Locoregional Recurrence Is Associated With Genomic Down-Regulation Of The Immune Response In Women With Locally Invasive Breast Cancer

Prior to the introduction of genomic testing, nearly all women with hormone receptor positive, invasive breast tumors were recommended to receive adjuvant chemotherapy. A parallel conceptual framework is emerging with respect to adjuvant whole breast and regional nodal radiation therapy, in which clinical and pathologic risk factors have been similarly unable to identify a group of patients in whom adjuvant whole breast radiation does not reduce the relative risk of recurrence. In this study we investigated genomic-based predictors of locoregional recurrence in women with early stage invasive breast adenocarcinoma. A total of 364 women with newly diagnosed locoregional invasive ductal carcinoma treated at our institution were retrospectively identified for analysis. Genomic-expression analysis was performed with the Affymetrix Rosetta/Merck Human RSTA Custom Affymetrix 2.0 microarray (HuRSTA_2a520709). Patient and tumor information and clinical outcomes were obtained by review of the clinical chart. Patients with any component of locoregional recurrence (ipsilateral breast or lymph nodes) were compared to patients with no evidence of local recurrence. Cutoffs for changes in gene expression include P < 0.01 and fold change > 1.3. or < 0.7. Gene ontology analysis of up- and down-regulated gene lists was performed using GATHER. A total of 281 women had available genomic profiling and were included for analysis. A total of 21 women (7.5%) experienced some component of locoregional recurrence, with 17 ipsilateral breast and 6 nodal events. Distant metastatic disease progression occurred in 46 women (16.4%). A total of 77 genes were upregulated and 27 genes downregulated in patients with locoregional failure. Genes upregulated in patients with locoregional recurrence were enriched for roles in mitotic activity (BRCA1 BUB1 CDC2 CENPE ESPL1 KNTC1 MPHOSPH9 NEK9; Bayes factor 12, P < 0.0001). In contrast, genes inhibited in patients with locoregional recurrence were enriched for immune response (CCL21 CCR6 CD1A CD1B CXCL6 F3 IL32 MS4A1 SERPINA1; Bayes factor 14, P < 0.0001). Patients with a component of locoregional recurrence had genomic profiles enriched for mitotic signaling and down regulation of immune response genes, suggesting a potential role of the immune system in promoting optimal locoregional control in breast cancer. However, metrics of immune-based activity are absent from established gene signatures of distant metastatic recurrence risks. Our work supports the hypothesis that immune therapy in patients with breast cancer may be a potential alternative strategy to improve locoregional, but not necessarily distant metastatic, control of disease. Current studies aiming to exclude adjuvant radiation therapy may be improved by incorporating immune-based genomic signatures or comparable metrics.