Incorporating RNA-based Risk Scores for Genomic Instability to Predict Breast Cancer Recurrence and Immunogenicity in a Diverse Population

Markers of genomic instability, including TP53 status and homologous recombination deficiency (HRD), are candidate biomarkers of immuno-genicity and immune-mediated survival, but little is known about the distribution of these markers in large, population-based cohorts of racially diverse patients with breast cancer. In prior clinical trials, DNA-based approaches have been emphasized, but recent data suggest that RNA -based assessment can capture pathway differences conveniently and may be streamlined with other RNA-based genomic risk scores. Thus, we used RNA expression to study genomic instability (HRD and TP53 pathways) in context of the breast cancer immune microenvironment in three datasets (total n = 4,892), including 1,942 samples from the Carolina Breast Can-cer Study, a population-based study that oversampled Black (n = 1,026) and younger women (n = 1,032). Across all studies, 36.9% of estrogen receptor (ER)-positive and 92.6% of ER-negative breast cancer had pres-ence of at least one genomic instability signature. TP53 and HRD status were significantly associated with immune expression in both ER-positive and ER-negative breast cancer. RNA-based genomic instability signatures were associated with higher PD-L1, CD8 T-cell marker, and global and multimarker immune cell expression. Among tumors with genomic insta-bility signatures, adaptive immune response was associated with improved recurrence-free survival regardless of ER status, highlighting genomic in-stability as a candidate marker for predicting immunotherapy response. Leveraging a convenient, integrated RNA-based approach, this analysis shows that genomic instability interacts with immune response, an impor-tant target in breast cancer overall and in Black women who experience higher frequency of TP53 and HR deficiency.Significance: Despite promising advances in breast cancer immunother-apy, predictive biomarkers that are valid across diverse populations and breast cancer subtypes are needed. Genomic instability signatures can be coordinated with other RNA-based scores to define immunogenic breast cancers and may have value in stratifying immunotherapy trial participants.