Approach

The diagnostic approach for metastatic breast cancer (MBC) includes identification of risk factors, a full clinical history and physical examination, laboratory investigations, imaging studies, and assessment of tumour biomarker status (where feasible).

Identification of risk factors

Key risk factors for developing breast cancer include: female sex, age >50 years, family history of breast cancer or other cancers associated with hereditary breast cancer (e.g., ovarian, pancreatic, and prostate cancer), and family and/or personal history of a pathogenic variant in a breast cancer susceptibility gene.​[15]​​​[17]​​​​​​​​​​[18]​​​[19][20][21][26]​​​​​​​​​​​​​​​​​​

A careful family history should be taken, with particular attention to close blood relatives with breast cancer (especially with early onset breast cancer or male breast cancer), ovarian cancer, pancreatic cancer, or metastatic, high-risk, or very-high-risk prostate cancer. Genetic evaluation, including genetic counseling and germline testing, is recommended for women at high risk for hereditary breast cancer (e.g., based on personal and/or family history).​​​​​​​[19]

Risk factors for developing metastatic disease in the presence of breast cancer include tumour >5 cm in diameter, high number of positive axillary lymph nodes (e.g., >10), lymphovascular invasion, and high-risk gene signatures.​​​​​​​​​​​​​​[28][29][30][31][32][33][34]​​​[35]

Clinical examination

All patients should undergo a thorough history and physical examination. MBC presents heterogeneously. Patients may have synchronous loco-regional and metastatic disease, or the loco-regional disease may have been treated for cure, with metastases presenting at a later time.

Symptoms and signs suggestive of metastasis or recurrence depend upon the site of recurrence, and include bone pain, palpation of a mass after treatment of the primary tumour, pleural effusion, shortness of breath, non-productive cough (which may occur in lymphangitic carcinomatosis), and neurological symptoms such as neuralgic pain, weakness, headaches, and seizures.[46][47]

Lack of appetite is a common general finding that may lead to weight loss. Anorexia may occur, typically in the terminal stage of disease.

Evaluation of patients suspected of having MBC

The work-up for patients suspected of having MBC includes the following:

  • Blood tests (full blood count [FBC], liver function tests [LFTs], and calcium)

  • Imaging studies

  • Biopsy of the metastatic lesion (if feasible and easily accessible)

  • Biomarker and germline testing

Blood tests can help to determine if a patient can tolerate chemotherapy or is a suitable candidate for another systemic therapy. They may occasionally help indicate sites of metastasis. For example, abnormal FBC and LFTs may indicate bone or liver metastasis. Elevated calcium (hypercalcaemia) may indicate bone metastasis.

Imaging studies

Required to detect metastatic lesions and for staging. Imaging should focus on the symptomatic areas.[26][27]​ Imaging studies used for initial metastatic work-up should be used for monitoring disease and assessing treatment response.[26]​​

Computed tomography (CT)

CT chest and abdomen should be ordered at baseline to detect lesions in the lungs and liver, respectively.[26][27]​​ CT chest may also detect pleural effusion.

The effusion may or may not be due to cancer, as these patients often develop comorbidities, including congestive heart failure, pneumonia, pulmonary embolism, and malnutrition, which can cause a pleural effusion to develop. Treatment depends on cause and, therefore, cytological assessment of the effusion is often performed to determine if malignant cells are present. However, a negative pleural cytology does not exclude a malignant pleural effusion.

