Li, Jing

AbstractBackgroundA recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.MethodsIn this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment.ResultsThe APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014).ConclusionsPatients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Abstract Introduction Recent advances in stereotactic radiosurgery (SRS) have improved clinical outcomes in patients with limited intracranial metastases. As a result of this high-dose radiation delivery to a focal area within the brain, tissue structural and functional changes within the treatment field are often difficult to distinguish from local tumor recurrence based on conventional imaging techniques. Here, we demonstrate that elevation of circulating cells of myeloid origin, the key regulators of inflammation and immune responses, can serve as a potential surrogate marker to differentiate radiation-induced tissues changes from local tumor recurrence. Materials and Methods We retrospectively identified 96 patients who were initially treated with Gamma-knife radiosurgery at MD Anderson Cancer Center from 2009-2013 for brain metastases, and subsequently underwent surgical resection of previous irradiated lesions after presenting with clinical symptoms and radiographic findings suggestive of tumor progression. All surgical specimens were centrally reviewed by neuropathology. Pre-operative circulating blood cell profiles were analyzed for monocytic, granulocytic and lymphocytic sub-populations. Results A total of 11 and 85 patients who underwent surgical resection after prior SRS for brain metastasis were pathologically confirmed to have radiation-induced changes or tumor recurrence, respectively. Among patients with confirmed recurrence vs. those with radiation-induced changes, the number of circulating immature granulocytes (mean = 0.093 × 103ul−1 vs 0.032 × 103ul−1, p = 0.075) and monocytes (mean = 0.632 × 103ul−1 vs 0.401 × 103ul−1, p = 0.007) were elevated when compared to patients with radiation-induced changes (combined: mean = 0.71 × 103ul−1 vs 0.43 × 103ul−1, p = 0.002). No statistically significant differences were observed among mature granulocytic or lymphocytic populations between the two groups. Receiver operating characteristic analysis showed significant discriminative utility of pre-operative myeloid cell count when compared to reference line of no discrimination (AUC = 0.774, p = 0.003). The cut-point for myeloid cell population was found be > = 0.5 × 103ul−1, which corresponds to a detection sensitivity of 73.3% and specificity of 72.7% for tumor recurrence. Conclusion Bone marrow cells of myeloid origin play important roles in mediate acute inflammatory reactions and in regulating adaptive immunity. We showed here that certain primitive cells of myeloid lineage may potentially be used to aid the differentiation of tumor recurrence from radiation-induced changes in patients who had SRS for brain metastasis. The identification of potential circulating biomarkers that can complement traditional imaging to distinguish the two distinct pathological entities has significant implications in the management of these patients. Note: This abstract was not presented at the meeting. Citation Format: Wen Jiang, Yvo Rodriguez, Nicolas S. Boehling, Sujit S. Prabhu, Betty Y.S. Kim, Patrick Hwu, Erik P. Sulman, Paul D. Brown, Jing Li. Circulating myeloid precursor profile as potential marker to differentiate radiation changes from tumor recurrence after brain stereotactic radiosurgery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 532. doi:10.1158/1538-7445.AM2015-532