What are the recommended adjuvant therapies for stage 4 breast cancer?

Recommended Adjuvant Therapies for Stage 4 Breast Cancer

For patients with stage 4 breast cancer, the recommended adjuvant therapy should include endocrine therapy with targeted agents for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, and chemotherapy for triple-negative or rapidly progressing disease. 1

Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

First-Line Therapy

• For women with HR-positive, HER2-negative metastatic breast cancer with no visceral crisis, endocrine therapy alone or in combination with targeted agents is the preferred initial approach 1
• Aromatase inhibitors (AIs) in combination with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival compared to AI alone and should be considered as first-line therapy 1
• Premenopausal women should receive adequate ovarian suppression/ablation and then be treated similarly to postmenopausal women 1

Second-Line and Subsequent Therapy

• Patients who progress on or within 12 months of completing adjuvant endocrine therapy are eligible for second-line endocrine therapy either as monotherapy or in combination with a targeted agent 1
• Options include:
  • Fulvestrant with a CDK4/6 inhibitor (category 1 recommendation) 1
  • For tumors with PIK3CA mutations, fulvestrant with alpelisib 1
  • Everolimus combined with an AI, tamoxifen, or fulvestrant 1
  • Monotherapy with fulvestrant, nonsteroidal or steroidal AI, or selective estrogen receptor modulator (SERM) 1

Bone-Targeted Therapy

• For patients with bone metastases, bisphosphonates or denosumab should be added to systemic therapy 1
• Recommended agents include:
  • Pamidronate 90 mg IV over 2 hours or zoledronic acid 4 mg IV over 15 minutes 1
  • Denosumab 120 mg subcutaneously every 4 weeks (shown to significantly delay time to first skeletal-related event compared to zoledronic acid) 1
• Monitor serum creatinine before each dose and adjust or discontinue if renal function is reduced 1

HER2-Positive Metastatic Breast Cancer

HER2-Positive, HR-Positive Disease

• Options include HER2-targeted therapy plus chemotherapy or endocrine therapy in combination with HER2-targeted therapy 1
• Adding trastuzumab or lapatinib to an AI has demonstrated progression-free survival advantage compared with AI alone 1
• Premenopausal women treated with HER2-targeted therapy and endocrine therapy should receive ovarian suppression or ablation 1

HER2-Positive, HR-Negative Disease

• HER2-targeted therapy in combination with chemotherapy is the standard approach 1
• For patients with brain metastases, neratinib plus capecitabine has shown efficacy and is a treatment option 1

Triple-Negative Breast Cancer

• Chemotherapy remains the primary systemic treatment option 1
• Anthracycline and taxane-based chemotherapy is recommended as initial treatment for triple-negative locally advanced breast cancer 1
• Common regimens include:
  • Docetaxel 75-100 mg/m² IV every 3 weeks 2
  • Paclitaxel 175 mg/m² IV over 3 hours every 3 weeks 3

Special Considerations

Locally Advanced Breast Cancer (LABC)

• A combined treatment modality based on a multidisciplinary approach (systemic therapy, surgery, and radiotherapy) is strongly indicated 1
• For triple-negative LABC, anthracycline and taxane-based chemotherapy is recommended as initial treatment 1
• For HER2-positive LABC, concurrent taxane and anti-HER2 therapy is recommended 1

Extended Adjuvant Therapy

• Many women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine treatment 1
• Extended therapy carries ongoing risks and side effects, which should be weighed against potential benefits 1

Treatment Algorithm Based on Subtype and Disease Burden

1. Assess hormone receptor and HER2 status
2. Evaluate disease burden and presence of visceral crisis
3. Select therapy based on subtype:
   • HR+/HER2-: Endocrine therapy with targeted agents (CDK4/6 inhibitors, mTOR inhibitors, or PI3K inhibitors)
   • HR+/HER2+: HER2-targeted therapy with either endocrine therapy or chemotherapy
   • HR-/HER2+: HER2-targeted therapy with chemotherapy
   • Triple-negative: Chemotherapy (anthracycline and taxane-based)
4. For bone metastases: Add bisphosphonate or denosumab
5. Monitor response every 2-3 months for endocrine therapy or after 2-3 cycles of chemotherapy
6. Upon progression, switch to next line of therapy

Common Pitfalls and Caveats

• Avoid using aromatase inhibitors alone in premenopausal patients without ovarian suppression as there is no evidence of efficacy 1
• Monitor bone mineral density in patients on aromatase inhibitors as they increase risk of osteoporosis and fractures 1
• Regular cardiac monitoring is essential for patients receiving trastuzumab due to potential cardiotoxicity 1
• Renal function should be monitored before each dose of bisphosphonates to prevent renal toxicity 1
• Extended use of aromatase inhibitors beyond 5 years should be carefully considered as benefits must be weighed against ongoing side effects 1