Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases

• Published in: Strahlentherapie und Onkologie Vol. 190; no. 7; pp. 676 - 685
• Main Authors: Berghoff, A. S., Ilhan-Mutlu, A., Wöhrer, A., Hackl, M., Widhalm, G., Hainfellner, J. A., Dieckmann, K., Melchardt, T., Dome, B., Heinzl, H., Birner, P., Preusser, M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2014; Springer Nature B.V
• Subjects: Biomarkers, Tumor - metabolism; Brain Neoplasms - diagnosis; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Brain Neoplasms - therapy; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - secondary; Carcinoma, Non-Small-Cell Lung - therapy; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ki-67 Antigen - metabolism; Male; Medicine; Medicine & Public Health; Microvessels - pathology; Middle Aged; Oncology; Original Article; Prevalence; Prognosis; Radiotherapy; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Survival Analysis; Whole-brain radiation therapy; Angiogenesis; Ganzhirnbestrahlung; Hypoxia; Angiogenese; Proliferation; Survival; Hypoxie; Überleben
• ISSN: 0179-7158; 1439-099X
• DOI: 10.1007/s00066-014-0639-8

Background Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters. Methods Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry. Results NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0 %) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5 %) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups. Conclusion Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies.