Approach

Breast cancer may present as a painless firm breast mass, especially when discovered in the early stages. Factors that support the diagnosis include:

  • Increasing size of the mass (fibrocystic disease may fluctuate in size with the menstrual cycle, but breast cancer progressively increases in size regardless of the menstrual cycle)

  • Nipple discharge

  • Axillary lymphadenopathy

  • Skin thickening or discoloration (more likely to be associated with locally advanced or inflammatory breast cancer)[127][Figure caption and citation for the preceding image starts]: Peau d'orangeFrom the collection of Dr Amal Melhem-Bertrandt; used with permission [Citation ends].com.bmj.content.model.Caption@29194fbc

  • Retraction, inversion, or scaling of the nipple (may be related to Paget's disease of the breast, or locally advanced breast cancer in association with a large breast mass with/without nipple or skin involvement).[Figure caption and citation for the preceding image starts]: Nipple retraction and asymmetryFrom the collection of Dr Amal Melhem-Bertrandt; used with permission [Citation ends].com.bmj.content.model.Caption@7defa90c

It should be remembered that breast cancers do not always present with a new breast mass. Many breast cancers are diagnosed on the basis of mammographic abnormalities (such as linear or pleomorphic microcalcifications), in the absence of a palpable mass.[102]

Occult breast cancer is found in approximately 0.3% of women diagnosed with axillary lymphadenopathy.[128]

A family history should be taken, paying particular attention to close blood relatives with diagnoses of breast, ovarian, or pancreatic cancer, or metastatic, high-risk, or very-high-risk prostate cancer, to identify patients at increased genetic/familial risk of breast cancer.[18]​ Genetic risk evaluation, including counselling and genetic testing, is recommended for patients with a strong family history or a known or likely pathogenic variant in a cancer susceptibility gene.[18][102]

Physical examination

The patient should be first examined in the sitting position to allow inspection for changes in skin colour, contour, dimpling, and asymmetry. The axilla is also evaluated by relaxing and adducting the arm. The supraclavicular and infraclavicular nodal basins should be evaluated to determine the extent of nodal disease.

Clinical assessment of nodal status is often inaccurate; therefore, imaging (e.g., ultrasonography, contrast-enhanced breast magnetic resonance imaging [MRI], or computed tomography [CT]) is required. A study by the National Surgical Adjuvant Breast Project (NSABP) found histological evidence of nodal metastases on pathological examination in 38% of a group of breast cancer patients who had been determined to be node-negative by clinical examination.[129] Conversely, no evidence of nodal disease was later found on pathological examination in 25% of the patients who had been clinically determined to have nodal metastases.[129]

The patient is then examined supine, with their arm raised so that the hand is behind the head and the breast tissue is distributed over the chest wall, facilitating thorough palpation of the entirety of the breast and nodal regions. The tissue at and beneath the nipple should be palpated.

Physical examination of the breasts and nodal basins should follow a methodical pattern, to prevent omission of any region.

Imaging

Recommended imaging modalities include mammography, ultrasound, and MRI. Systemic staging for women with locally advanced disease or suspected metastatic disease may involve CT, bone scan, and positron emission tomography (PET)/CT.

Mammography

Bilateral diagnostic mammography should be used as the initial imaging test to evaluate symptomatic adult patients aged ≥30 years, or as follow-up to evaluate abnormal findings on screening mammography or other imaging tests.[102][130][131]​​ The sensitivity and specificity of conventional mammography for diagnosing breast lesions have been reported as 78.9% and 82.7%, respectively.[132]

Digital breast tomosynthesis (DBT) is a three-dimensional mammographic technique that can be used to create thin-section reconstructed images of breast tissue. Diagnostic DBT may offer improved detection and lesion characterisation compared with conventional two-dimensional mammography, especially in patients with dense breast tissue.[130] In one study, DBT showed a higher overall sensitivity, compared with conventional mammography (88.2% vs. 78.3%, respectively), with a similar specificity.[133]​​