Magnetic resonance imaging (MRI)

MRI is often preferred to CT for the detection of metastatic lesions in the brain, spinal cord, and specific areas in bone.[26][27][48]​​​​​ MRI of the brain and spinal cord should be carried out only if there are signs or symptoms suggesting central nervous system or spinal metastasis.[26][27]

Scintigraphy

A bone scan (scintigraphy) should be ordered at baseline and when patients develop bone pain or have abnormal blood tests (FBC, LFTs, calcium) suggesting bone metastasis.[27] Bone scans are sensitive for osteoblastic lesions.[49] Radiological findings are not helpful if there is a need to exclude primary bone tumour as a possible differential diagnoses, as lesions in both MBC and primary bone tumour can be osteolytic, osteoblastic, or mixed.[50]

Positron emission tomography (PET/CT scan)

Fluorodeoxyglucose-(FDG) PET/CT scan may be considered instead of a bone scan.[26][27]​​​​ FDG-PET/CT scan is sensitive for osteolytic lesions.[49]

FDG-PET/CT scan may be preferred to CT or MRI, or used in conjunction with these imaging modalities if their results are equivocal.[26][27]

Evaluation of ventricular function

Echocardiogram or multi-gated acquisition scan should be carried out if treatment with doxorubicin or trastuzumab is being considered. These drugs are potentially cardiotoxic.[51][52][53]​​​​​​

Biopsy

When technically feasible and easily accessible, biopsy of the metastatic lesion should be carried out to confirm the diagnosis (histologically) and to assess tumour biomarker status (e.g., hormone [oestrogen, progesterone] receptor status, and human epidermal growth factor receptor 2 [HER2] status), which can inform prognosis and guide treatment (e.g., endocrine therapy, HER2-targeted therapy).[26][27]​​[54][55]

Hormone receptor discordance between the primary tumour and the metastatic site may be considerable (10% to 30% for oestrogen receptor status and 20% to 50% for progesterone receptor status).[56] Also, oestrogen receptor status may change from positive to negative over time.

In the presence of discordance, it is preferable to treat according to the receptor status of the metastatic lesion, if supported by the clinical scenario and patient's goals for care.[57]

Additional biomarker and germline testing

​Testing for the following biomarkers may be considered to guide treatment:[26][27][57][58]​​​​

  • PIK3CA mutation (for phosphatidylinositol 3-kinase inhibitor therapy)

  • PD-L1 expression (for immune checkpoint inhibitor therapy)

  • ESR1 mutation (for selective oestrogen receptor modulator/degrader therapy)

Patients may undergo testing for the following biomarkers if treatment with an immune checkpoint inhibitor or tyrosine receptor kinase inhibitor is being considered:[26][27]​​[57]

  • dMMR/MSI (deficient mismatch repair/microsatellite instability; for immune checkpoint inhibitor therapy)

  • TMB (tumour mutational burden; for immune checkpoint inhibitor therapy)

  • NTRK fusions (for tyrosine receptor kinase inhibitor therapy)

  • RET fusions (for tyrosine receptor kinase inhibitor therapy)

Elevated serum biomarkers (cancer antigen 15-3 [CA 15-3], cancer antigen 27.29 [CA 27.29], and carcinoembryonic antigen [CEA]) may be concerning for disease progression, but may also occur during disease response.[27]

Biomarkers may be used in conjunction with other evaluations, but not alone, to guide therapy.[57]

Germline testing

Patients with MBC should be considered for germline testing for mutations in high-penetrance breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) if:[19][26]

  • poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy is being considered, or

  • personal and/or family history suggests a pathogenic variant in a cancer susceptibility gene.

Mutations in these genes can inform prognosis and management decisions in patients with MBC, and may also highlight risk among family members.[19][26]

BRCA1 and BRCA2 germline mutations are the most common cause of hereditary breast cancer.[21]​ Testing for BRCA1 and BRCA2 germline mutations is required to identify those eligible for PARP inhibitor therapy.[19][25]​​​[26][27]

Germline testing for a specific pathogenic variant can be carried out, if known; tailored multi-gene panel testing is recommended if the variant is unknown. Selection of the specific multi-gene panel should take into account the patient's personal and family history.[19][59]

The American Society of Clinical Oncology (ASCO) recommends germline testing for BRCA1 and BRCA2 mutations in all patients age ≤65 years diagnosed with breast cancer, and in select patients >65 years based on personal or family history, ancestry, and eligibility for PARP inhibitor therapy. Individualised testing is recommended for additional high-penetrance genes (CDH1, PALB2, PTEN, STK11, and TP53).[25]

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