Skip to main content
Public beta This website is in public beta – please give your feedback.

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 1–3 breast cancer is limited to the breast and regional axillary lymph nodes, and is potentially curable with multi-modality treatment. Stage 4 or metastatic breast cancer describes breast cancer which has spread to distant tissues such as the bones, liver or lungs; this is treatable but not curable.

Histological

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

Ten percent 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 which 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 which 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.

Biological

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:

  • 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/HER2-negative: treated with hormonal therapies +/ systemic chemotherapy.
  • ER-negative or positive and HER2-positive: treated with chemotherapy plus anti-HER2 therapies +/- hormonal therapy depending on ER status.
  • ER-negative / HER2-negative : these tumours are usually also progesterone receptor negative and hence are 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.

Molecular

Pioneering gene expression analysis of primary breast tumours identified four main subsets of tumours with prognostic implications:¹

  • 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 but is used as a tool for stratification of interventions in research studies and has also provided the scientific rationale behind commercial 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 years 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.
  • Inherited breast cancer is more likely to occur at a younger age than sporadic cancer.
  • Approximately 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 (contraceptives, hormone replacement therapy). Reproductive factors (age at menarche and menopause, having children and breast feeding) also influence 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 2–3 times risk of breast cancer than the general female population.

Genetics of breast cancer

Somatic (tumour) genetics and breast cancer

  • Most cases of breast cancer are caused by somatic (tumour) mutations acquired during an individual’s lifetime, affecting genes that control cell growth and division or DNA repair mechanisms. Somatic mutations 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) mutations found in breast cancers are PIK3CA mutations, which are present in 25–40% of tumours and may confer eligibility for treatment with the PIK3CA inhibitor alpesalib in the metastatic setting.
  • ESR1 mutations 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 mutations might be more sensitive to fulvestrant than aromatase inhibitors.
  • Mutation of 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/BRCA2 mutations are found in 5–7% of breast cancers, a significant proportion of which are constitutional (germline) in origin. Certain types of pathogenic variants are not easily detected by tumour testing, and negative somatic (tumour) BRCA1/BRCA2 mutation testing does not replace the need for constitutional testing when clinically appropriate. Clinical studies are underway to determine whether somatic BRCA1/BRCA2 mutations confer clinical benefit from PARP inhibitors in breast cancer.
  • AKT1 mutations occur in less than 5% of breast cancers. Novel drugs targeting altered AKT proteins are being investigated in research studies but are currently not licensed for clinical use.

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, 61–77% for BRCA2; as 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) than the general population.
    • BRCA1 and BRCA2 are key mediators of DNA repair by homologous recombination.
  • Other high penetrance breast cancer predisposition genes include:
    • PALB2;
    • STK11 (Peutz-Jeghers syndrome);
    • PTEN (PTEN hamartoma tumour syndrome/Cowden syndrome);
    • TP53 (TP53 tumour predisposition syndromes/Li-Fraumeni syndrome); and
    • CDH1 (hereditary diffuse gastric cancer syndrome).
  • Variants in moderate penetrance breast cancer susceptibility genes including CHEK2, ATM, RAD51C and RAD51D are associated with breast cancer lifetime risks of 2–4 times the general population risk. Risks associated with moderately penetrant genetic variants depend on the type of variant (with truncating variants conferring higher risks than missense variants in certain genes), family history, environmental/lifestyle modifiers of disease, as well as other co-inherited genetic modifiers of risk.

Management implications of genomic testing

  • If a constitutional (germline) pathogenic variant in BRCA1/BRCA2 is identified in an individual with breast cancer, it may have implications for the choice of treatment for their current cancer. Read this ‘Knowledge hub’ article for more information.
  • If a constitutional (germline) high-penetrance breast cancer predisposition gene variant is identified, there are also implications for management of the patient’s own 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.

Resources

For clinicians

References:

For patients

Tagged: Breast cancer

↑ Back to top
  • Last reviewed: 09/05/2022
  • Next review due: 09/05/2023
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Terri McVeigh