Blood Biomarkers Useful for Understanding NSCLC Prognosis

A study of patients with inoperable non-small cell lung cancer (NSCLC) has found that certain blood biomarkers may have prognostic value and could enhance treatment decision-making for providers. 

To improve outcomes for patients with lung cancer, health care professionals are increasingly looking at ways to better stratify patients and provide care that is targeted and more personalized. One way they have done this is by looking at the genetics of cancer tumors and cells, but this can be difficult when tissue sampling is not possible—which is often the case in patients with lung cancer. Thus, using blood sampling to analyze the presence of oncoproteins—produced by or in response to tumor cells—in the bloodstream represents a promising alternative for patients and providers. 

In a study published in Radiotherapy & Oncology, researchers led by Sara Carvalho, PhD applicant at the University of Maastricht (The Netherlands), analyzed how certain proteins found in the blood of patients with cancer were related to disease prognosis and treatment response and used them to create a model capable of enhancing clinical decision-making.  
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The researchers focused on blood biomarkers that could be measured in daily clinical practice and have been associated with treatment outcomes in past studies with large data sets. With this as a guideline, they chose to investigate biological functions related to the processes of hypoxia (osteopontin [OPN]) and carbonic anhydrase IX [CA-IX]); inflammation (interleukin 6 [IL-6], IL-8, and C-reactive protein [CRP]); and tumor load (carcinoembryonic antigen [CEA] and cytokeratin fragment [CYFRA 21-1]). As an exploratory step, they also looked at additional markers related to immunological response that could be incorporated into immunotherapy assessment studies (alpha-2-macroglobulin [α2M], serum IL-2 receptor [sIL2R], toll-like receptor 4 [TLR4], and vascular endothelial growth factor [VEGF]).

To evaluate these potential biomarkers, the research team created a development dataset (n = 195) and validation dataset (n = 200) of patients with NSCLC to support statistical analysis of the different markers. In the development set, all patients were treated with chemoradiotherapy between October 2003 and October 2008 with blood samples collected prospectively to ensure standardization. In the validation set, patient characteristics were the same, except they were treated between March 2007 and September 2013. The primary endpoint was overall survival from the start of treatment. 

The researchers then used statistical analysis techniques to construct a model analyzing the usefulness of blood biomarkers and their relation to clinical features and patient characteristics. At analysis, 161 and 132 patients had died in the development and validation cohorts, respectively (median follow-up, 8.2 years and 3.6 years, respectively).

There were only small differences observed between the presence of each biomarker in the validation and development sets, with the exception of IL-8, which was significantly higher in the validation set, though it did not have a drastically higher median. Adding blood biomarkers related to hypoxia and tumor load reflected statistically significant improvement in the performance of a clinical model predicting disease progression. 

In the exploratory model, α2M, sIL2r, and VEGF were found to be representative of worse prognosis, especially α2M, which past studies have shown to be associated with radiation pneumonitis. High IL-2R levels were also associated with shorter survival in patients with advanced NSCLC, reinforcing its use as an important measure for patients receiving immunotherapy. 

Researchers noted that their study had limitations, most significantly the fact that it was impossible to validate their latest findings using newer biomarkers, as they were only used in the validation dataset. This should be addressed in future studies by gathering data from other external institutes. 

“In conclusion, we improved a clinical model by the inclusion of blood-biomarkers related to hypoxia and tumor load,” researchers wrote. “This improvement was validated externally, which reinforces its potential relevance for shared decision-making.” –Sean McGuire


Carvalho S, Troost EG, Bons J, Menheere P, Lambin P, Oberije C. Prognostic value of blood-biomarkers related to hypoxia, inflammation, immune response and tumour load in non-small cell lung cancer - a survival model with external validation [published online ahead of print April 29, 2016]. Radiother Oncol. doi: 10.1016/j.radonc.2016.04.024.