Testing Women for Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is diagnosed through immunohistochemistry (IHC) testing of breast tissue that demonstrates absence of estrogen receptor (ER), progesterone receptor (PgR), and HER2 expression—specifically ER-negative, PgR-negative, and HER2-negative. 1
Diagnostic Testing Approach
Initial Tissue Acquisition and Testing
The diagnosis requires obtaining breast tissue through:
- Core needle biopsy (preferred over fine needle aspiration for better antigen preservation) 1
- Testing must include IHC for three markers:
- Estrogen receptor (ER)
- Progesterone receptor (PgR)
- HER2 status
Critical caveat: If all three markers are negative on the initial biopsy specimen, retesting on the surgical specimen is mandatory to account for tumor heterogeneity 1. In cases of discrepancy, the surgical specimen results are considered definitive.
Defining Triple-Negative Status
- ER absent (< 1% positive cells)
- PgR absent (< 1% positive cells)
- HER2-negative (no overexpression or amplification)
This represents approximately 10-20% of all invasive breast cancers 2.
Additional Recommended Testing
Germline Genetic Testing
All women diagnosed with TNBC before age 60 should be offered genetic testing for BRCA1/2 and other cancer predisposition genes, regardless of family history 1, 3, 4. This recommendation is based on:
- TNBC patients have the highest prevalence of pathogenic variants (23%) among breast cancer subtypes 5
- BRCA1/2 pathogenic variant rates in TNBC patients ≥60 years range from 2.3-4.9% 3
- For women diagnosed ≤50 years: 78 of 100 pathogenic variants were detected in this age group 5
- Women aged 50-59 with TNBC show 11.3% pathogenic variant prevalence 6
Specific genetic testing criteria for TNBC 1, 3:
- Diagnosis before age 60 years (regardless of family history)
- Any age if strong family history of breast/ovarian/pancreatic/prostate cancer
- All ages if personal history of bilateral breast cancer or ovarian cancer
Testing should include BRCA1, BRCA2, and a panel of other cancer predisposition genes (PALB2, ATM, CHEK2, TP53, etc.) 3, 5.
Prognostic Biomarkers
Tumor-infiltrating lymphocytes (TILs) should be scored as a prognostic marker in TNBC 1. Each 10% increase in TILs provides approximately 15-20% relative improvement in survival. However, TIL scoring should NOT be used to make treatment decisions or escalate/de-escalate therapy 1.
Screening and Detection Considerations
Imaging for Detection
Standard breast imaging includes 1:
- Bilateral mammography
- Ultrasound of breasts and axillae
- MRI is recommended for high-risk women (those with BRCA mutations or strong family history)
Important note: TNBC is more difficult to detect on mammography compared to other breast cancer subtypes, but screening mammography still provides significant survival benefit through early detection, particularly for African American women who have twice the incidence of TNBC 7.
High-Risk Populations Requiring Enhanced Surveillance
TNBC disproportionately affects 2, 8:
- Younger women (premenopausal, particularly those <50 years)
- African American women (39% higher prevalence than White women)
- BRCA1 mutation carriers (51% develop TNBC subtype) 9
Common Pitfalls to Avoid
Do not rely solely on biopsy results: Always retest negative ER/PgR/HER2 results on surgical specimens to avoid missing heterogeneous tumors 1
Do not skip genetic testing based on age alone: The 10% threshold for pathogenic variants extends to age 60 for TNBC patients, not just age 50 3, 6
Do not confuse triple-negative with basal-like: Only 80% of triple-negative cancers are basal-like subtype; TNBC also includes special histological types like medullary carcinoma, secretory carcinoma, and adenoid cystic carcinoma 1
Do not use genomic assays for TNBC: Oncotype DX, MammaPrint, Prosigna, and other multi-gene assays should NOT be used to guide treatment decisions in triple-negative breast cancer 8