ER and PR Classification in Breast Cancer
ER and PR status in breast cancer is not reported in "stages" but rather as categorical classifications based on the percentage of tumor cells with nuclear staining by immunohistochemistry, with specific thresholds determining positivity and treatment eligibility.
Classification Categories for ER Status
The ASCO/CAP guidelines establish three distinct reporting categories for ER 1:
- ER Negative: <1% or 0% of tumor cell nuclei show immunoreactive staining 1
- ER Low Positive: 1-10% of tumor cell nuclei are positive (new reporting category as of 2020) 1
- ER Positive: ≥10% to 100% of tumor cell nuclei are positive 1
Critical Nuance for ER Low Positive Cases
Tumors with 1-10% ER staining must be reported as "ER Low Positive" with a mandatory comment explaining the limited clinical data and heterogeneous biology of this subgroup 1. This distinction is crucial because:
- These tumors often have clinical outcomes and molecular profiles more similar to ER-negative cancers than high ER expressers 1
- Evidence for endocrine therapy benefit in this range is limited, though some benefit may exist based on historical tamoxifen data showing risk reduction even at 10-20 fmol/mg by ligand-binding assay 1
- The 1% threshold remains the cutoff for considering endocrine therapy due to relatively low toxicity and desire to minimize false-negatives 1
Classification Categories for PR Status
PR follows simpler binary classification 1:
- PR Negative: <1% or 0% of tumor cell nuclei show nuclear staining 1
- PR Positive: ≥1% to 100% of tumor cell nuclei show nuclear staining 1
The "Low Positive" reporting category does not apply to PR testing 1. PR is used primarily for prognostic purposes in the setting of ER-positive cancer rather than as a primary predictor of endocrine therapy benefit 1.
Historical Context and Evolution
The older 2005 ESMO guidelines used a ≥10% threshold for considering ER/PR positive 1, and some endocrine responsiveness was noted even at 1-10% positivity 1. The 2020 ASCO/CAP update lowered the positive threshold to ≥1% but added the "Low Positive" category to acknowledge the biological heterogeneity 1.
Reporting Requirements
Both percentage and intensity of staining must be reported in addition to the categorical interpretation 1. For cases with 0-10% staining, the status of controls must also be documented 1.
Clinical Implications by Category
ER-Positive/PR-Positive Pattern
- Most favorable prognosis and best response to endocrine therapy 1, 2
- Standard recommendation for 5 years of tamoxifen or aromatase inhibitors 1, 3
ER-Positive/PR-Negative Pattern
- More aggressive phenotype with larger tumor size, higher S-phase fraction, and more frequent aneuploidy 2
- Three times more likely to express HER-1 (25% vs 8%) and 50% more likely to overexpress HER-2 (21% vs 14%) compared to ER+/PR+ tumors 2
- Associated with worse disease-free survival and potential tamoxifen resistance, particularly when HER-1 or HER-2 are overexpressed 2, 4
- Despite concerns about efficacy, hormone blocking therapy still shows survival benefit and should be offered 4
ER-Negative/PR-Positive Pattern
This phenotype is extremely rare if it exists at all 5. A reevaluation study of 205 cases initially reported as ER-negative/PR-positive found that after careful review with 1% cutoff, 181 of 182 reevaluable cases changed their phenotype—most converting to dual-positive (n=124) or dual-negative (n=31) 5. Any case with this pattern should prompt immediate retesting and reassessment 5.
Common Pitfalls to Avoid
- Never use the term "stages" when discussing ER/PR status—this creates confusion with TNM cancer staging 1
- Do not omit the "Low Positive" designation for 1-10% ER cases—this is a mandatory reporting element as of 2020 1
- Do not apply the "Low Positive" category to PR results—PR uses only positive/negative binary classification 1
- Always retest ER-negative/PR-positive results—this pattern is almost always due to technical or interpretive error 5