Metastatic Breast Cancer

Background

• Metastatic breast cancer is breast cancer that has spread beyond the breast and regional lymph nodes to other organs (most often bones, lungs, liver, or brain) and refers to either breast cancer with metastasis at the time of initial diagnosis, often called de novo stage IV breast cancer, or to a metastatic recurrence.
• Metastatic disease is present in about 6% of women at the time of breast cancer diagnosis in the United States, although greater incidence is reported in Black women. Beyond race, risk factors for metastatic disease include primary cancer advanced stage, tumor subtype, size, and grade.
• Clinical presentation of metastatic disease may be with generalized symptoms such as weight loss and fatigue or symptoms may be specific to the site of metastases such as headache or vision changes with brain metastases, bone pain or fractures with bone disease, shortness of breath or cough with lung metastases, and abdominal pain or nausea with liver metastases.
• Metastatic breast cancer is considered incurable with currently available therapies. The goals of therapy include prolonging survival and maintaining quality of life. Estimated survival varies based on tumor subtype, site of metastases, race, age, and tumor grade.

Evaluation

• Perform an assessment for treatment planning including a history and physical exam, blood tests such as a complete blood count and comprehensive metabolic panel, and imaging to assess for the extent of metastatic disease (Strong recommendation).
• Biopsy the metastatic site, if possible, and determine hormone receptor (HR) status and human epidermal growth factor 2 (HER2) status (Weak recommendation).
• Assess the status of biomarkers that predict benefit from specific therapies, such as germline BRCA1/2 mutations, programmed cell death ligand 1 (PD-L1) expression in HR negative/HER2 negative disease, PIK3CA mutation if HR positive/HER2 negative disease (Strong recommendation), neurotrophic receptor tyrosine kinase (NTRK) fusion mutation, and microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as appropriate if targeted therapies available (Weak recommendation).

