Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study

Abstract

Background Metastatic breast cancer (MBC) is a challenging disease, and despite new therapies, prognosis is still poor for a majority of patients. There is a clinical need for improved prognostication where immuno-oncology markers can provide important information. The aim of this study was to evaluate serum immuno-oncology markers in MBC patients and their respective relevance for prediction of survival. Patients and methods We investigated a broad panel of 92 immuno-oncology proteins in serum from 136 MBC patients included in a prospective observational study (NCT01322893) with long-term follow-up. Serum samples were collected before start of systemic therapy and analyzed using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Multiple machine learning techniques were used to identify serum markers with highest importance for prediction of overall and progression-free survival (OS and PFS), and associations to survival were further evaluated using Cox regression analyses. False discovery rate was then used to adjust for multiple comparisons. Results Using random forest and random survival forest analyses, we identified the top nine and ten variables of highest predictive importance for OS and PFS, respectively. Cox regression analyses revealed significant associations (P < 0.005) of higher serum levels of IL-8, IL-10 and CAIX with worse OS in multivariable analyses, adjusted for established clinical prognostic factors including circulating tumor cells (CTCs). Similarly, high serum levels of IL-8, IL-10, ADA and CASP8 significantly associated with worse PFS. Interestingly, high serum levels of FasL significantly associated with improved OS and PFS. In addition, CSF-1, IL-6, MUC16, TFNSFR4 and CD244 showed suggestive evidence (P < 0.05) for an association to survival in multivariable analyses. After correction for multiple comparisons, IL-8 still showed strong evidence for correlation to survival. Conclusion To conclude, we found six serum immuno-oncology markers that were significantly associated with OS and/or PFS in MBC patients, independently of other established prognostic factors including CTCs. Furthermore, an additional five serum immuno-oncology markers provided suggestive evidence for an independent association to survival. These findings highlight the relevance of immuno-oncology serum markers in MBC patients and support their usefulness for improved prognostication. Trial registration Clinical Trials (NCT01322893), registered March 25, 2011.

Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor

“…FASLG is expressed on cytotoxic T cells, where it is an inducer of apoptosis through its binding with the Fas receptor [32]. Previous studies have found an association between FASLG expression and anti-cancer activity [33,34]. A recent study by Gunnarsdottir et al using Olink PEA showed an association between high serum FASLG levels and improved OS and PFS rates in breast cancer [34], which is similar to the results shown in this study.…”

Serum protein profiling reveals an inflammation signature as a predictor of early breast cancer survival

“…Another protein of the IL family included in the prognostic model was IL-10, a pleiotropic inflammatory and immune system regulator, which was only one of the nine identified proteins in the signature that predicted improved outcome [ 27 ]. Recently, high PEA-measured IL-10 levels were reported to be associated with worse progression-free survival in metastatic breast cancer [ 28 ]. In line with our results, high tissue expression of IL-10 was associated with improved DFS and BCSS in a series of 1380 early breast cancer patients in univariate analysis [ 29 ].…”

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study

“…IL-6 is a major regulator of myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumour functions of T and NK-cells. High plasma IL-6 is therefore associated with a worse prognosis as it leads to increased tumour cell proliferation and metastasis [ 45 – 47 ]. Additionally, more extensive surgical trauma and sympathetic activation during mastectomy may cause greater adrenergic and prostaglandin responses, which also affect immune function.…”