What is the role of Oncotype Dx (Oncotype DNA test) in determining treatment for hormone receptor-positive, HER2-negative breast cancer?

Role of Oncotype DX in Hormone Receptor-Positive, HER2-Negative Breast Cancer Treatment

Oncotype DX testing is recommended for guiding adjuvant chemotherapy decisions in patients with estrogen receptor-positive, lymph node-negative, HER2-negative early breast cancer who are at intermediate risk of recurrence, as it helps predict the benefit of chemotherapy and informs treatment planning. 1

Clinical Validity and Utility

• Oncotype DX provides a Recurrence Score (RS) that stratifies patients into risk categories for distant recurrence, with established clinical validity in both node-negative and node-positive disease 1
• The test has been shown to predict benefit from chemotherapy in both lymph node-negative and lymph node-positive disease through retrospective analyses of prospective trials 1
• Oncotype DX changes treatment decisions regarding chemotherapy in clinical practice, though direct evidence that this leads to improved clinical outcomes is still being gathered through ongoing trials 1
• The UK National Institute for Health and Care Excellence (NICE) recommends Oncotype DX for patients assessed as being at intermediate risk where the biological information would help predict disease course and guide chemotherapy decisions 1

Patient Selection for Testing

• Oncotype DX is most appropriate for patients with hormone receptor-positive, HER2-negative breast cancer where the benefit of adding chemotherapy to endocrine therapy is uncertain 1, 2
• Testing is particularly valuable in:
  • Patients with node-negative disease where chemotherapy indication is uncertain 1
  • Selected patients with 1-3 positive lymph nodes 1, 2
  • Patients under age 35 where more aggressive treatment may be warranted 1
• The National Comprehensive Cancer Network (NCCN) considers RT-PCR analysis (e.g., Oncotype DX) to refine risk stratification for adjuvant chemotherapy in node-negative, ER-positive, HER2-negative breast cancers larger than 0.5 cm (category 2B recommendation) 1

Interpretation of Recurrence Scores

• Low RS (0-10): Indicates very low risk of distant recurrence with endocrine therapy alone 2
• Intermediate RS (11-25): Shows limited additional benefit from chemotherapy in postmenopausal women 2
• High RS (≥26): Demonstrates clear benefit from adjuvant chemotherapy 1, 2
• Recent research suggests that patients ≤45 years with RS ≥18 may benefit from adding chemotherapy to endocrine therapy, as demonstrated by improved disease-free survival 3

Integration with Other Clinical Factors

• Oncotype DX provides prognostic information independent of that derived from the Adjuvant! algorithm 1
• Combining RS with clinicopathological features may provide improved risk assessment over RS alone 1
• Factors associated with Oncotype DX utilization include age 50-64, tumor size 10.1-20mm, and grade 2 histology, reflecting clinical uncertainty about chemotherapy benefit in these subgroups 4
• Pathological factors that correlate with RS include progesterone receptor status and mitotic count, with negative PR and high mitotic count associated with higher RS 5

Limitations and Considerations

• The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient direct evidence that Oncotype DX testing leads to improved clinical outcomes, despite its established clinical validity 1
• Cost-effectiveness studies suggest Oncotype DX may be cost-effective or cost-saving, but these are based on assumptions about clinical utility that require confirmation 1
• Other gene expression profiling tests should not currently be considered equivalent to Oncotype DX with respect to data generated or risk stratification 1
• Machine learning approaches using conventional pathological variables may eventually help predict Oncotype DX results, potentially optimizing test utilization 6, 7

Clinical Application Algorithm

1. Identify patients with early-stage (I-II), hormone receptor-positive, HER2-negative breast cancer 1
2. Consider Oncotype DX testing for:
   • Node-negative patients with tumors >0.5 cm where chemotherapy benefit is uncertain 1, 2
   • Selected patients with 1-3 positive nodes 1, 2
   • Patients where standard clinicopathological features provide conflicting risk assessment 2
3. Use the Recurrence Score to guide treatment:
   • Low RS (0-10): Endocrine therapy alone 2
   • Intermediate RS (11-25): Consider patient age and other risk factors; chemotherapy benefit is limited in postmenopausal women 2
   • High RS (≥26): Add chemotherapy to endocrine therapy 1, 2
4. For younger patients (≤45 years), consider chemotherapy at a lower threshold (RS ≥18) 3