Proposal of an automated tumor-stromal ratio assessment algorithm and a nomogram for prognosis in early-stage invasive breast cancer

Abstract

Background: The tumor-stromal ratio (TSR) has been verified to be a prognostic factor in many solid tumors. In most studies, it was manually assessed on routinely stained H&E slides. This study aimed to assess the TSR using image analysis algorithms developed by the Qupath software, and integrate the TSR into a nomogram for prediction of the survival in invasive breast cancer (BC) patients.

Methods: A modified TSR assessment algorithm based on the recognition of tumor and stroma tissues was developed using the Qupath software. The TSR of 234 invasive BC specimens in H&E-stained tissue microarrays (TMAs) were assessed with the algorithm and categorized as stroma-low or stroma-high. The consistency of TSR estimation between Qupath prediction and pathologist annotation was analyzed. Univariable and multivariable analyses were applied to select potential risk factors and a nomogram for predicting survival in invasive BC patients was constructed and validated. An extra TMA containing 110 specimens was obtained to validate the conclusion as an independent cohort.

Results: In the discovery cohort, stroma-low and stroma-high were identified in 43.6% and 56.4% cases, respectively. Good concordance was observed between the pathologist annotated and Qupath predicted TSR. The Kaplan-Meier curve showed that stroma-high patients were associated with worse 5-DFS compared to stroma-low patients (p = 0.007). Multivariable analysis identified age, T stage, N status, histological grade, ER status, HER-2 gene, and TSR as potential risk predictors, which were included in the nomogram. The nomogram was well calibrated and showed a favorable predictive value for the recurrence of BC. Kaplan-Meier curves showed that the nomogram had a better risk stratification capability than the TNM staging system. In the external validation of the nomogram, the results were further validated.

Conclusions: Based on H&E-stained TMAs, this study successfully developed image analysis algorithms for TSR assessment and constructed a nomogram for predicting survival in invasive BC.

Keywords: breast cancer; image analysis algorithm; qupath; tumor stromal ratio.