Metastatic Pathophysiology of Breast Cancer
Molecular Mechanisms of Metastasis
Breast cancer metastasis occurs through a molecular selection process where tumor cells acquire specific biological characteristics that enable them to survive in distant organs, with preferential spread to bone (51%), lung (17%), brain (16%), and liver (6%). 1, 2
The metastatic cascade involves:
Tumor heterogeneity and clonal selection: Primary breast tumors contain heterogeneous cell populations, and systemic therapy exerts selective pressure that allows resistant clones to survive and metastasize, resulting in more aggressive tumor biology in the metastatic setting compared to the original primary tumor 1
Organ-specific tropism: Different breast cancer subtypes exhibit distinct metastatic patterns—luminal tumors preferentially metastasize to bone, while basal-like breast cancer (triple-negative) shows lung tropism 3, 4
Microenvironment interactions: Metastatic breast cancer cells must successfully colonize the target organ by interacting with the local microenvironment, including establishing a pre-metastatic niche and evading immune surveillance 4
Diagnostic Confirmation and Biological Reassessment
At first diagnosis of metastatic disease, biopsy must be performed to confirm histology and reassess ER, PgR, and HER2 status, as receptor conversion occurs in up to 20-40% of cases due to clonal evolution. 1
Critical diagnostic steps include:
Avoid bone biopsies when possible due to technical limitations of biomarker detection in decalcified tissue; prioritize soft tissue or visceral metastases for biopsy 1
Complete staging work-up: CT chest and abdomen plus bone scintigraphy as minimum; 18F-FDG PET-CT may replace conventional imaging 1
Reassess therapeutically relevant biomarkers: germline BRCA1/2 in HER2-negative disease, PD-L1 in triple-negative disease, and PIK3CA mutations in ER-positive/HER2-negative disease 1
Treatment Approach Based on Receptor Status
Hormone Receptor-Positive/HER2-Negative Disease
For postmenopausal patients with hormone receptor-positive/HER2-negative metastatic breast cancer, initiate third-generation aromatase inhibitors (anastrozole, letrozole, or exemestane) as first-line therapy unless rapidly progressive visceral disease mandates immediate chemotherapy response. 1, 5
Premenopausal patients: Tamoxifen plus ovarian ablation (LHRH analogue, surgery, or radiation) if no prior adjuvant tamoxifen or discontinued >12 months; otherwise consider aromatase inhibitors with ovarian suppression 1, 5
Endocrine resistance: Switch to chemotherapy when evidence of endocrine resistance develops 1
ER-low tumors (1-9% positivity): May have limited sensitivity to endocrine therapy alone but can benefit from endocrine therapy plus CDK4/6 inhibitor combinations 1
HER2-Positive Disease
For HER2-positive metastatic breast cancer, administer trastuzumab combined with paclitaxel as first-line therapy, with initial loading dose of 4 mg/kg IV over 90 minutes followed by 2 mg/kg weekly, or 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks. 6
Critical management considerations:
Cardiac monitoring mandatory: Assess LVEF before initiation and at regular intervals during treatment; discontinue for clinically significant decrease in left ventricular function 6
Avoid anthracyclines with trastuzumab due to increased cardiotoxicity risk 7, 6
Single-agent trastuzumab: Indicated for patients who received ≥1 prior chemotherapy regimen for metastatic disease 6
Triple-Negative Breast Cancer
For triple-negative metastatic breast cancer, use chemotherapy with or without immune checkpoint inhibitors based on PD-L1 status, or consider antibody-drug conjugates as targeted therapy options. 1
Chemotherapy Selection
Sequential single-agent chemotherapy produces equivalent overall survival to combination regimens with significantly less toxicity and better quality of life, making it the preferred strategy for most patients. 7
Selection criteria:
Reserve combination chemotherapy for rapidly progressive visceral disease requiring immediate response 7
Base agent selection on tumor characteristics, prior treatment exposure, and patient-specific factors including performance status and comorbidities 5
Supportive and Local Therapies
Bisphosphonates are effective for hypercalcemia and palliate symptoms from lytic bone metastases; initiate at diagnosis of bone involvement. 1, 5
Radiation therapy: Integral component of palliative treatment for bone metastases, brain metastases, and symptomatic soft tissue masses 7, 5
Surgical resection of oligometastatic disease: Consider for solitary or limited metastatic lesions (1-10% of newly diagnosed metastatic patients), particularly with long disease-free interval, as this subset may achieve prolonged survival with aggressive multidisciplinary approach 1
Receptor Discordance Management
When ER/PgR or HER2 status differs between primary tumor and metastatic site, use endocrine therapy or anti-HER2 therapy if receptors are positive in at least one biopsy, regardless of timing. 1
Decision-making factors:
Consider baseline biological features, degree of biomarker heterogeneity, prior treatments that may have selected resistant clones, and disease burden 1
Multidisciplinary tumor board discussion required for all cases with receptor discordance 1
Re-biopsy may be appropriate in cases of mixed response to account for evolving tumor heterogeneity 1
Prognostic Factors
The most favorable prognosis occurs with: long disease-free interval (>1-2 years), limited metastatic sites without bulky disease, absence of visceral involvement, and positive hormone receptor status 1, 8, 5. Liver metastasis carries the worst prognosis with median survival of only 1 month, compared to 12 months for bone and lung lesions, and 3 months for brain metastases 2.