A 38-year-old woman has a 2.5 cm breast mass. Histology shows infiltrating tumor cells arranged in solid nests without tubule formation, with nuclear pleomorphism (grade 3 nuclei) and >10 mitoses/10 HPF. ER, PR, HER2 IHC are all negative on two separate assays. What is the molecular subtype, and which genetic association is most important to screen for?

• A Triple-negative breast cancer (TNBC), basal-like subtype; screen for BRCA1 germline mutation ✓
• B Luminal A subtype; screen for CDH1 germline mutation
• C HER2-enriched subtype; screen for ERBB2 amplification by FISH
• D Luminal B subtype; screen for PIK3CA somatic mutation

Explanation

Triple-negative breast cancer (ER−, PR−, HER2−) accounts for ~15–20% of breast cancers and is disproportionately represented in the basal-like molecular subtype (characterized by expression of basal cytokeratins CK5/6, CK14, EGFR). TNBC is strongly associated with BRCA1 germline mutations (~20–25% of TNBC in unselected patients; much higher in young women and high-risk populations). BRCA1-associated tumors are typically grade 3, have pushing margins, and show medullary-like features. Genetic counseling and BRCA1/2 germline testing are mandated for TNBC patients. CDH1 mutations cause lobular carcinoma; PIK3CA mutations are common in ER+ luminal tumors; ERBB2 amplification is the HER2-enriched subtype.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.