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Classification of breast cancer

A small but significant proportion of breast cancer is caused by high-risk constitutional (germline) pathogenic variants in cancer predisposition genes, most commonly BRCA1 and BRCA2.

Stage I to stage III breast cancer is limited to the breast and regional axillary lymph nodes, and is potentially curable with multi-modality treatment. Stage IV or metastatic breast cancer has spread to distant tissues such as the bones, liver and/or lungs; this is treatable but not curable.


75% of invasive breast malignancies originate from the epithelial cells of the milk ducts and are adenocarcinomas (previously described as invasive ductal carcinomas). Most invasive ductal carcinomas have no specific histological characteristics other than invasion through the basement membrane of the breast duct, and are now classified as ‘no special type’.

In total, 10% of invasive breast cancers arise from the milk-producing lobules; these lobular invasive carcinomas have a tendency to spread through the breast in a more diffuse pattern than invasive ductal carcinomas. Some breast tumours show features of both invasive ductal and lobular carcinomas, and are described as mixed invasive ductal and lobular tumours.

A smaller number of primary breast tumours have histological characteristics that permit classification into special types, including:

  • tubular carcinomas;
  • cribriform carcinomas;
  • mucinous carcinomas;
  • medullary carcinomas;
  • papillary carcinomas;
  • metaplastic carcinomas;
  • apocrine carcinomas; and
  • adenoid cystic carcinomas.

Inflammatory breast cancer is a clinical diagnosis describing malignancies that present as reddening and swelling of the breast, and typically behave in an aggressive fashion. There are no unique histological identifiers of inflammatory breast cancer, although dermal lymphatic invasion with tumour emboli is generally considered to be a histological hallmark.


Modern management of invasive breast cancer is highly dependent on the level of expression of oestrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) proteins by the malignant cells. Both of these proteins have prognostic and predictive implications, as described below.

  • ER-positive status generally indicates cancers that have a less aggressive natural history than ER-negative tumours and respond to treatment with hormonal therapies, such as tamoxifen and aromatase inhibitors.
  • HER2-positive breast cancers are more aggressive than HER2-negative cancers and confer eligibility for treatment with specific anti-HER2 targeted therapies, such as trastuzumab and pertuzumab.

ER and HER2 status are initially assessed via immunohistochemical analysis of tumour cells, with ‘in situ’ hybridisation techniques used to measure HER2 gene expression in cases of equivocal HER2 protein expression. Clinical management pathways divide breast tumours into three groups:

  • ER-positive or HER2-negative: these are treated with hormonal therapies with or without systemic chemotherapy;
  • ER-negative or positive and HER2-positive: these are treated with chemotherapy plus anti-HER2 therapies with or without hormonal therapy, depending on ER status; and
  • ER-negative or HER2-negative: these tumours are usually also progesterone receptor (PR)-negative and are therefore known as triple-negative tumours. They are associated with high risk of metastases and usually require treatment with chemotherapy. Expression of the PDL-1 protein may confer eligibility for treatment with immunotherapy in the metastatic setting.


Pioneering gene expression analysis of primary breast tumours identified four main subsets of tumours with prognostic implications:

  • ER-positive luminal-like;
  • basal-like;
  • ErbB2-positive; and
  • normal-like.

Subsequent studies have further classified luminal tumours into luminal A and luminal B subclasses, with luminal A tumours carrying a better prognosis than luminal B tumours.

Gene expression analysis is not currently performed as a standard diagnostic test for primary breast tumours; however, it is used as a tool for stratification of interventions in research studies and has also provided the scientific rationale behind commercial molecular profiling tests for ER-positive and HER2-negative breast tumours (for example, Oncotype DX and Prosigna), which can be used to inform individual patient recommendations regarding adjuvant systemic therapies.

Epidemiology of breast cancer

  • The vast majority of breast cancer cases occur in women, with only 1%–2% of cases occurring in men.
  • Incidence rates increase in women with age, climbing slowly from age 25 and more steeply from age 35, with almost a quarter of cases diagnosed in women aged 75 years and older. In men, incidence rates are very low in the under 60s and rise from this age.
  • Breast cancer associated with an underlying heritable predisposition is more likely to occur at a younger age than sporadic cancer (around 12% of patients diagnosed with breast cancer aged 40 or under have a pathogenic variant in BRCA1 or BRCA2).
  • About 23% of UK breast cancers are attributable to modifiable risk factors, including obesity (post-menopausal breast cancer only), alcohol use, lack of physical activity and exogenous oestrogens (such as contraceptives and hormone replacement therapy). Reproductive factors (such as age at menarche and menopause, having children and breastfeeding) also influence a patient’s risk.
  • A small number of invasive breast cancers are caused by previous radiation treatment to the chest region.
  • A previous history of ‘in situ’ breast carcinoma is associated with a two to three times higher risk of breast cancer than is found in the general female population.