Diagnostic conventional mammography or diagnostic DBT may be used as alternative options or in combination.[131][134]​ National Comprehensive Cancer Network (NCCN) guidelines recommend diagnostic mammography with DBT.[102]​ Contrast-enhanced mammography with ultrasound may be a further option for initial diagnostic imaging.[102][134]​​

The sensitivity of conventional mammography is lower in women with dense breasts; therefore, DBT, or supplemental ultrasound or MRI may be warranted in these women.​​[102]​​[135]​​​[136]​​​​​​

Breast ultrasound

Evaluation of a new mass in a woman aged <30 years should usually begin with ultrasound (followed by mammography if results are suggestive of breast cancer).[102]​ However, if there is a high suspicion of malignancy (e.g., based on personal or family history, clinical breast examination, or ultrasound results), a mammogram should be performed first.[102]​ If there is a low clinical suspicion, observation of the mass for 1-2 menstrual cycles may be considered, followed by ultrasound or mammography if symptoms persist.[102]

For women aged ≥30 years with palpable symptoms, and patients with other suspicious symptoms at any age, ultrasound may be performed in addition to diagnostic mammography and/or DBT.[102][131][134]​​​​​ Breast ultrasound has demonstrated utility as an adjunct to mammography through specificity (by differentiating cysts from solid masses), evaluating breast or axillary masses that are not sufficiently assessed by mammogram, evaluating axillary lymph nodal involvement, and monitoring for tumour response during neoadjuvant chemotherapy.[137][138][139][140]

Three-dimensional breast ultrasound has a sensitivity of 92.3% and a specificity of 87.2% for diagnosing breast cancer in women with breast nodules or mass lesion.[141]

Breast MRI

Sensitivity of breast MRI is higher than for mammogram, but specificity is limited (sensitivity for breast cancer is approximately 88% to 91%; specificity approximately 68%).[142]​ Despite increased sensitivity, MRI has not been shown to decrease rates of reoperation when added to the work-up of women with primary breast cancer undergoing wide local excision.[143]​ Breast MRI is not recommended routinely for diagnostic evaluation, because of the risk of false positives and potential for overtreatment.[144] Breast MRI (without and with contrast) may, however, be useful for evaluation and decision-making in certain circumstances:[102][117]​​​​[144]

  • Evaluation of suspicious nipple discharge, inversion, or retraction, or suspicious breast skin changes when ultrasound or mammography are not diagnostic. MRI may facilitate a diagnosis of inflammatory breast cancer.

  • Staging evaluation (to define extent of cancer or presence of multifocal or multicentric cancer), if indicated, or to screen for cancer in the contralateral breast at diagnosis.

  • Evaluation before and after preoperative systemic therapy (to define the extent of disease, response to treatment, and potential for breast-conserving surgery).

  • Identifying occult primary tumours in patients with clinically positive axillary nodes; or with Paget's disease (to define the extent of disease); or with invasive lobular carcinoma (not adequately identified on mammography, ultrasound, or physical examination).

Systemic staging

Routine systemic staging is not indicated for early-stage breast cancer in the absence of signs or symptoms of metastasis.[117] In women with symptoms or signs suggestive of metastatic disease or those with locally advanced disease (T3, N1-2, M0) additional imaging should be considered.[144] See Metastatic breast cancer.​

Pulmonary symptoms should be investigated with chest CT (without or with contrast). Radionucleotide bone scan or sodium fluoride PET/CT scan should be performed in patients with localised bone pain or elevated alkaline phosphatase. Abdominal and pelvic imaging using CT with contrast or MRI with contrast is indicated for abdominal or pelvic symptoms or signs, elevated alkaline phosphatase, or abnormal liver function tests.[117]

PET/CT scan is not indicated in stage I, stage II, or operable stage III breast cancer because of its high false-negative rate for small lesions, low sensitivity for detection of axillary lymph node metastases, and high rate of false-positive scans. PET/CT is most helpful in advanced disease and invasive ductal histology when standard staging investigations are equivocal.[117][134][144]

