Abstract
BackgroundPrimary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form. Osteosarcomas are commonly treated with multi-drug neoadjuvant chemotherapy and therapy success as well as patient survival is affected by the presence of tumor suppressors. In order to assess the prognostic value of tumor-suppressive biomarkers, primary osteosarcoma tissues were analyzed prior to and after neoadjuvant chemotherapy.MethodsWe constructed a tissue microarray from high grade osteosarcoma samples, consisting of 48 chemotherapy naïve biopsies (BXs) and 47 tumor resections (RXs) after neoadjuvant chemotherapy. We performed immunohistochemical stainings of P53, P16, maspin, PTEN, BMI1 and Ki67, characterized the subcellular localization and related staining outcome with chemotherapy response and overall survival. Binary logistic regression analysis was used to analyze chemotherapy response and Kaplan-Meier-analysis as well as the Cox proportional hazards model was applied for analysis of patient survival.ResultsNo significant associations between biomarker expression in BXs and patient survival or chemotherapy response were detected. In univariate analysis, positive immunohistochemistry of P53 (P = 0.008) and P16 (P16; P = 0.033) in RXs was significantly associated with poor survival prognosis. In addition, presence of P16 in RXs was associated with poor survival in multivariate regression analysis (P = 0.003; HR = 0.067) while absence of P16 was associated with good chemotherapy response (P = 0.004; OR = 74.076). Presence of PTEN on tumor RXs was significantly associated with an improved survival prognosis (P = 0.022).ConclusionsPositive immunohistochemistry (IHC) of P16 and P53 in RXs was indicative for poor overall patient survival whereas positive IHC of PTEN was prognostic for good overall patient survival. In addition, we found that P16 might be a marker of osteosarcoma chemotherapy resistance. Therefore, our study supports the use of tumor RXs to assess the prognostic value of biomarkers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1397-4) contains supplementary material, which is available to authorized users.
Highlights
Primary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form
Table 1), we found that changes in gradings of Ki67 (P = 0.0004, log-rank test) and maspin (P = 0.029, logrank test) had significant prognostic value for overall survival (Fig. 4), where a decrease in grading of both markers was associated with better survival compared to no change or an increase
We found that an increase in maspin expression in matched tumor specimens had a worse survival prognosis compared to patients in which maspin gradings decreased or remained unchanged
Summary
Primary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form. Osteosarcomas are commonly treated with multi-drug neoadjuvant chemotherapy and therapy success as well as patient survival is affected by the presence of tumor suppressors. In order to assess the prognostic value of tumor-suppressive biomarkers, primary osteosarcoma tissues were analyzed prior to and after neoadjuvant chemotherapy. Osteosarcoma patients are commonly treated with multiagent neoadjuvant chemotherapy, combined with surgery to remove the primary tumor mass and subsequent adjuvant chemotherapy. The presence of metastases is a strong prognostic factor for poor survival rates of 30 % or less [4]. For osteosarcoma, a patient’s response to neoadjuvant chemotherapy has a considerable prognostic value and has replaced single adjuvant chemotherapy [5, 6]. Necrosis of tumor resections (RXs) above 90 %, only a crude read out, is still used in clinical practice due to its prognostic
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