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Reliable, easy-to-read patient information on common medical conditions — written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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Breast cancer classification

Introduction

Breast cancer classification

Breast cancer classification

Breast cancer classification uses three complementary axes: histopathologic type, biomarker-defined clinical subtype, and intrinsic gene-expression subtype. These categories describe different features and are not interchangeable.[1][2]

Histopathologic classification

Breast epithelial lesions are classified as in situ or invasive. In situ categories include Ductal carcinoma in situ (DCIS) and lobular neoplasia, including Lobular carcinoma in situ (LCIS). Classic LCIS is generally regarded as a risk marker/non-obligate precursor rather than invasive carcinoma.[1]

Invasive carcinomas are classified by morphology:

  • Invasive carcinoma of no special type (IBC-NST): the most common invasive histotype; formerly termed invasive ductal carcinoma.
  • Invasive lobular carcinoma (ILC): commonly shows discohesive, single-file growth. Loss of E-cadherin supports lobular differentiation but is not required for diagnosis.
  • Special histologic types: include tubular, cribriform, mucinous, micropapillary, apocrine, metaplastic, adenoid cystic, secretory, neuroendocrine, tall cell carcinoma with reversed polarity, and salivary gland-type carcinomas.

A special histologic type generally requires at least 90% of the tumor to show that morphology; otherwise, report a mixed IBC-NST and special-type carcinoma. Core biopsy may not establish whole-tumor purity.[3][4]

Invasive carcinoma grade is reported separately from histologic type. The Nottingham (Elston-Ellis) system scores tubule formation, nuclear pleomorphism, and mitotic count to assign grade 1–3.[3] DCIS is classified by nuclear grade as low, intermediate, or high.[4]

The 2026 WHO classification recognizes ILC with extracellular mucin and updates criteria for mucinous and neuroendocrine carcinoma, among other refinements.[5]

Biomarker-defined clinical subtypes

ER, PR, and HER2 should be assessed on every new primary and newly metastatic invasive breast cancer using validated ASCO/CAP methodology.[6][7][4] ER and PR are positive when at least 1% of tumor-cell nuclei stain. HER2 status is determined by validated immunohistochemistry (IHC) and in situ hybridization (ISH) criteria.[6][7]

Clinical category Biomarker definition Approximate frequency
Hormone receptor-positive (HR-positive), HER2-negative ER and/or PR positive (≥1%); HER2-negative by IHC/ISH. ~70%
HER2-positive HER2 IHC 3+, or IHC 2+ with ISH amplification; may be HR-positive or HR-negative. ~15%
Triple-negative breast cancer (TNBC) ER <1%, PR <1%, and HER2-negative by IHC/ISH. ~15%

Frequency estimates vary by cohort. HER2-low and HER2-ultralow are cross-cutting expression categories and are not mutually exclusive with HR status.[1][4]

An ER result of 1–10% is reported as ER-low-positive; results below 1% are ER-negative.[6] ER-low tumors are heterogeneous, and some have biology resembling ER-negative/TNBC disease. The endocrine benefit remains uncertain: the ASCO/CAP-recommended comment notes limited data, while recent observational meta-analyses associate endocrine therapy with improved outcomes. These findings do not establish the magnitude of benefit for an individual patient.[6][8][9][10]

HER2 expression categories

HER2 IHC scores are 0, 1+, 2+, and 3+. IHC 2+ is equivocal and requires reflex ISH testing; amplification establishes HER2-positive status.[7][4]

HER2 result Classification
IHC 3+: intense, complete membrane staining in >10% of tumor cells HER2-positive
IHC 2+ Equivocal; perform ISH. If ISH is negative, the tumor is HER2-negative and falls in the HER2-low expression category.
IHC 1+ HER2-negative; HER2-low expression category.
IHC 0 with faint, incomplete membrane staining in ≤10% of tumor cells (sometimes recorded as 0+) HER2-ultralow expression category.
IHC 0 with no membrane staining HER2-null; HER2-negative with no detectable membrane staining.

