Breast Cancer

Synonyms: -

Material:

FFPE tissue sections

TAT:

varies depending on the analysis

Method:

NGS

Overview

Breast cancer accounted for an estimated 2,434,087 new cases worldwide in 2024 and is the second most commonly diagnosed cancer globally. Invasive breast carcinomas are a large and heterogeneous group of malignant epithelial neoplasms, and they are subgrouped into four categories depending on estrogen receptor (ER) and ERBB2 (HER2) status, each showing distinct outcomes and responses to therapy.

Clinical background and relevance

Several targeted and biomarker-based therapeutics are available for breast cancer treatment, therefore, the identification of therapy-relevant molecular alterations is a major component of the diagnostic work-up. In advanced breast cancer, international guidelines set out a defined panel of genes for molecular assessment. The analyses listed below detect somatic sequence variants in BRCA1, BRCA2, ERBB2, PIK3CA and PTEN and gene fusions of NTRK and RET, and establishes mismatch repair (as microsatellite instability) status. The detected molecular alterations may directly guide treatment selection in advanced disease.

BRCA1 and BRCA2 are firstly relevant in the germline, as pathogenic germline alterations are causative for Hereditary Breast and Ovarian Cancer syndrome (HBOC). Somatic inactivating variants in BRCA1 or BRCA2 were found in only about 3 per cent of 273 unselected breast carcinomas and can be therapeutically relevant for advanced disease.

Somatic ERBB2 (HER2) sequence variants are reported at an overall rate of about 1.6 per cent in a pooled analysis of 1,499 tumours. ERBB2 mutations in advanced breast cancers can represent treatment targets.

In one large series of 2,433 tumours, PIK3CA was the most frequently mutated gene, with coding mutations in 40.1 per cent, with AKT1 and PTEN belonging to the same signalling pathway. Alterations within the PI3K/AKT/mTOR signaling pathway represent targets for kinase inhibitors.

Although NTRK and RET gene fusions are detected in only a very small proportion of breast cancers (estimated 0.21 per cent for NTRK fusions; RET fusions have been reported), patients with NTRK/RET rearrangements may benefit from tumour-agnostic TRK-inhibitor or RET-directed therapy, respectively.

NCCN and ESMO recommend MSI/MMR testing for advanced breast carcinoma. In recurrent or advanced disease, dMMR or MSI-H status may identify patients for whom tumour-agnostic immune-checkpoint therapy is an option. MSI analysis and MMR-protein immunohistochemistry are complementary approaches and should not be treated as synonymous tests.

Table 1: Clinical relevance of biomarker findings in breast cancer

Biomarker finding	Result to report	Potential clinical relevance
PI3K/AKT/mTOR signaling pathway alteration (PIK3CA, PTEN)	Activating PIK3CA variants or inactivating variants in PTEN	Identification of therapy targets of PI3K/AKT/mTOR signaling pathway
ERBB2 mutation	Somatic ERBB2 variants	Can be therapeutically relevant in advanced disease
BRCA1/BRCA2 alteration	Somatic disease-causing BRCA1 or BRCA2 variant	May inform maintenance-therapy selection; may indicate the need for germline confirmation and genetic counselling
NTRK/RET fusion	NTRK1/2/3 fusion; RET fusion	May identify eligibility for tumour-agnostic TRK-inhibitor therapy, may identify eligibility for RET-directed therapy in recurrent disease
Mismatch repair deficiency	MSI-H, microsatellite stable, or indeterminate	MSI-H may indicate dMMR biology and eligibility for tumour-agnostic immunotherapy in the appropriate clinical setting

Available tests

The analyses listed below can be requested individually or as a combined molecular analysis. The selected test should be based on histotype, disease setting, previous biomarker results, available tissue, and the clinical question. The assays described here represent a focused set of biomarkers and do not replace comprehensive biomarker profiling when broader testing is clinically indicated.

Single-method analysis	Panel	Gene scope	Purpose
Sequencing	Panel00709	BRCA1, BRCA2, ERBB2, PIK3CA, PTEN	Detection of somatic sequence variants in the tumour
Fusion gene analysis	Panel00707	NTRK1, NTRK2, NTRK3, RET	Detection of gene fusions in the tumour
Microsatellite instability (MSI)	Panel00708	Microsatellite marker analysis	Determination of microsatellite instability (MSI) status

Combined analysis	Panel	Gene scope
Targeted analysis	Panel00536	BRCA1, BRCA2, ERBB2, NTRK1, NTRK2, NTRK3, PIK3CA, PTEN, RET, MSI assessment

Depending on the clinical setting, additional biomarkers not included in the focused panels may be required. These additional analyses on tumour tissue are also available (see Panel 00617 – ).

Therapy

References

Ervik M, Laversanne M, Lam F, Colombet M, Ferlay J, Filho AM, Bray F. Global Cancer Observatory: Cancer Today (2024 estimates, version 1.0). Lyon: International Agency for Research on Cancer; 2026. Breast fact sheet. , accessed 7 August 2026.
WHO Classification of Tumours Editorial Board. Breast tumours. WHO Classification of Tumours, 5th ed., vol. 2. Lyon: International Agency for Research on Cancer; 2019.
Malapelle U, Buglioni S, Castellano I, Criscitiello C, Curigliano G, d’Amati G, et al. Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2- metastatic breast cancer. Pathologica. 2025;117(6):546-558. PMID: . PMCID: PMC13094335.
O’Haire S, Franchini F, Kang YJ, Steinberg J, Canfell K, Desai J, et al. Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Sci Rep. 2023;13(1):4116. PMID: . PMCID: PMC10011574.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer, version 6.2026. , accessed 7 August 2026.
Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479. PMID: . PMCID: PMC4866047.
de Azambuja E, Barrios CH, Bartsch R, Curigliano G, Dent R, Gennari A, et al. Metastatic breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2026 May 29. Epub ahead of print. PMID: . https://www.esmo.org/guidelines
Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224-237. PMID: . PMCID: PMC3570596.
Winter C, Nilsson MP, Olsson E, George AM, Chen Y, Kvist A, et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol. 2016;27(8):1532-1538. PMID: . PMCID: PMC4959927.
Parimi V, Tolba K, Danziger N, Kuang Z, Sun D, Lin DI, et al. Genomic landscape of 891 RET fusions detected across diverse solid tumor types. NPJ Precis Oncol. 2023;7(1):10. PMID: . PMCID: PMC9870857.
Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol. 2019;37(4):286-295. PMID: . PMCID: PMC6553803.
Gallon R, McCormick L, Saetta A, Albuquerque C, Butler S, Cranston T, et al. EMQN best practice guidelines for analysis and reporting of microsatellite instability in solid tumours. Eur J Hum Genet. 2026;34(1):134-146. PMID: . PMCID: PMC12816731.

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Our editorial team consists of medical specialists and scientists in the field of human genetics. All content is created and reviewed in accordance with current scientific standards.

Last Update : 24.09.2026

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