How to determine the risk of relapse in early breast cancers without lymph node involvement?

Risk Stratification for Early Breast Cancer Without Lymph Node Involvement

In node-negative early breast cancer, risk of relapse is determined primarily through a combination of tumor size, histologic grade, hormone receptor status, HER2 status, and proliferative markers (Ki-67), with genomic assays (Oncotype DX, MammaPrint) reserved for cases where treatment decisions remain uncertain after evaluating these clinicopathologic factors.

Primary Clinicopathologic Risk Factors

The strongest prognostic factors for determining relapse risk in node-negative disease include 1:

• Tumor size: Tumors ≤2 cm have favorable prognosis; those >2 cm carry higher risk 1, 2
• Histologic grade: Low grade (Grade 1) indicates lower risk; high grade (Grade 3) predicts higher recurrence 1, 2
• Hormone receptor status: ER/PR-positive tumors have better long-term prognosis, though late relapses (>5-8 years) are more common 1
• HER2 status: HER2-positive disease requires specific risk stratification and targeted therapy 1
• Ki-67 proliferation index: Low Ki-67 (<15-20%) indicates lower risk; elevated Ki-67 suggests higher proliferative activity and increased recurrence risk 1

Algorithmic Approach to Risk Assessment

Step 1: Establish Basic Tumor Characteristics

Confirm the following pathologic features 1:

• Tumor size (pathologic T stage)
• Lymph node status (confirmed pN0)
• Histologic grade (1,2, or 3)
• Lymphovascular invasion presence or absence 1

Step 2: Determine Molecular Subtype

Evaluate mandatory biomarkers 1:

• ER/PR status by immunohistochemistry (IHC)
• HER2 status by IHC or in situ hybridization (FISH/CISH)
• Ki-67 proliferative index by IHC

Step 3: Stratify by Molecular Subtype-Specific Risk

For Luminal A-like (ER+ and/or PR+, HER2-, low Ki-67, low grade):

• Lowest risk group overall 1, 3
• Tumor size <2 cm with Grade 1: very low risk, may not require chemotherapy 2
• Tumor size >2 cm or Grade 2: consider genomic testing if treatment decision uncertain 1

For Luminal B-like (ER+ and/or PR+, HER2-, high Ki-67 or high grade):

• Intermediate to high risk 1, 3
• Genomic assays particularly useful in this subgroup for chemotherapy decisions 1

For HER2-positive (regardless of HR status):

• Risk stratification based on tumor size and HR status 1
• Tumors <2 cm (T1) without nodal involvement: lower risk, may consider de-escalated therapy 1
• Tumors ≥2 cm: higher risk, typically require HER2-targeted therapy 1

For Triple-negative (ER-, PR-, HER2-):

• Higher early recurrence risk (peaks within 2-3 years) 1, 3
• Even small tumors carry significant risk 2, 3
• Lobular histology in triple-negative disease particularly high risk 4

Genomic Assays for Refined Risk Assessment

When clinicopathologic factors leave treatment decisions uncertain (particularly Grade 2, ER+/HER2- tumors), validated genomic assays provide additional prognostic information 1:

Oncotype DX (21-gene assay):

• Validated in ER+/HER2-, node-negative disease 1
• Provides recurrence score (RS) as continuous variable
• Low RS: low risk, chemotherapy may be avoided
• High RS: high risk, chemotherapy recommended

MammaPrint (70-gene assay):

• Validated for node-negative and limited node-positive (pN0-1) disease 1
• Classifies as low or high genomic risk
• Can be used across all breast cancer subtypes 1

Important caveat: These assays should be used in conjunction with all clinicopathologic factors, not as standalone decision tools 1. Results from ongoing prospective trials (MINDACT, TAILORx, RxPONDER) continue to refine their optimal use 1.

Additional Prognostic Considerations

Patient age and menopausal status:

• Younger age (<40 years) associated with higher recurrence risk 1, 2
• Premenopausal status may indicate more aggressive biology 1

Lymphovascular invasion (LVI):

• Presence of LVI increases risk of both local and distant recurrence 1
• Should be routinely assessed on pathology 1

Common Pitfalls to Avoid

• Do not rely on imaging alone (CT, MRI, PET) to determine nodal status; histologic examination via sentinel lymph node biopsy remains the gold standard 1
• Do not assume all node-negative cancers are low risk: approximately 30% of node-negative patients will develop distant recurrence without systemic therapy 2
• Do not use genomic assays in HER2-positive or triple-negative disease for chemotherapy decisions, as these subtypes generally require chemotherapy regardless of genomic score 1
• Do not forget to reassess receptor status if recurrence occurs, as biology may differ from primary tumor 5
• Recognize that ER-positive tumors have persistent late relapse risk (5-20 years), while ER-negative tumors have higher early risk but lower late risk 1

Risk-Based Treatment Decision Framework

Very low risk (T1a-b, Grade 1, ER+/PR+, HER2-, Ki-67 <15%, no LVI):

• May consider endocrine therapy alone 2

Low-intermediate risk (T1c-T2, Grade 1-2, ER+, HER2-, uncertain proliferation):

• Consider genomic testing to guide chemotherapy decision 1

High risk (T2-T3, Grade 3, or triple-negative, or HER2+):

• Systemic chemotherapy typically indicated 1, 2