Breast cancer is the most common nondermatological malignancy diagnosed in women, although it can be treatable and survivable when caught early. Between 20 and 30 percent of early-stage breast cancer becomes metastatic or stage IV, the most aggressive and devastating form of breast cancer, often missed until it becomes difficult to control. Awareness of metastatic breast cancer among patients and clinicians alike can help drive better outcomes. Understanding the factors that contribute to why it goes undetected, as well as current trends in treatment and potential therapy, may help inform better clinical decision-making.
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Metastatic breast cancer is not readily apparent because it lacks unique symptomology. Symptoms may be subtle or nonspecific, making it easily mistaken for other conditions. Patients frequently report symptoms such as generalized fatigue, back or joint pain, bloating and loss of appetite. When a patient presents with fatigue, for example, it can be challenging to obtain imaging that is comprehensive enough to reliably intercept potential metastasis sites.
The risk of missing metastasis is further compounded by the likelihood of one or more radiographic errors. Any known lesions may be wrongly marked as stable if they are slow growing, while satisfaction of reporting may hinder the type of further scrutiny that might detect metastasis sites.
Common sites of breast cancer metastasis include the lungs, bones, liver and brain. By far, the most common location for a primary tumor to spread is the bones, with more than half of patients with stage IV breast cancer having this type of metastasis. The nonspecific nature of symptoms associated with bone metastases, combined with the size and complexity of the skeletal system, increases the likelihood of physicians missing this type of metastasis. For example, it may be easily confused with arthritis pain or overexertion from exercise.
Alongside the use of diagnostic imaging to detect breast cancer metastasis, clinical researchers seek to leverage biomarkers to assess risk and even predict responsiveness to therapeutics. One well-characterized potential target is the ERBB2 gene that encodes HER2, a surface receptor protein and member of the epidermal growth factor (EGF) receptor family. HER2 overexpression occurs in about one-fifth of all breast cancers, although it is not present in all cases of metastatic breast cancer or even all types of breast cancer. HER2-positive tumors do correlate with a more aggressive phenotype, but the good news is that targeting this surface protein is selective and has shown clinical success.
A recent JAMA Oncology review noted that instead of focusing exclusively on ERBB2-positivity as a binary outcome, ERBB2-low breast cancer should also be considered due to its differential responsiveness to anti-ERBB2 therapies. Further testing and characterization are warranted before any clinically relevant recommendations may be made.
Seven genes have been found to be mutated in metastatic breast cancer but not primary breast cancer: MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2 and ESR1. Each gene is implicated in different cellular signaling pathways, with possible roles in conferring treatment resistance. Again, further study is needed before these genes can be named as effective therapeutic targets.
With primary breast cancers, the focus is on working to cure the malignancy. With metastatic breast cancer, which has no cure, the aim is controlling the growth of any lesions and further spread in the body. This shift in clinical mindset may prove challenging for patients and their families.
A primary goal is to maximize patient quality of life. This may include treatments targeted for specific parts of the body (surgery and radiation) or systemic therapy (chemotherapy, hormonal therapy, immunotherapy and more). Clinicians should work with their patients to weigh the potential benefits of aggressive therapeutic efforts against factors such as survival, functional status and cost of care. Early discussion of palliative care options has been shown to enhance quality of care outcomes in patients with metastatic or terminal cancer.
Knowing that metastatic breast cancer drives the highest percentage of breast cancer–related deaths, and that the five-year survival rate for women with metastatic breast cancer is 29 percent, awareness and caution may help drive earlier diagnoses and interventions to maximize patient quality of life and extend survival.
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