How is the risk of relapse determined in patients with early Hormone Receptor positive (HR+) Human Epidermal growth factor Receptor 2 negative (HER2-) breast cancers without nodal involvement?

Risk Stratification in Early HR+ HER2- Node-Negative Breast Cancer

Risk of relapse in early HR+ HER2- breast cancers without nodal involvement is determined primarily through a combination of traditional clinicopathologic features (tumor size, grade, Ki67) and multigene expression assays, with the 21-gene Oncotype DX Recurrence Score being the most validated tool for both predicting recurrence risk and chemotherapy benefit. 1, 2

Traditional Clinicopathologic Risk Factors

Tumor size serves as the initial stratification point:

• Tumors ≤0.5 cm have such favorable prognosis that adjuvant systemic therapy beyond endocrine therapy is not recommended 1
• Tumors 0.6-1.0 cm require assessment of unfavorable features including high nuclear grade, high histologic grade, or presence of lymphovascular invasion 1
• Tumors >1 cm are appropriate candidates for adjuvant systemic therapy consideration 1

Histologic grade directly correlates with recurrence risk:

• Low grade (Grade 1) tumors have minimal recurrence risk with endocrine therapy alone 1
• Grade 2 tumors require additional risk stratification, particularly when combined with Ki67 ≥20% 3
• Grade 3 tumors indicate higher risk and warrant consideration of chemotherapy 1, 3

Ki67 proliferation index provides additional prognostic information:

• Ki67 ≥20% in Grade 2 tumors elevates risk category and may indicate need for genomic testing 3
• This marker is particularly relevant in Stage IIA node-negative disease 3

Multigene Expression Assays

21-Gene Assay (Oncotype DX) - Most Validated

This is the only multigene assay clinically validated for predicting chemotherapy benefit, not just prognosis 2, 4

Low Recurrence Score (RS 0-10):

• Distant recurrence risk <5% at 9 years with endocrine therapy alone 1, 2
• No incremental benefit from adding chemotherapy 1, 2
• These patients should receive endocrine therapy only 1

Intermediate Recurrence Score (RS 11-25):

• In postmenopausal women, chemotherapy provides no additional benefit beyond endocrine therapy 1, 2
• Critical exception: Women ≤50 years with RS 16-25 had 12.3% distant recurrence at 9 years with endocrine therapy alone versus lower rates with added chemotherapy 2
• Age becomes a decisive factor in this RS range 1, 2

High Recurrence Score (RS ≥31):

• Clear benefit from adjuvant chemotherapy demonstrated in prospective studies 1, 2
• These patients should receive chemotherapy plus endocrine therapy 1

The NCCN considers the 21-gene assay an option for tumors 0.6-1.0 cm with unfavorable features or >1 cm, when node-negative, HR-positive, and HER2-negative (Category 2B) 1

70-Gene Assay (MammaPrint)

Provides genomic risk stratification independent of clinical features:

• Low genomic risk patients have 5-year survival without distant metastasis of 95.7% with endocrine therapy alone, even with high clinical risk features 1
• The MINDACT trial demonstrated that 93.2% of node-negative patients with high clinical risk/low genomic risk had 5-year survival without distant metastasis on endocrine therapy alone 1
• The additional benefit of chemotherapy in high clinical risk/low genomic risk patients is likely very small 1

50-Gene Assay (PAM50)

Stratifies patients into low, medium, and high risk of recurrence (ROR) categories:

• Low ROR score: 5.0% distant recurrence risk in node-negative tumors 1
• High ROR score: 17.8% distant recurrence risk 1
• Low ROR score places patients in same prognostic category as T1a-T1b tumors regardless of actual size 1

12-Gene Assay (EndoPredict)

Identifies very low-risk subgroups:

• Low-risk score: 4% distant recurrence at 10 years with endocrine therapy alone 1
• Prognostic value independent of conventional clinicopathological factors 1
• Particularly useful for identifying patients at low risk for late recurrence 1

Algorithmic Approach to Risk Determination

Step 1: Assess tumor size

• If ≤0.5 cm → Endocrine therapy only (no genomic testing needed) 1
• If 0.6-1.0 cm → Proceed to Step 2
• If >1 cm → Proceed to Step 2

Step 2: Evaluate unfavorable features

• High grade (Grade 3) 1
• Lymphovascular invasion 1
• Ki67 ≥20% (in Grade 2 tumors) 3
• If present → Proceed to Step 3
• If absent and tumor 0.6-1.0 cm → Consider endocrine therapy only

Step 3: Obtain genomic testing (preferably Oncotype DX)

• RS 0-10 → Endocrine therapy only 1, 2
• RS 11-25 → Age-dependent decision:
  • If >50 years → Endocrine therapy only 1, 2
  • If ≤50 years AND RS 16-25 → Consider chemotherapy + endocrine therapy 1, 2
  • If ≤50 years AND RS 11-15 → Endocrine therapy only 1
• RS ≥31 → Chemotherapy + endocrine therapy 1, 2

Critical Pitfalls to Avoid

Do not assume all HR-positive patients need chemotherapy - the incremental benefit in low-risk disease is minimal and must be weighed against toxicity 2

Do not withhold chemotherapy solely based on ER-positive status - other high-risk features may override this 1

Do not use genomic assays interchangeably - only Oncotype DX is validated for predicting chemotherapy benefit; other assays are prognostic only 2, 4

Do not ignore age in intermediate RS (11-25) patients - premenopausal women ≤50 years with RS 16-25 derive chemotherapy benefit that postmenopausal women do not 1, 2

Do not order genomic testing in very small tumors (≤0.5 cm) - these have such favorable prognosis that testing adds no clinical value 1, 5

Recognize discordant clinical-genomic risk scenarios - patients with high clinical risk but low genomic risk have excellent outcomes with endocrine therapy alone, and chemotherapy adds minimal benefit 1