual Conference of Hereditary Cancers, 67 women with stage I to III breast cancer were treated with cisplatin for four cycles prior as neoadjuvant treatment; the pathologic complete response was 67%. However, survival results were not presented. While these results support the sensitivity of BRCA1-associated cancer to platinum salts, they must be considered hypothesis generating. More compelling evidence supports a role for poly ADP ribose polymerase (PARP) inhibition in BRCA1/2 carriers.
Sporadic (nonfamilial) triple-negative breast cancer
In spite of the concept of “BRCAness” described above, the data do not support that sporadic triple-negative breast cancers have a higher degree of sensitivity to platinum agents than other breast cancer subtypes. In addition, there are no data that demonstrate improved survival outcomes when platinum agents are used (as a single agent or in combination) over other standard treatment. Women may reduce their risk of breast cancer by maintaining a healthy weight, drinking less alcohol, being physically active, and breastfeeding their children. These modifications might prevent 38% of breast cancers in the United States. The benefits of moderate exercise, such as brisk walking, are seen at all age groups, including postmenopausal women. Marine omega-3 polyunsaturated fatty acids appear to reduce the risk.
Removal of both breasts before any cancer has been diagnosed or any suspicious lump or other lesion has appeared (a procedure known as prophylactic bilateral mastectomy) may be considered in people with BRCA1 and BRCA2 mutations, which are associated with a substantially heightened risk for an eventual diagnosis of breast cancer. BRCA testing is recommended in those with a high family risk after genetic counseling. It is not recommended routinely. This is because there are many different forms of changes in BRCA genes, ranging from harmless mutations to obviously dangerous frame shift mutations. The effect of most of identifiable changes in the genes is uncertain. Testing in an average-risk person is particularly likely to return one of these indeterminate, useless results.
The selective estrogen receptor modulators (such as tamoxifen) reduce the risk of breast cancer but increase the risk of thromboembolism and endometrial cancer. There is no overall change in the risk of death. They are thus not recommended for the prevention of breast cancer in women at average risk but may be offered for those at high risk. The benefit of breast cancer reduction continues for at least five years after stopping a course of treatment with these medications.
Statistics and Prognosis of Breast Cancer
Breast cancer is the most common cancer among American women, except for skin cancers. About 1 in 8 (12%) women in the United States will develop invasive breast cancer during their lifetime. The American Cancer Society estimates 232,670 new cases of invasive breast cancer will be diagnosed in women in the United States in 2014. About 62,570 new cases of carcinoma in situ (CIS) will be diagnosed (CIS is noninvasive and is the earliest form of breast cancer). About 40,000 women will die from breast cancer.
Breast Cancer and Novel Treatment Options
Epithelial
