Breast cancer cells that express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced bone metastatic capacity (Bidwell et al, Nat Med 2012). However, viral or bacterial infections can restore this IFN signature and activate an anti-tumor immune response. Objectives of the study were to evaluate if the occurrence of “severe infection” could be a clinical surrogate of this phenomenon and/or if the presence of high levels of an IRF7 signature during neoadjuvant chemotherapy (NACT) was associated with a reduced distant relapse risk, specifically of bony metastases.
Clinical data of the EORTC 10994/BIG 1-00 phase III trial were used which evaluated NACT in 1856 early-stage breast cancers. “Severe infection” was defined as febrile neutropenia or other infective adverse events (grade 3-4) during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients. Cox models for distant relapse free interval (DRFI) investigated the effect of the severe infection (landmark approach) and IRF7. Fine & Gray models studied the secondary endpoint of bone metastases as first distant relapse.
No major associations were observed between the occurrence of a severe infection during NACT and baseline patient and tumor characteristics. Median follow-up was 4.8 years. No significant association between severe infection and DFRI was observed (HR = 0.99, 90% CI = 0.81-1.20, N = 1615). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50-unit increase, 90% CI = 0.78-1.02, 1-sided p = 0.081). However higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: HR = 0.76 for a 50-unit increase, (95% CI, 0.62-0.94, p = 0.012).
The occurrence of a severe infection during NACT was not associated with decreased DRFI. High expression of the IRF7 signature was significantly associated with reduced risk of bone relapse supporting preclinical evidence that tumor intrinsic innate immunity is crucial for bone metastases prevention. This may be useful for guiding future adjuvant bisphosphonate/denosumab use.
Clinical trial identification
Legal entity responsible for the study
Cancer Research Fund and EORTC Breast Cancer Group
All authors have declared no conflicts of interest.