Copy Number–Based Chromosomal Instability Ex-Score Predicts Breast Cancer Malignancy

Abstract Background Histological grade (HG) is an essential pathological factor of malignancy in breast cancer, but its evaluation remains partly subjective and affected by interobserver variability. Because genomic instability reflects intrinsic tumor aggressiveness, we hypothesized that genome-wide copy number variation (CNV) profiles in primary tumors may serve as an objective indicator of malignancy. We therefore developed the Copy Number–based Chromosomal Instability Ex-Score (CIS) and evaluated its ability to predict HG. Methods Two independent cohorts of estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER-positive/HER2-negative) breast cancers were analyzed: The Cancer Genome Atlas (TCGA, n = 175) and an independent Asian validation cohort (n = 31). Genome-wide CNVs were extracted using ASCAT (version 2.5), and the numbers of copy gains, losses, and loss of heterozygosity (LOH) were integrated via logistic regression to generate CIS. An ASCAT-derived aberrant cell fraction (ACF)–based quality-control step was applied to enhance CNV reliability. The predictive ability of CIS for HG was assessed using receiver operating characteristic analysis. Results CIS showed a strong association with HG, achieving an AUC of 0.852 in the TCGA cohort, which improved to 0.878 after applying the ACF threshold (ACF < 0.72). Its reproducibility was confirmed in the Asian cohort, supporting cross-ethnic generalizability. CIS showed predictive performance comparable to or exceeding that of the homologous recombination deficiency (HRD) score. Conclusions CIS, reflecting CNV-driven chromosomal instability, provides an objective predictor of histological grade in breast cancer and may enhance the accuracy and objectivity of pathological assessment in clinical practice.