Biopsy

Biopsy is required for definitive diagnosis. An image-guided core biopsy is usually the preferred method of diagnosis because it enables differentiation between pre-invasive and invasive disease, is less likely to be associated with inadequate sampling, and enables assessment of receptor status.[Figure caption and citation for the preceding image starts]: Inflammatory breast carcinoma showing dermal lymphatic invasion by tumour cellsFrom the collection of Dr Massimo Cristofanilli; used with permission [Citation ends].com.bmj.content.model.Caption@63f13ba1

Excisional biopsy may be indicated if core needle biopsy cannot be performed; or results are indeterminate, or are benign and discordant with imaging; or where larger tissue samples are needed. However, it is associated with poorer cosmesis and is more invasive than needle biopsy.[117]

Fine needle aspiration (FNA) is useful in obtaining a rapid diagnosis of breast malignancy, and it may be the only test required for diagnosis when plans for immediate surgery are already in place. Sensitivity and specificity of FNA are reported to be 98% and 97%, respectively, when performed by experienced clinicians.[145] However, diagnostic accuracy with FNA is likely to decline if performed by less experienced clinicians.

Hormone-receptor and human epidermal growth factor receptor 2 (HER2) testing

If a diagnosis of invasive breast cancer is made, the oestrogen receptor (OR), progesterone receptor (PR), and HER2 receptor status of the cancer should be determined to aid treatment and prognostication.[146][147]

OR and PR status is assayed using immunohistochemistry (IHC). The American Society of Clinical Oncology (ASCO) and the College of American Pathologists recommend that OR and PR assays should be considered positive if there are at least 1% positive tumour nuclei in the initial biopsy sample.[146] Women who are OR-borderline are managed in the same way as women who are OR-positive.

Patients diagnosed with breast cancer (early-stage or metastatic disease) should have at least one tumour sample tested for HER2 expression. A HER2 test includes testing for HER2 protein expression (IHC assay) or HER2 gene amplification by in situ hybridisation (ISH).[147] IHC scoring ranges from 0 to 3+ as determined by intensity of staining, and percentage (>10%) of contiguous and homogeneous positive tumour cells. HER2 status can be classified as follows, based on the IHC score:[147]

  • HER2 negative: IHC score 0 or 1+

  • Equivocal: IHC score 2+ (requires reflex testing with ISH assay)

  • HER2 positive: IHC score 3+.

Single-probe ISH assays measure the average HER2 copy number (signals/cell); dual-probe ISH assay measures the HER2/CEP17 ratio.[147] The single-probe approach is not preferentially recommended; if used, cases with average HER2 copy number ≥4.0 and <6.0 signals/cell should base final results on concurrent IHC and if 2+ reflexed to dual-probe ISH testing.[117]

Assuming no apparent histopathological discordance observed by the pathologist, HER2 status can be classified as follows, based on concurrent IHC and ISH results:[147]

  • HER2 negative:

    • HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell (concurrent IHC result not required)

    • HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC score 0, 1+, or 2+

    • HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC score 0 or 1+

    • HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC score 0, 1+, or 2+

  • HER2 positive:

    • HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC score 3+

    • HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC score 2+ or 3+

    • HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC score 3+

    • HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥4.0 signals/cell (concurrent IHC result not required).

Genetic testing

Performed to detect germline mutations associated with increased cancer risk. It is estimated that 5% to 10% of breast cancers are linked to inherited genetic mutations.[12][13][14]​ BRCA1 and BRCA2 mutations are the most common inherited genetic mutations found in breast cancer.[14][15][16][41]

Genetic testing can inform prognosis, and aid in systemic therapy and surgical decision-making (e.g., adjuvant olaparib treatment for high-risk, HER2-negative breast cancer; risk-reducing surgery).[18]

​Genetic counselling and testing for high-penetrance breast cancer susceptibility genes is recommended for certain patients at diagnosis, based on personal or family history, ancestry, diagnosis at an early age, or eligibility for olaparib therapy.[18][117][148]

