What are the treatment options for a patient with stage 4 (metastatic) breast cancer?

Treatment of Stage 4 Breast Cancer

Stage 4 (metastatic) breast cancer is incurable but treatable, with systemic therapy—not surgery—as the primary treatment approach, tailored to tumor subtype (hormone receptor status, HER2 status, and triple-negative classification) to prolong survival and maintain quality of life. 1, 2

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following:

• Core biopsy of a metastatic lesion (if easily accessible) to confirm diagnosis and reassess biological markers including estrogen receptor (ER), progesterone receptor (PR), and HER2 status, as receptor status may change from the primary tumor 1, 2
• Comprehensive staging workup including history, physical examination, laboratory tests, and imaging of chest, abdomen, and bone (preferably CT scans or PET-CT if available) 2
• Brain imaging is NOT routinely recommended in asymptomatic patients, even with HER2-positive or triple-negative disease 2
• Genetic testing for BRCA1/2 mutations should be offered to all patients being considered for PARP inhibitor therapy, regardless of age, family history, or breast cancer subtype 1

Treatment Goals and General Principles

The primary objectives are:

• Palliating symptoms, prolonging survival, and maintaining or improving quality of life—not cure 2, 3
• Sequential single-agent chemotherapy is generally preferred over combination chemotherapy to minimize toxicity while maintaining efficacy, unless rapid symptom control is needed for life-threatening visceral metastases 2
• Early introduction of expert palliative care, including effective pain control, should be a priority from the outset 1

Treatment by Molecular Subtype

Hormone Receptor-Positive, HER2-Negative Disease (70% of patients)

Endocrine therapy is the preferred first-line treatment unless there is documented endocrine resistance, rapidly progressive disease requiring urgent response, or life-threatening visceral crisis 2, 4

First-line options:

• Aromatase inhibitor (AI) plus CDK4/6 inhibitor (preferred combination with demonstrated improved progression-free survival) 4
• Premenopausal women require ovarian suppression/ablation (LHRH agonist or orchidectomy) before being treated with AI-based regimens 4

Second-line options (after progression on or within 12 months of completing adjuvant endocrine therapy):

• Fulvestrant plus CDK4/6 inhibitor 4
• Fulvestrant plus alpelisib (for PIK3CA-mutated tumors) 4
• Everolimus combined with AI 4
• Endocrine monotherapy (fulvestrant, AI, or selective estrogen receptor modulator) 4

HER2-Positive Disease (15-20% of patients)

HER2-targeted therapy combined with chemotherapy is the standard approach for HER2-positive, hormone receptor-negative disease 4

First-line treatment:

• Pertuzumab plus trastuzumab plus docetaxel (median progression-free survival 18.5 months with 34% reduction in death risk) 4

For HER2-positive, hormone receptor-positive disease:

• HER2-targeted therapy plus chemotherapy, OR
• HER2-targeted therapy plus endocrine therapy (trastuzumab or lapatinib with AI has shown progression-free survival advantage over AI alone) 4

Critical principle: Continue HER2-targeted therapy even after progression, as sequential HER2-targeted therapies remain beneficial 4, 5

Triple-Negative Breast Cancer (15% of patients)

Chemotherapy is the primary systemic treatment, with anthracycline and taxane-based regimens recommended as initial therapy 2, 4

Chemotherapy sequencing:

• For patients not previously exposed to anthracyclines or taxanes, these are first-line options 2
• For patients previously treated with anthracyclines and taxanes, options include capecitabine, vinorelbine, or eribulin 2
• Sequential monotherapy is preferred over combination chemotherapy to minimize toxicity 2

Site-Specific Management

Bone Metastases

All patients with bone metastases should receive bone-modifying agents (BMAs) regardless of symptoms 1

BMA options:

• Denosumab 120 mg subcutaneously every 4 weeks (more effective than zoledronate in delaying first and subsequent skeletal-related events) 1
• Zoledronate 4 mg IV can be administered every 12 weeks in patients with stable disease after 3-6 monthly treatments 1

Before initiating BMAs:

• Complete dental evaluation and complete any required dental treatment 1
• Prescribe calcium and vitamin D supplements 1
• Optimal duration is undefined, but reasonable to interrupt therapy after 2 years for patients in remission 1

For symptomatic bone lesions:

• Single 8-Gy radiation fraction is as effective as fractionated schemes for uncomplicated bone metastases 1
• Orthopedic evaluation for significant lesions in long bones or vertebrae 1

Primary Tumor Management in Stage IV Disease

Locoregional treatment of the primary tumor does NOT lead to overall survival benefit and is not routinely recommended in the absence of symptomatic local disease 1

Surgery of the primary tumor may be considered only for:

• Patients with bone-only metastasis 1
• HR-positive, HER2-negative tumors 1
• Patients <55 years 1
• Patients with oligometastatic disease 1
• Those with good response to initial systemic therapy 1
• Palliation of local symptoms (bleeding, ulceration, pain) 5

Oligometastatic Disease

Multimodality treatment approaches involving local-regional therapy (high conformal radiotherapy, image-guided ablation, or surgery) combined with systemic treatments are recommended after multidisciplinary discussion 1

Document tumor response with systemic treatment before suggesting local-regional therapy 1

Monitoring and Treatment Adjustment

Evaluation schedule:

• Every 2-4 months for endocrine therapy 2, 4
• After 2-4 cycles for chemotherapy 2, 4
• Tumor markers may aid in evaluating response, particularly in patients with non-measurable disease, but do NOT rely on tumor markers alone to initiate treatment changes 2, 4

Critical Pitfalls to Avoid

• Do NOT withhold effective therapy based solely on patient age 2
• Do NOT perform surgery solely for local control without considering systemic disease burden and patient prognosis—surgery in stage IV disease is palliative only and should not delay systemic therapy 2, 5
• Do NOT use combination chemotherapy routinely—sequential single agents are preferred unless rapid response is needed for visceral crisis 2
• Do NOT discontinue HER2-targeted therapy at first progression in HER2-positive disease—continue through multiple lines 4, 5
• Avoid invasive dental procedures during treatment with bone-modifying agents due to osteonecrosis of the jaw risk 5

Special Populations and Considerations

For patients with BRCA1/2 germline mutations:

• PARP inhibitors are treatment options and should be offered regardless of prior platinum exposure 1
• Genetic testing should be performed before offering PARP inhibitor therapy 1

For heavily pretreated HR-positive, HER2-negative disease:

• Single-agent abemaciclib (median progression-free survival 6 months, median overall survival 22.3 months) 4
• Later-line options include megestrol acetate, estradiol, or androgens 4