Aleix Prat, MD
As reported in The Lancet Oncology, Prat et al have developed a prognostic risk score model—HER2DX—that can be used to identify patients with early-stage HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment.
As stated by the investigators, “In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.”
Study Details
The combined prognostic model was derived using retrospective clinical-pathologic data on stromal tumor-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients from the phase III Short-HER trial, with a maximum of 92 features being evaluated in constructing the model. In the trial, patients with newly diagnosed disease who were node-positive, or with at least one risk factor if node-negative, were randomly assigned to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Median follow-up was 91.4 months.
“The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.”— Prat et al
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The primary objective in the current work was to develop a combined prognostic score associated with distant metastasis–free survival in the trial participants. The final prognostic model was evaluated in an independent dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2–based combinations from four additional studies with disease-free survival outcome data (evaluation cohort).
Key Findings
The final model, HER2DX—derived from data from 435 (35%) of 1,254 patients in the Short-HER trial with available relevant clinical-pathologic and molecular data—included 17 components: tumor size (T1 vs rest), nodal status (N0 vs rest), number of tumor-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes.
In the Short-HER cohort, HER2DX score was significantly associated with distant metastasis–free survival as a continuous variable (P < .0001).
In the Short-HER cohort, the median score for score quartiles 1–2 was used as the cutoff for low-risk patients, and the score separating score quartile 3 from quartile 4 was used as the cutoff for medium-risk vs high-risk patients. The 5-year distant metastasis–free survival rates were 98.1%, 88.9%, and 73.9% in the low-, medium-, and high-risk groups. The hazard ratio (HR) for low-risk vs high-risk was 0.04 (95% confidence interval [CI] = 0.0–0.1, P < .0001) and the HR for low-risk vs medium-risk was 0.11 (95% CI = 0.0–0.3, P < .0001).
In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR = 2.77, 95% CI = 1.4–5.6, P = .0040). The 5-year disease-free survival rate was 93.5% in the low-risk group vs 81.1% in the high-risk group (HR = 0.27, 95% CI = 0.1–0.7, P = .005). Disease-free survival at 8 years was 91.7% vs 54.1%.
The investigators concluded, “The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.”
Aleix Prat, MD, of the Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Instituto Salud Carlos III, Asociación Española Contra el Cáncer, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, Italian Association for Cancer Research, and others. For full disclosures of the study authors, visit thelancet.com.