All male patients with breast cancer diagnosed at any age should have genetic testing.[18][117][148]​​

National Comprehensive Cancer Network (NCCN) guidelines recommend genetic counselling and testing for high-penetrance breast cancer susceptibility genes (e.g., BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) at diagnosis for the following patients:[18][117]​​​

  • Diagnosed at aged ≤50 years

  • With Ashkenazi Jewish ancestry and diagnosed at any age

  • Males diagnosed at any age

  • With triple-negative breast cancer, or multiple primary (synchronous or metachronous) breast cancers, or lobular breast cancer (with a personal or family history of diffuse gastric cancer) diagnosed at any age

  • Candidate for adjuvant olaparib therapy

  • With any blood relative with a known pathogenic/likely pathogenic variant in a cancer susceptibility gene

  • With a strong family history, including:

    • ≥1 close blood relative diagnosed with breast cancer at aged ≤50 years, or with male breast cancer, ovarian or pancreatic cancer, or prostate cancer (with metastatic, or high- or very high-risk group) at any age; or

    • ≥3 diagnoses of breast and/or prostate cancer on the same side of the family (including the patient being assessed).

The American Society of Clinical Oncology (ASCO) found that expanding the NCCN age criteria to include all women ≤65 years improved the sensitivity of the criteria (to 98% for BRCA1 or BRCA2). ASCO recommends germline testing for BRCA1 and BRCA2 mutations at diagnosis in the following patients:[148]

  • All patients diagnosed with breast cancer aged ≤65 years

  • Select patients >65 years diagnosed with breast cancer, based on personal or family history, ancestry, eligibility for olaparib therapy.

ASCO guidelines recommend individualised testing for additional high-penetrance genes (e.g., CDH1, PALB2, PTEN, STK11, and TP53) based on personal or family history.[148]

Genetic testing for a specific pathogenic variant can be carried out, if known; germline multigene panel testing is recommended if the variant is unknown.[18]​ Selection of the specific multigene panel should take into account the patient's personal and family history.[148]

Assessing risk of recurrence

Gene expression assays may be used for prognostication and to guide decisions on adjuvant chemotherapy.[149][150][151][152][153]

Oncotype DX® is the preferred assay to determine whether the addition of chemotherapy to endocrine therapy would be of benefit in patients with HR-positive, HER2-negative disease who are node-negative or post-menopausal with node-positive disease (1-3 positive nodes).[117][153]​​[154]

Oncotype DX® is a reverse transcription polymerase chain reaction-based multigene assay that evaluates the expression of 21 genes within the patient's paraffin-embedded tumour slides.[155]​ Based on this expression, a low (≤10), intermediate (11-25), or high (26-100) recurrence score can be calculated. The recurrence score can aid decision-making on whether a patient with hormone receptor-positive breast cancer who is node-negative or positive for 1-3 nodes would benefit from adjuvant chemotherapy, or if adjuvant endocrine therapy alone would be sufficient.[149][156][157][158]​ 

Pre-menopausal patients with 1-3 positive nodes benefit from chemotherapy regardless of genomic assay result. The clinical utility of assays in node-positive disease with ≥4 nodes is unknown.[153]

Other assays, such as Mammaprint®, Breast Cancer Index (BCI), Prosigna®, and EndoPredict®, may be used to provide prognostic information in post-menopausal women or women aged >50 years who are node negative. Mammaprint® and EndoPredict® may also be used for post-menopausal women or women aged >50 years with 1-3 positive nodes. However, the ability of these assays to predict therapeutic benefit is less certain.[117][153]

Blood tests

Blood tests are not generally recommended as part of staging and preoperative work-up.

A full blood count, a comprehensive metabolic panel, liver function tests, and an alkaline phosphatase test should be considered only if the patient is a candidate for preoperative or adjuvant systemic therapy.[117] Patients with a clinical/pathological diagnosis of inflammatory breast cancer without distant metastasis should have a full blood count and platelet count.[117]

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