The prognostic time dependence of intra-tumoural IFNγ mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy

Abstract

To cite this article: Todorović-Raković N, Radulovic M, Vujasinović T, Milovanović J, Nikolić-Vukosavljević D. The prognostic time dependence of intra-tumoural IFN␥ mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy. Eur. Cytokine Netw. 2017; 28(4): 151-6 ABSTRACT. There is increasing evidence for the importance of immunity in breast cancer. IFN␥ is expected to have a prognostic value based on its major role in innate and specific cell-mediated immunity. In this retrospective study, based on the 14-year follow-up of 73 patients with breast cancer after surgery and radiotherapy but no subsequent systemic therapy, we investigated the prognostic time dependence of intra-tumoural IFN␥ mRNA and protein levels. Over the entire 14 years of follow-up, neither IFN␥ mRNA nor protein was significantly associated with metastasis outcome by AUC and Cox regression criteria. However, evaluation of the shorter periods has revealed a prognostic significance in the late follow-up period of 7-14 years for IFN␥ mRNA and protein with the maximal respective AUCs of 0.72 and 0.73 and hazard ratios of 6.1 and 5.2, respectively. Interestingly, the opposite prognostic association was discovered for IFN␥ mRNA and protein in the first 7 years of follow-up, possibly due to the negative correlation of IFN␥ protein and mRNA. Moreover, the prognostic association of IFN␥ mRNA has shifted from marking the favourable outcome in the first 7 years to poor outcome thereafter. This study contributes to clarification of the previously inconsistent prognostic performance of IFN␥ by providing the first prognostic evaluation with long follow-up, time-dependence assessment and absence of any chemotherapy influence.

The prognostic significance of serum interferon-gamma (IFN-γ) in hormonally dependent breast cancer

“…Over the entire period of 14 years of follow-up neither IFN-γ mRNA nor IFN-γ protein levels were significantly associated with breast cancer outcome by ROC analysis or Cox regression criteria, but intratumoral IFN-γ mRNA was associated significantly with favorable disease outcome over the first 7 years of follow-up. [19]. The current study demonstrates the prognostic value of measuring IFN-γ in the serum of patients with breast cancer; this allows easy sampling and repeated measurements.…”

“…In our previous study, based upon the long-term follow-up of 73 pN0M0 breast cancer patients after surgery & radiotherapy receiving no subsequent systemic therapy, we investigated the prognostic value of intratumoral IFN-γ mRNA and protein levels [19]. Over the entire period of 14 years of follow-up neither IFN-γ mRNA nor IFN-γ protein levels were significantly associated with breast cancer outcome by ROC analysis or Cox regression criteria, but intratumoral IFN-γ mRNA was associated significantly with favorable disease outcome over the first 7 years of follow-up.…”

Cytokine Modulation in Breast Cancer Patients Undergoing Radiotherapy: A Revision of the Most Recent Studies

“…For this review, 45 studies were retrieved from PubMed and another 2 by searching the bibliographies of other papers. Of these, only 15 studies [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41] were included in the analysis, and the reasons for exclusion are reported and detailed in the Supplementary Materials (Table S1). Results of the studies included in our analysis are reported in Table 1 and Table 2.…”

“…Todorović-Raković et al [30] adopted longer timepoints analyzing the protein and mRNA at the intratumoral level up to 14 years after RT and revealed a consistent prognostic association of IFN-γ protein with a poor disease outcome in patients with a longer follow-up (>7 years). Similarly, for IFN-γ mRNA, a peculiar time-dependent prognostic shift has been reported: from 6 months after RT and until 7 years, IFN-γ mRNA is associated with a good outcome, whereas in patients with a longer follow-up (>7 years), it has been related to a poor prognosis.…”

“…Some studies also reported survival curves estimating different endpoints (i.e., progression-free survival (PFS), MFS, or OS) in correlation to individual cytokine level modulation [29,30,32,42,43], thus indicating possible biomarkers useful for patient stratification. For example, a low basal level of IL-10 before SBRT correlates to a high probability of PFS, as well as a high NF-κB level in natural killer cells [29].…”