Novel Assay Identifies Low-Risk Patients With ER+ Early Breast Cancer

A novel prognostic assay, integrating routine clinicopathologic variables with computationally derived features from a single digitized hematoxylin-and-eosin-stained slide, has demonstrated robust performance in identifying a subgroup of patients with clinically high-risk estrogen receptor-positive (ER+), HER2-negative (–) early breast cancer who have a low risk of distant recurrence after standard therapy.¹

Published in the Journal of Clinical Oncology, the study presents an assay that could spare approximately 20% of these patients from the added toxicity and cost associated with treatment escalation, such as with CDK4/6 inhibitors, which are now widely recommended for this patient population.

In a combined validation cohort of 633 patients with high-risk ER+/HER2– early breast cancer from the prospective CANTO (NCT01993498) and UNIRAD (NCT01805271) trials, the assay classified 19.4% of patients into a low-risk group. At a 9-year follow-up, 95.4% of patients in this low-risk group remained free of distant recurrence and death from breast cancer, in stark contrast to the 76.8% rate observed in the not low-risk group. This difference was statistically significant, with a subdistribution hazard ratio (sHR) for distant recurrence-free interval (DRFI) of 0.21 (95% CI, 0.09–0.52; P <.001). The assay also showed statistically significant improvements for invasive disease-free survival (IDFS) and overall survival (OS) in the combined cohort.

The clinical utility of this assay lies in its ability to restratify patients traditionally considered to be at high risk for relapse. In recent years, adjuvant treatment for this patient population has escalated to include agents like CDK4/6 inhibitors, a practice influenced by landmark trials such as monarchE (NCT03155997) and NATALEE (NCT03701334). While these therapies have improved outcomes, a substantial portion of patients may already be cured with standard chemoendocrine therapy and would not benefit from additional treatment, thus exposing them to unnecessary adverse effects and decreased quality of life. The newly developed assay addresses this critical clinical gap by identifying a subgroup of patients for whom treatment escalation beyond standard chemoendocrine therapy may be futile.

The assay's development was based on a large retrospective cohort of 6164 patients with ER+/HER2– early breast cancer. Researchers utilized a Cox proportional-hazards model to integrate 4 routine clinicopathologic variables—number of positive lymph nodes, pathologic tumor size, grade, and percentage of progesterone receptor-positive cells—with 10 features derived from a single digitized hematoxylin-and-eosin-stained surgical resection slide. These slide-derived features capture key aspects of the tumor microenvironment, architecture, and proliferation^.The assay generates a continuous risk score that is then converted into a binary classification of low-risk or not low-risk.

“The prospective-retrospective design of this study offers a significant strength, replicating the conditions of a prospective trial. Importantly, the assay was locked-down after development, without any changes afterward, and the validation was blinded to outcomes and to cohort distributions,” study authors wrote.

Clinical validation was performed on 2 independent external cohorts of patients with high-risk ER+/HER2– early breast cancer. The CANTO cohort included 402 patients,² while the UNIRAD cohort included 231 patients from the control arm who did not receive everolimus.³ In the CANTO cohort, the assay assigned 21.1% of patients to the low-risk group. At 9 years, 94.7% of low-risk patients were free from distant recurrence and death, compared to 77.4% of not low-risk patients¹⁶. In the smaller UNIRAD cohort, 16.5% of patients were classified as low-risk, and 97.3% of these patients remained free from distant recurrence and death at 9 years, compared with 74.9% of the not low-risk patients. While the DRFI result in the UNIRAD cohort did not reach statistical significance, the combined analysis of both cohorts confirmed the assay's strong prognostic capability.

Furthermore, the study's analytical validation confirmed the assay's robustness against common sources of input variability, including different slide-scanning platforms and tumor heterogeneity. The findings suggest that the assay is a reliable prognostic tool that adds significant predictive value beyond standard clinicopathologic factors. The ability to accurately identify patients at minimal risk of relapse after standard therapy represents a major advancement in the management of high-risk ER+/HER2– breast cancer, paving the way for more personalized and less toxic treatment strategies.

REFERENCES:

1. Bidard FC, Gessain G, Bachelot T, et al. 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. J Clin Oncol. 0, JCO-25-00742. doi:10.1200/JCO-25-00742

2. Vaz-Luis I, Cottu P, Mesleard C, et al. UNICANCER: French prospective cohort study of treatment-related chronic toxicity in women with localised breast cancer (CANTO). ESMO Open. 2019 Sep 8;4(5):e000562. doi: 10.1136/esmoopen-2019-000562. eCollection 2019.

3. Giacchetti S, Laas E, Bachelot T, et al. Influence of hormone therapy timing intake on disease free survival (DFS) for patients with high-risk early breast cancer: Results of the UCBG-UNIRAD phase III randomized trial. J Clin Oncol. 41, 546-546(2023). doi:10.1200/JCO.2023.41.16_suppl.546