HER2-low generally denotes IHC 1+ or IHC 2+/ISH-negative disease; HER2-ultralow denotes IHC 0 with faint, incomplete membrane staining in ≤10% of tumor cells. These are expression/reporting categories within HER2-negative disease, not separate intrinsic gene-expression subtypes. Reported estimates suggest HER2-low expression occurs in roughly half of breast cancers, and about 88% of HER2-low tumors are HR-positive; estimates vary by cohort and assay.[11][12][13]

Document the specific IHC score and staining pattern, including the distinction between HER2-null (IHC 0/absent staining) and HER2-ultralow (IHC 0+/faint incomplete staining in ≤10%). This distinction can affect biomarker eligibility for trastuzumab deruxtecan in certain metastatic settings; HER2-null does not meet the HER2-low/ultralow expression criterion for that indication.[4][14][15]

Scoring near the IHC 0/1+ boundary has limited reproducibility in reported cohorts. One report found a change between IHC 0 and HER2-low in approximately 40% of paired primary/metastatic samples; in an expert re-review series, approximately 55% of initially IHC 0 cases were reclassified as HER2-ultralow.[7][16]

Re-review with consideration of repeat or consultative HER2 testing is recommended when a grade 1 tumor of any histologic type, or a pure mucinous, tubular, or cribriform carcinoma, tests HER2-positive, because the result is biologically unexpected.[4]

Intrinsic molecular subtypes

Gene-expression classifiers such as PAM50 define intrinsic molecular subtypes. They describe tumor biology and are distinct from the IHC-defined clinical categories.[2][1]

Intrinsic subtype Gene-expression pattern
Luminal A Higher estrogen-related expression and lower proliferation-related expression.
Luminal B Higher proliferation-related expression and lower estrogen-related expression than luminal A.
HER2-enriched Enrichment of HER2-amplicon-related gene expression; this subtype is not synonymous with HER2-positive IHC/ISH status.
Basal-like Basal-associated gene-expression pattern; it overlaps substantially with, but is not synonymous with, TNBC.
Normal-like Normal-breast-like expression pattern; may reflect low tumor cellularity or admixture of normal tissue.

Immunohistochemical surrogate subtyping

IHC-based surrogate schemes may subdivide HR-positive/HER2-negative cancers into luminal A-like (lower proliferation) and luminal B-like (higher proliferation) groups. These are approximations and do not reproduce PAM50 subtyping exactly. No standardized Ki-67 cutoff separates luminal A-like from luminal B-like; 14% and 20% thresholds have both been used. Ki-67 in an intermediate range should not be used as the sole basis for assigning a subtype.[17][18]

Clinical and intrinsic molecular subtypes are not interchangeable; a meaningful minority of tumors are discordant between IHC-based classification and gene-expression classification.[19][20]

References

References

  1. ↑ 1.0 1.1 1.2 1.3 Harbeck N, Penault-Llorca F, Cortes J; et al. (2019). “Breast cancer”. Nature Reviews Disease Primers. 5 (1): 66. doi:10.1038/s41572-019-0111-2.
  2. ↑ 2.0 2.1 Rios-Hoyo A, Shan NL, Karn PL, Pusztai L. Clinical Implications of Breast Cancer Intrinsic Subtypes. Advances in Experimental Medicine and Biology. 2025;1464:435-448. doi:10.1007/978-3-031-70875-6_21.
  3. ↑ 3.0 3.1 Ellis I, Webster F, Allison KH; et al. (2024). “Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR)”. Histopathology. 85 (3): 418–436. doi:10.1111/his.15191.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 National Comprehensive Cancer Network. Breast Cancer. NCCN Clinical Practice Guidelines in Oncology. Version 7.2026; updated September 25, 2026. Guideline.
  5. ↑ Quinn C, Tan PH, Allison KH; et al. (2026). “World Health Organization Classification of Tumours of the Breast 6th Edition 2026”. Histopathology. 89 (2): 199–218. doi:10.1111/his.70149.
  6. ↑ 6.0 6.1 6.2 6.3 Allison KH, Hammond MEH, Dowsett M; et al. (2020). “Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update”. Journal of Clinical Oncology. 38 (12): 1346–1366. doi:10.1200/JCO.19.02309.
  7. ↑ 7.0 7.1 7.2 7.3 Wolff AC, Somerfield MR, Dowsett M; et al. (2023). “Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update”. Journal of Clinical Oncology. 41 (22): 3867–3872. doi:10.1200/JCO.22.02864.
  8. ↑ Choong GM, Hoskin TL, Boughey JC, Ingle JN, Goetz MP (2025). “Endocrine therapy omission in estrogen receptor-low (1–10%) early-stage breast cancer”. Journal of Clinical Oncology. 43 (16): 1875–1885. doi:10.1200/JCO-24-02263.
  9. ↑ Massa D, Chiappe E, Delucchi V, et al. Endocrine Therapy in Early-Stage Estrogen Receptor-Low Breast Cancer: A Systematic Review and Meta-Analysis. Journal of the National Cancer Institute. 2026; article djag281. doi:10.1093/jnci/djag281.
  10. ↑ Xia F, Hu X, Zhang L, Peng X, Xie M. Association Between Endocrine Therapy and Survival Outcomes in Estrogen Receptor-Low Breast Cancer: A Systematic Review and Meta-Analysis. The Oncologist. 2026;31(7):oyag230. doi:10.1093/oncolo/oyag230.
  11. ↑ Rakha EA, Tan PH, Van Bockstal MR, et al. International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories. Modern Pathology. 2026;39(1):100925. doi:10.1016/j.modpat.2025.100925.
  12. ↑ Roy AM, Kumarasamy VM, Dhakal A, O’Regan R, Gandhi S (2023). “A Review of Treatment Options in HER2-low Breast Cancer and Proposed Treatment Sequencing Algorithm”. Cancer. 129 (18): 2773–2788. doi:10.1002/cncr.34904.
  13. ↑ Bagegni NA, Giridhar KV, Stewart D (2025). “HER2-Low and HER2-Ultralow Metastatic Breast Cancer and Trastuzumab Deruxtecan: Common Clinical Questions and Answers”. Cancers. 17 (24): 4021. doi:10.3390/cancers17244021.
  14. ↑ Food and Drug Administration. Enhertu (fam-trastuzumab deruxtecan-nxki) prescribing information. Updated May 15, 2026. DailyMed.
  15. ↑ Dilawari A, Zhang H, Shah M; et al. (2025). “US Food and Drug Administration Approval Summary: Trastuzumab Deruxtecan for the Treatment of Adult Patients With Hormone Receptor-Positive, Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2-Low or Human Epidermal Growth Factor Receptor 2-Ultralow Breast Cancer”. Journal of Clinical Oncology. 43 (26): 2942–2951. doi:10.1200/JCO-25-00812.
  16. ↑ Morrar D, Brogi E, Schwartz CJ; et al. (2025). “Human Epidermal Growth Factor Receptor 2 (HER2)-Ultralow Breast Cancer: Incidence, Clinicopathologic Features, and Need for Refined Scoring System”. Modern Pathology. 38 (12): 100901. doi:10.1016/j.modpat.2025.100901.
  17. ↑ Chen L, Chen Y, Xie Z; et al. (2022). “Comparison of immunohistochemistry and RT-qPCR for assessing ER, PR, HER2, and Ki67 and evaluating subtypes in patients with breast cancer”. Breast Cancer Research and Treatment. 194 (3): 517–529. doi:10.1007/s10549-022-06649-6.
  18. ↑ Harbeck N, Gnant M (2017). “Breast Cancer”. The Lancet. 389 (10074): 1134–1150. doi:10.1016/S0140-6736(16)31891-8.
  19. ↑ Szymiczek A, Lone A, Akbari MR (2021). “Molecular intrinsic versus clinical subtyping in breast cancer: A comprehensive review”. Clinical Genetics. 99 (5): 613–637. doi:10.1111/cge.13900.
  20. ↑ Dix-Peek T, Phakathi BP, van den Berg EJ; et al. (2023). “Discordance between PAM50 intrinsic subtyping and immunohistochemistry in South African women with breast cancer”. Breast Cancer Research and Treatment. 199 (1): 1–12. doi:10.1007/s10549-023-06886-3.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mirdula Sharma, MBBS [2] Soroush Seifirad, M.D.[3] Nehal Eid, M.D.[4]