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.

Automated summary

Markers of genomic instability, including TP53 status and HRD, are candidate biomarkers of immunogenicity and immune-mediated survival in breast cancer. This study used RNA expression to investigate the association between genomic instability and the breast cancer immune microenvironment. The results showed that genomic instability signatures were associated with immune expression and improved recurrence-free survival, highlighting the potential of genomic instability as a marker for predicting immunotherapy response.