Teaching pack: Carcinoma with medullary pattern (medullary breast cancer)

Medullary carcinoma was defined by a circumscribed, syncytial growth pattern, high nuclear grade and a dense lymphoplasmacytic infiltrate; because pathologists agreed poorly on the diagnosis and the molecular profile overlaps basal-like carcinoma, the 5th edition of the WHO classification (2019) reclassified it as invasive breast carcinoma of no special type with medullary pattern, alongside the other patterns of common ductal-origin carcinoma (Cserni 2020; Thomas 2023). Its behaviour is better than its grade suggests: among 12,409 patients in 13 International Breast Cancer Study Group trials, 14-year distant recurrence-free interval was 76 percent for 127 medullary against 64 percent for 8,096 invasive ductal tumours (hazard ratio 0.52) and overall survival 66 against 57 percent (0.75); restricted to ER-negative grade 3 tumours the figures were 89 against 63 percent (0.24) and 74 against 54 percent (0.55) (Huober 2012). Medullary tumours are BRCA1-related (odds ratio for BRCA2 versus BRCA1 carrier status 0.25 in the CIMBA pathology series, Mavaddat 2012), and the claudin-low subtype shows frequent medullary differentiation (Prat 2010). The immune infiltrate is the same feature now scored as stromal tumour-infiltrating lymphocytes across triple-negative disease.

• KEYNOTE-522 (phase 3, n=1,174): Pathologic complete response (ypT0/Tis ypN0): 64.8% vs 51.2%

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. Did KEYNOTE-522 improve overall survival?
   Answer

   Yes. Seven-year overall survival was 85.1% vs 77.2% (ASCO 2026 update); five-year EFS 81.2% vs 72.2%; pCR 64.8% vs 51.2%.
3. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
4. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.

• Huober, Ann Oncol 2012: prognosis of medullary breast cancer in 13 IBCSG trials: https://doi.org/10.1093/annonc/mds105
• Cserni, Pathologica 2020: histological type and typing of breast carcinomas and WHO classification changes: https://doi.org/10.32074/1591-951x-1-20
• Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer: https://doi.org/10.1038/s41523-023-00554-x
• Mavaddat, Cancer Epidemiol Biomarkers Prev 2012: pathology of breast cancers in BRCA1 and BRCA2 carriers (CIMBA): https://doi.org/10.1158/1055-9965.epi-11-0775
• Prat, Breast Cancer Res 2010: phenotypic and molecular characterisation of the claudin-low intrinsic subtype: https://doi.org/10.1186/bcr2635
• Tan et al., Histopathology 2020: the 2019 WHO classification of tumours of the breast (5th edition): https://doi.org/10.1111/his.14091
• Quinn et al., Histopathology 2026;89(2):199 to 218: World Health Organization classification of tumours of the breast, 6th edition 2026: https://doi.org/10.1111/his.70149
• Wikipedia: https://en.wikipedia.org/wiki/Medullary_breast_carcinoma