Genetics of breast cancer

Somatic (tumour) genetics and breast cancer

  • Most cases of breast cancer are caused by somatic (tumour) variants acquired during an individual’s lifetime, affecting genes that control cell growth and division or DNA repair mechanisms. Somatic variants are those that have arisen in the tumour, and are not present constitutionally. They are therefore not present in the germline and cannot be passed on to offspring.
  • The most common somatic (tumour) variants found in breast cancers are PIK3CA variants, which are present in 25%–40% of tumours and may confer eligibility for treatment with the PIK3CA inhibitor alpelisib in the metastatic setting.
  • ESR1 variants are present in up to 20% of metastatic ER-positive breast cancers and are associated with resistance to endocrine therapies. Retrospective analyses suggest that patients with ESR1 variants might be more sensitive to fulvestrant than aromatase inhibitors. Elacestrant is a novel selective ER degrader therapy that has been licensed as second-line therapy in post-menopausal ER-positive, HER2-negative metastatic breast cancer with an activating ESR1 variant.
  • Variants in the HER2 gene occurs in approximately 2% of HER2-negative cancers and approximately 10% of trastuzumab‐resistant HER2-amplified breast cancers. Use of the tyrosine kinase inhibitors neratinib and tucatinib in HER2-mutated breast cancer is currently under investigation.
  • BRCA1 and/or BRCA2 variants are found in 5%–7% of all breast cancers, a significant proportion of which are constitutional (germline) in origin. Certain types of pathogenic variant are not easily detected by tumour testing, and negative somatic (tumour) BRCA1 and/or BRCA2 variant testing does not replace the need for constitutional testing when clinically appropriate. Clinical studies are underway to determine whether somatic BRCA1 and/or BRCA2 variants confer clinical benefit from PARP inhibitors in breast cancer.
  • AKT1 variants occur in fewer than 5% of breast cancers. Capiversatib is a first-in-class oral AKT inhibitor. Based on the results of the CAPItello-291 phase-three trial, capiversatib has now been approved by the US Food and Drug Administration, in combination with fulvestrant, for treatment of ER-positive, HER2-negative metastatic breast cancer with biomarker variants in PIK3CA, AKT1 or PTEN.

Constitutional (germline) genetics and breast cancer

  • Approximately 5%–10% of breast cancer cases are attributed to monogenic hereditary cancer predisposition syndromes, while an additional 20% of breast cancers are considered familial – with clustering of multiple affected first- and/or second-degree relatives in the absence of obvious underlying genetic risk factors. Many such cases may be explained by oligogenic or polygenic risk factors.
  • The majority of breast cancer-associated, high-risk constitutional (germline) pathogenic variants are in the BRCA1 and BRCA2 genes, and are associated with a high lifetime risk of developing breast cancer (65%–79% for BRCA1 and 61%–77% for BRCA2, compared to a 12% risk in the general population) as well as higher lifetime risks of ovarian cancer (36%–53% for BRCA1, 11%–25% for BRCA2).
    • BRCA1 and BRCA2 are key mediators of DNA repair by homologous recombination.
  • Constitutional (germline) variants in a number of other genes confer a high risk of breast cancer as part of other broader cancer predisposition syndromes, including:
  • Variants in a number of other breast cancer susceptibility genes including CHEK2, ATM, RAD51C and RAD51D are associated with moderately increased risks of breast cancer, with estimated lifetime risks of two to four times the general population risk. Risks associated with variants in such genes depend on the type of variant (with truncating variants conferring higher risks than missense variants in certain genes), family history and environmental and lifestyle modifiers of disease, as well as other co-inherited genetic modifiers of risk.

Management implications of genomic testing

Somatic (tumour) genomic testing

The presence of a PIK3CA variant in a tumour sample from a patient with metastatic ER-positive, HER2-negative breast cancer may confer eligibility for treatment with alpelisib. Full eligibility criteria are provided in the Cancer Drugs Fund list.

Currently, therapies targeted at somatic (tumour) variants in ESR1, BRCA1, BRCA2, HER2 and AKT are not available within the NHS. However, identification of somatic variants in these genes may facilitate access to novel treatments within clinical trials.

Constitutional (germline) genomic testing

If a constitutional (germline) pathogenic variant in BRCA1 or BRCA2 is identified in an individual with breast cancer, it may have implications for the choice of treatment for their current cancer.

  • Patients with a ‘high risk’ early breast cancer and a constitutional (germline) BRCA1 or BRCA2 pathogenic variant may be eligible for adjuvant treatment with the PARP inhibitor olaparib. Full eligibility criteria are provided in the Cancer Drugs Fund list.
  • Patients with metastatic HER2-negative breast cancer and a constitutional (germline) BRCA1 or BRCA2 pathogenic variant who have progressed through first-line systemic therapy may be eligible for palliative treatment with the PARP inhibitor talazoparib. Full eligibility criteria are provided in the Cancer Drugs Fund list.
  • If a constitutional (germline) variant is identified in a breast cancer susceptibility gene, there are implications for management of the patient’s future cancer risk and that of their relatives. The cancer risk associated with pathogenic variants in BRCA1, BRCA2 and most other breast cancer predisposition genes is inherited in an autosomal dominant pattern.


For clinicians


For patients

Tagged: Breast cancer

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  • Last reviewed: 11/02/2024
  • Next review due: 11/02/2026
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh