Artigo

Identifying Patients With Low Relapse Rate Despite High-Risk Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer: Development and Validation of a Clinicopathologic Assay

Autor(es): François-Cl´ ementBidard, MD, PhD 1; Gr´ egoireGessain, MD, PhD 2; Thomas Bachelot, MD, PhD 3; Lucie Frechin, MSc 4 ; Anne Vincent-Salomon, MD, PhD 1; Damien Drubay, PhD 2,5; J´ erˆ omeLemonnier, PhD 6 ; Thomas Walter, PhD 1,7,8 ; Fr´ ed´ eriquePenault-Llorca, MD, PhD 9; Anne-Laure Martin, PhD 6 ; Catherine Gaudin, BSc 6 ; Antoine Bichat, PhD 4; Farah Sassi, MD 2 ; Sylvain Berlemont, PhD 4 ; Mariana Chavez-MacGregor, MD 10; Hope S. Rugo, MD 11; C´ ecileBadoual, MD, PhD 2,12; Barbara Pistilli, MD, PhD 2 ; Joana Ribeiro, MD 2 ; Antonio Di Meglio, MD, PhD 13,14; Magali Lacroix-Triki, MD, PhD 2 ; Ines Vaz Luis, MD, PhD 2,13,14;Marvin Lerousseau, PhD 4; and Fabrice Andr´ eMD, PhD 2,13

ABSTRACT

PURPOSE
Escalation of adjuvant systemic therapies (eg, with cyclin-dependent kinase 4 and 6 inhibitors) is now indicated for patients with clinically defined high- risk estrogen receptor–positive (ER1)/human epidermal growth factor re-ceptor 2–negative (HER2–) early breast cancer, although it is unclear which will benefit from additional therapies. We developed and validated a prognostic clinicopathologic assay identifying a subpopulation of high-risk patients with good prognosis after standard adjuvant therapies, who may safely forgo treatment escalation.

METHODS
We trained a Cox proportional-hazards model that integrates clinicopathologic variables with features derived from digitized hematoxylin-and-eosin–stained resection slides from a retrospective data set. The model assigns each patient to a low-risk or not low-risk group, reflecting their predicted risk of recurrence. Blind validation was successively performed on high-risk patients from the prospective trials CANTO (ClinicalTrials.gov identifier: NCT01993498) and UNIRAD (ClinicalTrials.gov identifier: NCT01805271).

RESULTS
Built on data from 6,164 patients with ER1/HER2– early-stage breast cancer, this assay integrates four clinicopathologic variables, and 10 slide-derived features capturing tumor architecture, microenvironment, and proliferation. In the combined CANTO and UNIRAD trials (n 5 633), 95.4% of the low-risk patients remained free of distant recurrence and death from breast cancer at 9 years, compared with 76.8% for the not low-risk group. Distant recurrence-free interval (subdistribution hazard ratio [HR], 0.21 [95% CI, 0.09 to 0.52]; P < .001), invasive disease-free survival (HR, 0.31 [95% CI, 0.16 to 0.60]; P < .001), and overall survival (HR, 0.35 [95% CI, 0.13 to 0.97]; P 5 .044) were all sta-
tistically significant. Multivariate analyses showed that the assay provided predictive information beyond clinicopathologic variables. Analytical validation showed robustness to data variability.

CONCLUSION The assay demonstrated robust performance in identifying a core group of patients with high-risk ER1/HER2– breast cancer for whom additional adju-vant treatment may be futile.