Metastatic breast cancer (MBC), also referred to as Stage IV, is breast cancer that has spread beyond the breast and nearby lymph nodes to distant parts of the body. The goal of treatment for MBC is generally not curative, but to control the disease for as long as possible, manage symptoms, and maintain the best possible quality of life. Recent advancements in targeted therapies and immunotherapy have transformed the landscape of MBC care, offering more personalized and effective treatment options.
Classifying Metastatic Breast Cancer for Treatment
The determination of MBC treatment begins by classifying the tumor based on specific biological markers. This classification relies on testing cancer cells for the presence or absence of three receptors: the Estrogen Receptor (ER), the Progesterone Receptor (PR), and the Human Epidermal Growth Factor Receptor 2 (HER2). The combination of these results dictates the treatment pathway. If a tumor tests positive for ER and PR, it is Hormone Receptor-Positive (HR+), and treatment focuses on blocking hormone pathways. Overexpression of the HER2 protein classifies the tumor as HER2-Positive, allowing for specific anti-HER2 drugs. When all three markers are negative, the tumor is Triple-Negative Breast Cancer (TNBC), requiring different therapeutic approaches.
Targeted Treatments for Hormone Receptor Positive Disease
HR+ MBC is the most common subtype, and its treatment has been revolutionized by the advent of targeted agents combined with endocrine therapy. Endocrine therapy, such as aromatase inhibitors or the estrogen receptor antagonist fulvestrant, blocks the effects of estrogen, which fuels cancer cell growth. The standard of care pairs these hormone blockers with Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitors.
CDK4/6 inhibitors (e.g., palbociclib, ribociclib, and abemaciclib) are the preferred first-line treatment because they interrupt the cancer cell cycle progression. By inhibiting the CDK4 and CDK6 proteins, these drugs prevent cell division, greatly enhancing the effectiveness of the accompanying endocrine therapy. This combination improves the time patients live without their disease progressing.
When resistance develops, molecular testing for specific mutations opens further targeted options. The PIK3CA gene is frequently mutated in HR+ breast cancer, driving endocrine resistance. For patients with this genetic change, PIK3CA inhibitors like alpelisib or inavolisib are approved in combination with endocrine therapy. For instance, adding inavolisib to palbociclib and fulvestrant has prolonged progression-free survival in patients with the PIK3CA mutation.
Advances in HER2 Positive Treatment
The treatment of HER2-Positive MBC has undergone a transformation from being an aggressive disease to one that is highly treatable due to potent targeted therapies. The foundation of treatment remains monoclonal antibodies like trastuzumab and pertuzumab, which directly target and block the HER2 receptor. The major recent advance is the development and use of next-generation Antibody-Drug Conjugates (ADCs).
An ADC uses a monoclonal antibody to deliver a potent payload of chemotherapy directly to the cancer cell. Trastuzumab deruxtecan (T-DXd) has shown effectiveness, especially in patients whose disease has progressed after initial HER2-targeted therapy. T-DXd links an anti-HER2 antibody to a powerful topoisomerase I inhibitor drug via a cleavable linker, allowing the drug to be released inside the cancer cell.
T-DXd significantly extends progression-free survival compared to older ADCs. It has also expanded treatable breast cancer to include HER2-Low tumors, which previously lacked targeted options. Tyrosine Kinase Inhibitors (TKIs), small molecules that can cross the blood-brain barrier, are important for managing disease spread to the brain.
Immunotherapy and Novel Approaches for Triple Negative Cancer
Triple-Negative Breast Cancer (TNBC) is an aggressive subtype that lacks the three common receptors. Historically, treatment relied solely on chemotherapy. Recent strategies focus on harnessing the patient’s own immune system. Immunotherapy, using PD-L1 checkpoint inhibitors like pembrolizumab, is now a standard treatment for metastatic TNBC.
These inhibitors block the PD-1/PD-L1 pathway, which cancer cells use to evade the immune system, thereby activating the immune response. This therapy requires testing the tumor for the PD-L1 protein, as it is effective for PD-L1-positive tumors. Immunotherapy is typically given in combination with chemotherapy as a first-line treatment.
PARP inhibitors, such as olaparib or talazoparib, are available for patients who have a specific genetic mutation. These drugs are an option for TNBC patients carrying a germline BRCA1 or BRCA2 mutation, which impairs DNA repair. The PARP inhibitor blocks a secondary DNA repair mechanism, leading to cancer cell death due to unrepaired damage. Furthermore, the Antibody-Drug Conjugate sacituzumab govitecan has demonstrated efficacy in pretreated metastatic TNBC, delivering chemotherapy to cancer cells that express the Trop-2 protein.
The Role of Palliative and Supportive Care
Modern management of metastatic breast cancer integrates palliative and supportive care alongside systemic anti-cancer treatments. Palliative care is specialized medical care focused on providing relief from the symptoms and stress of a serious illness, aiming to improve quality of life for the patient and their family. This care can be provided at any stage of the illness while a patient is receiving active treatment.
The palliative care team, which may include doctors, nurses, and social workers, addresses pain, fatigue, anxiety, and difficulty sleeping caused by the disease or its treatment. Management of bone metastases often involves the use of bisphosphonates or denosumab to reduce the risk of fractures and ease bone pain, sometimes combined with targeted radiation therapy. Psychosocial and spiritual support helps patients and their families cope with the emotional distress and uncertainty accompanying the diagnosis.