History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors for developing breast cancer include: female sex, age >50 years, family history of breast and/or ovarian cancer, and family and/or personal history of breast cancer susceptibility genes.[16][18][8]​[20][21][60][27]​[28]​[46]

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.[29]​[30]​[31][32][33][34][35][36]

bone pain

May be due to disease spread to bone.[47]​​

pleural effusion

Pleural effusion in a patient with confirmed metastatic breast cancer suggests possible disease in the pleural cavity.

A sample of pleural fluid should be sent for cytological assessment to determine if malignant cells are present. However, a negative pleural cytology does not exclude a malignant pleural effusion.

uncommon

palpable mass after treatment of the primary tumour

May demonstrate recurrent disease.[48]​​

Other diagnostic factors

common

shortness of breath

Commonly secondary to pleural effusions.[47]

Less commonly due to lung metastases.

cough (non-productive)

May occur secondary to pleural effusions, or due to lung metastases or lymphangitic carcinomatosis.

anorexia

General symptom of metastatic breast cancer.

Common in the terminal stage of the disease but less common in the early stage.

weight loss

General sign of metastatic breast cancer.

Often related to lack of appetite.

uncommon

neurological symptoms (e.g., neuralgic pain, weakness, headaches, seizures)

Suggests possible brain or peripheral nervous system metastases.[47]

Risk factors

strong

female sex

Women develop 99% of all breast cancers.​[16][18]​​

age >50 years

Breast cancer risk increases with age.[16]​​

Median age at breast cancer diagnosis in women in the US is 63 years.[19]

family history of breast and/or ovarian cancer

Breast cancer risk increases if there is a history in the family of multiple first-degree relatives with early onset breast and/or ovarian cancer.[20][21]

Testing for high-penetrance breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) is indicated in certain patients with a family history of breast and/or ovarian cancer (see Primary invasive breast cancer [Screening])​.[22][23][24][25][26]​​​​​

breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53)

An estimated 5% to 10% of breast cancer cases are hereditary.[27]​ BRCA1 and BRCA2 germline mutations are the most common cause of hereditary breast cancer.[21]

Testing for high-penetrance breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) is indicated in certain patients with a personal breast cancer history, or who have a family history of breast and/or ovarian cancer (see Primary invasive breast cancer [Screening])​.[22][23][24][25][26]​​​​​

Patients with metastatic breast cancer (MBC) should be tested for high-penetrance breast cancer susceptibility genes.[22][28]​​​ Mutations in these genes can inform prognosis and guide treatment, such as use of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy.[22][28]

tumour >5 cm in diameter

Larger tumours are more often associated with MBC.[29][30]

Tumours ≤2 cm in diameter have the lowest risk of metastatic spread; tumours 2.1 to 5.0 cm are associated with intermediate risk; and tumours >5 cm have the highest risk of spread.[31]

high number of positive axillary lymph nodes (e.g., >10)

Pathological nodal staging classifies tumours as having: no nodal spread; spread to of 1-3 axillary lymph nodes; spread to 4-9 axillary lymph nodes; or spread to ≥10 axillary lymph nodes.[31]

A greater number of positive axillary lymph nodes increases the risk of distant metastases.[32]

lymphovascular invasion

The presence of this finding on histology increases risk of tumour recurrence (local or metastatic) and death.[33]​​

high-risk 70-gene signature

The 70-gene signature assay (Mammaprint®) can predict the risk of disease recurrence (metastasis) in post-menopausal women or women aged >50 years who have early-stage, node-negative breast cancer.[34]

high-risk 21-gene signature

The 21-gene signature assay (Oncotype DX®) can predict the risk of disease recurrence (metastasis) in patients with early-stage, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer.[35]

The 21-gene assay recurrence score ranges from 0 to 100. Recurrence score (≥26) indicates more aggressive tumour characteristics, and is predictive of chemotherapy benefit. Low recurrence score (0 to 10) is prognostic for reduced risk of distant recurrence (2% to 3%) at 10 years that is unlikely to be influenced by adjuvant chemotherapy.[35]​ Among women with a midrange recurrence score (11 to 25), adjuvant endocrine therapy and chemoendocrine therapy were similarly effective.[35]

high-risk PAM50 gene signature

The PAM50-gene signature assay (Prosigna®) can predict the risk of disease recurrence (metastasis) in patients with hormone receptor-positive breast cancer.[36]

Score ranges from 0 to 100. Node-negative cancers are classified as low risk (0-40), intermediate risk (41-60), or high risk (61-100). Node-positive cancers (1-3 nodes) are classified as low risk (0-40) or high risk (41-100).

In node-negative patients, 10-year risk of distant recurrence was 5.0% and 17.8% for patients with low or high risk of recurrence scores, respectively.[36]​ In node-positive patients (1-3), 10-year risk of distant recurrence was 3.5% in the low-risk group and 22.1% for high risk patients. 

weak

Lynch syndrome (hereditary non-polyposis colorectal cancer)

Patients with Lynch syndrome (hereditary non-polyposis colorectal cancer) are at increased risk of developing genetically related breast cancer.[37]

CHEK2 mutations

CHEK2 mutations have been reported to significantly increase breast cancer risk compared with population-matched controls (odds ratio 3.90).[38]

​CHEK2 has a stronger association with oestrogen receptor (OR)-positive breast cancer than with OR-negative breast cancer.[39]

ATM mutations

ATM mutations are associated with modestly increased risk for breast cancer. One meta-analysis of 7 case-control studies reported an adjusted odds ratio of 1.67.[40]

​ATM has a stronger association with oestrogen receptor (OR)-positive breast cancer than with OR-negative breast cancer.[39]

minimal residual disease (MRD)

The detection of MRD in the bone marrow of patients with breast cancer, after adjuvant therapy, has been associated with shorter disease-free survival, in some but not all studies.[41]

bone metastasis and lung metastasis gene signatures

Gene signatures that predict preferential distant relapse of primary breast cancer to bone or lung have been identified.[42][43][44]​​​​​​ Further study is required to establish their prognostic, diagnostic, and therapeutic utility.[45]

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