How Low-Estrogen Breast Tumors Are Being Overlooked in Cancer Risk Testing
When Sarah was diagnosed with breast cancer at 48, her pathology report showed weakly positive estrogen receptors (1-10% staining) and HER2-negative status. Though treated aggressively, her cancer recurred within two years. Only then did genetic testing reveal a BRCA2 mutation—a discovery that might have changed her initial treatment and alerted her sisters to their own cancer risks.
Tragically, Sarah's story reflects a systemic blind spot in oncology: low-ER/HER2- breast tumors are not routinely referred for germline testing, despite harboring hereditary cancer mutations at rates matching triple-negative breast cancer 1 4 .
Low-ER/HER2- tumors (1-10% staining) behave biologically like triple-negative breast cancer but are often excluded from genetic testing guidelines.
Estrogen receptor (ER) status determines breast cancer treatment and prognosis. In 2010, guidelines redefined ER positivity as tumors with ≥1% stained cells, excluding low-ER (1-10% staining)/HER2- tumors from the triple-negative breast cancer (TNBC) category 4 . Biologically, however, these tumors behave differently:
Until recently, only TNBC patients diagnosed ≤60 qualified for germline testing under NCCN guidelines. Low-ER/HER2- patients faced exclusion despite biological similarities. A 2020 study exposed this disparity: only 67.7% of low-ER patients met testing criteria versus 81.1% of TNBC patients 4 .
Researchers analyzed 314 breast cancer patients (60 low-ER/HER2-, 254 TNBC) from the Clinical Breast Care Project (2010-2019) 4 :
| Characteristic | Low-ER/HER2- (n=60) | TNBC (n=254) | p-value |
|---|---|---|---|
| Age ≤45 years | 18.3% | 21.7% | 0.443 |
| Family history (≥1 relative) | 70% | 57.5% | 0.197 |
| Tumor grade (poorly differentiated) | 75.0% | 83.0% | 0.488 |
| Stage III/IV disease | 20.0% | 13.4% | 0.092 |
BRCA1 (28.6%), BRCA2 (21.4%), CHEK2 (21.4%), PALB2 (14.3%)
Clinical impact: 33% of mutation carriers had no family history—underscoring the need for universal testing 4
| Tumor Type | Patients Tested | Mutation Frequency | Most Common Mutations |
|---|---|---|---|
| Low-ER/HER2- | 56 | 16.1% | BRCA1, BRCA2, CHEK2 |
| TNBC | 222 | 16.7% | BRCA1, BRCA2, PALB2 |
Even when tumor sequencing suggests hereditary risk, germline testing falls short:
Misses 6.6% of germline variants due to assay limitations or interpretation differences
Lung, colorectal, and unknown-primary cancers show the highest referral gaps 6
| Reason | Frequency | Example Cases |
|---|---|---|
| Not referred | 67.2% | 50% had BRCA/Lynch mutations 6 |
| Assay design differences | 61.9% | Large deletions undetected by somatic panels |
| Bioinformatic filtering | 23.8% | Variants deep in introns excluded |
Automatic germline referrals for all low-ER/HER2- or TNBC patients—regardless of age/family history 4
New platforms like Illumina's TruSight assess both somatic and germline variants simultaneously, reducing omissions
| Reagent/Technology | Function | Example Use in Studies |
|---|---|---|
| TruSight Cancer Panel (Illumina) | 94-gene NGS panel | Detected germline variants in research cohort 4 |
| Circulating tumor DNA (ctDNA) | Liquid biopsy for tumor DNA | Monitored ESR1 mutations in SERENA-6 trial 5 |
| Qubit Fluorometer (Thermo Fisher) | DNA quantification | Standardized DNA input for sequencing 4 |
| PROTAC molecules | Targeted protein degraders | Vepdegestrant outperformed fulvestrant in ESR1+ cancers 5 |
Low-ER/HER2- breast tumors represent a critical frontier in precision oncology. With 1 in 6 patients carrying hereditary mutations, restricting testing to TNBC excludes thousands from life-saving interventions. As Dr. Erika Hamilton emphasized at ASCO 2025, we're in an era of "moving targeted therapies up" in treatment lines—but this requires matching the right genetics to the right drugs 8 .