Management

• Consider for all patients with metastatic breast cancer enrollment in a clinical trial (Weak recommendation).
• Palliative and supportive care should be offered to all patients throughout the course of metastatic disease (Strong recommendation).
• Treatment typically involves systemic therapy with endocrine therapy, chemotherapy, and/or targeted/biologic therapy based on HR status, HER2 status, BRCA1/2 mutation status, programmed cell death ligand 1 (PD-L1) status, the status of other biomarkers, comorbidities, and the severity of disease.
  • For HR positive, HER2 negative breast cancer:
    • Offer endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor for first-line therapy unless there is a visceral crisis (Strong recommendation) Offer ovarian ablation or suppression in addition to endocrine therapy for premenopausal women (Strong recommendation) May consider a selective estrogen receptor modulator without ovarian suppression or ablation in select women who have not been on endocrine therapy for a year (Weak recommendation). If there is a visceral crisis, consider chemotherapy or targeted therapy for first-line therapy (Weak recommendation).
    • Continue therapy until disease progression or intolerable toxicity (Strong recommendation) then, weighing benefits and harms, consider a different line of endocrine therapy, targeted therapy, and/or chemotherapy while continuing supportive care (Weak recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
    • May consider single-agent poly adenosine diphosphate ribose polymerase (PARP) inhibitors for patients with a germline BRCA1/2 mutation after progression on endocrine therapy plus CDK4/6 inhibitor (Weak recommendation).
  • For HR positive, HER2 positive breast cancer:
    • Offer chemotherapy plus HER2 targeted therapy (Strong recommendation). May consider endocrine therapy plus HER2 targeted therapy for maintenance therapy following completion of chemotherapy and continued until progression or unacceptable toxicity (Weak recommendation). In select patients, may consider endocrine therapy, with ovarian suppression or ablation for premenopausal women, with or without HER2 targeted therapy as first-line therapy (Weak recommendation). For select premenopausal women, may consider a selective estrogen receptor modulator (SERM) plus HER2 targeted therapy without ovarian ablation or suppression (Weak recommendation).
    • Continue therapy until progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, offer a different line of chemotherapy plus HER2 targeted therapy, other HER2 targeted therapy, or endocrine therapy with or without HER2 targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
  • For HR negative, HER2 positive breast cancer:
    • Offer chemotherapy plus HER2 targeted therapy (Strong recommendation).
    • Therapy should be continued until progression or intolerable toxicity (Strong recommendation) then, weighing benefits and harms, offer a different line of chemotherapy plus HER2 targeted therapy, other HER2 targeted therapy, or other targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
    • May consider single-agent poly adenosine diphosphate ribose polymerase (PARP) inhibitors for patients with a germline BRCA1/2 mutation, although they are not FDA-approved for HER2 positive breast cancer (Weak recommendation).
  • For HR negative, HER2 negative (triple-negative) breast cancer:
    • Offer chemotherapy and/or targeted therapy (Strong recommendation) until progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, offer a different line of chemotherapy and/or targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
• For metastasis to bone:
  • Offer systemic therapy, including endocrine therapy, chemotherapy, and/or targeted or biologic therapies based on menopausal status, biomarkers, prior therapies used, the burden of metastatic disease, and balance of toxicities (Strong recommendation)
  • Offer bone-modifying agents such as bisphosphonates or denosumab, with calcium and vitamin D supplement, for all patients with bone metastases (Strong recommendation).
  • Consider surgery for patients at high risk for developing a fracture or spinal cord compression (Weak recommendation).
  • Offer radiation therapy for palliation of pain or as therapy for impending fracture or spinal cord compression (Strong recommendation) may consider radiation therapy for potential definitive therapy of bone oligometastases (Weak recommendation).
• For metastasis to the brain, a multimodal treatment approach is based on performance status, prognosis, number, size, and location of brain metastases.
  • Consider steroids for patients who are symptomatic due to brain metastases or spinal cord compression (Weak recommendation). Do not offer routine prophylactic antiseizure medications (Strong recommendation), although they may be considered perioperatively (Weak recommendation).
  • For single metastasis in a patient with a good prognosis (survival ≥ 3 months), consider any of the following options:
    • Surgical resection alone (Weak recommendation) or followed by stereotactic radiosurgery (SRS) (Weak recommendation) or whole-brain radiation therapy (WBRT) (Weak recommendation)
    • For metastases ≤ 3-4 cm in size, SRS alone (Weak recommendation) or followed by WBRT (however, the addition of WBRT is discouraged as it is associated with increased neurocognitive deficits with no benefit in survival) (Weak recommendation).
  • For multiple metastases with no mass effect in a patient with a good prognosis (survival ≥ 3 months), consider any of the following options:
    • surgical resection (Weak recommendation) followed by SRS (preferred if limited metastasis defined as size and extent controlled equally by SRS or WBRT) or WBRT (however, the addition of WBRT is generally not recommended as it is associated with increased neurocognitive deficits with no benefit in survival) (Weak recommendation)
    • for limited metastases ≤ 3-4 cm in size, SRS alone (Weak recommendation) or followed by WBRT (however, the addition of WBRT if all brain sites are completely treated by SRS is generally not recommended as it is associated with increased neurocognitive deficits with no benefit in survival) (Weak recommendation), or WBRT alone (Weak recommendation)
    • for select patients with extensive small asymptomatic metastases, systemic therapy alone with good CNS penetration (Weak recommendation).
  • For multiple metastases with mass effect in a patient with a good prognosis (survival ≥ 3 months), consider the following options: surgical resection of the metastasis causing the mass effect or symptoms followed by WBRT, SRS, or systemic therapy (Weak recommendation), or radiation therapy alone (SRS in select patients with low overall tumor volume or WBRT) (Weak recommendation)
  • For patients with a poor prognosis, consider the following options: WBRT (Weak recommendation), SRS in select patients with limited brain metastases (Weak recommendation), or palliative and supportive care only (Weak recommendation)
  • For leptomeningeal metastases, the choice of treatment options includes systemic therapy, intra-cerebrospinal fluid (CSF) therapy (intrathecal therapy), radiation therapy, and supportive care. Treatment decisions should be based on prognostic evaluation and multidisciplinary discussion.
    • For patients with a good risk status such as those with a Karnofsky Performance Status (KPS) ≥ 60, with no major neurologic deficits, and minimal systemic disease with reasonable systemic treatments consider the following options:
      • systemic chemotherapy with CNS penetration (Weak recommendation).
      • intra-CSF chemotherapy or targeted therapy in select patients with unobstructed CSF flow; however, this carries the risk of significant toxicity (Weak recommendation). Intra-CSF regimen options include methotrexate for any subtype or trastuzumab for HER2 positive breast cancer (Weak recommendation). The addition of intrathecal therapy to systemic therapy with CNS penetration does not improve overall survival, quality of life, or clinical meaningful CSF progression (Weak recommendation).
      • SRS or WBRT and/or involved-field radiation therapy to bulky areas of disease and neurologically symptomatic sites (for example cranial neuropathies or painful sites) (Weak recommendation).
    • For patients with poor-risk status such as those with KPS < 60, multiple major neurologic deficits, extensive systemic disease with few treatment options, bulky CNS disease or encephalopathy, offer palliative or best supportive care (Weak recommendation). Consider palliative involved-field radiation therapy to neurologically symptomatic or painful sites (including spine and intracranial disease) (Weak recommendation).
• Surveillance includes periodic assessment of symptoms, physical exam findings, laboratory tests, imaging studies, and blood biomarkers where appropriate (Strong recommendation). The optimal frequency of testing is unknown, but generally consider every 2-4 months for endocrine therapy and every 2-3 cycles for chemotherapy (Weak recommendation). For patients with brain metastases, consider following with brain MRI every 2-3 months for 1-2 years, and then every 4-6 months thereafter (Weak recommendation).