Outcome of Patients With an Ultralow-Risk 70-Gene Signature in the MINDACT Trial.

Purpose: Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date.
Methods: Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer-specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression.
Results: Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node-negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100).
Conclusion: Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects.
Competing Interests: Emiel J. T. RutgersHonoraria: Guerbet Annuska M. GlasEmployment: Agendia Anke WitteveenEmployment: AgendiaStock and Other Ownership Interets: Agendia Fatima CardosoConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Teva, Astellas Pharma, Merus, Celgene, Eisai, Daiichi Sankyo, Genentech, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Macrogenics, Amgen, GE Healthcare, GlaxoSmithKline, Mylan, Mundipharma, Seattle Genetics, Samsung Bioepis, Medscape, Prime OncologyTravel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Martine PiccartConsulting or Advisory Role: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Seattle Genetics, NBE Therapeutics, Frame TherapeuticsResearch Funding: AstraZeneca (Inst), Lilly (Inst), MSD (Inst), Novartis (Inst), Pfizer (Inst), Roche/Genentech (Inst), Radius Health (Inst), Synthon (Inst), Servier (Inst), Immunomedics/Gilead (Inst), Menarini (Inst)Other Relationship: Oncolytics, EU Cancer Mission Board Laura J. EssermanConsulting or Advisory Role: Blue Cross Blue Shield AssociationResearch Funding: MerckTravel, Accommodations, Expenses: Blue Cross Blue Shield AssociationUncompensated Relationships: Quantum Leap Healthcare Collaborative Laura J. van 't VeerEmployment: AgendiaStock and Other Ownership Interets: AgendiaNo other potential conflicts of interest were reported.