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The clinical use of biomarkers as prognostic factors in Ewing sarcoma.

van Maldegem AM, Hogendoorn PC, Hassan AB - Clin Sarcoma Res (2012)

Bottom Line: Good histological response (necrosis > 90%) after treatment appeared a significant predictor for a positive outcome.Our recommendation is that we can stratify patients according to their stage and using the phenotypic features of metastases, tumour size and histological response.For biological biomarkers, we suggest a number of validating studies including markers for 9p21 locus, heat shock proteins, telomerase related markers, interleukins, tumour necrosis factors, VEGF pathway, lymphocyte count, and a number of other markers including Ki-67.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology University of Oxford, Oxford, OX3 7LJ, UK. bass.hassan@path.ox.ac.uk.

ABSTRACT
Ewing Sarcoma is the second most common primary bone sarcoma with 900 new diagnoses per year in Europe (EU27). It has a poor survival rate in the face of metastatic disease, with no more than 10% survival of the 35% who develop recurrence. Despite the remaining majority having localised disease, approximately 30% still relapse and die despite salvage therapies. Prognostic factors may identify patients at higher risk that might require differential therapeutic interventions. Aside from phenotypic features, quantitative biomarkers based on biological measurements may help identify tumours that are more aggressive. We audited the research which has been done to identify prognostic biomarkers for Ewing sarcoma in the past 15 years. We identified 86 articles were identified using defined search criteria. A total of 11,625 patients were reported, although this number reflects reanalysis of several cohorts. For phenotypic markers, independent reports suggest that tumour size > 8 cm and the presence of metastasis appeared strong predictors of negative outcome. Good histological response (necrosis > 90%) after treatment appeared a significant predictor for a positive outcome. However, data proposing biological biomarkers for practical clinical use remain un-validated with only one secondary report published. Our recommendation is that we can stratify patients according to their stage and using the phenotypic features of metastases, tumour size and histological response. For biological biomarkers, we suggest a number of validating studies including markers for 9p21 locus, heat shock proteins, telomerase related markers, interleukins, tumour necrosis factors, VEGF pathway, lymphocyte count, and a number of other markers including Ki-67.

No MeSH data available.


Related in: MedlinePlus

Distribution of p related to patient number for the biological markers related to cell cycle, karyotype, immunological, blood products and remaining markers. The red line shows the cut-off point of p = 0.05. Note, there is no line for immunological phenotypic markers because for all the results p < 0.05.
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Figure 3: Distribution of p related to patient number for the biological markers related to cell cycle, karyotype, immunological, blood products and remaining markers. The red line shows the cut-off point of p = 0.05. Note, there is no line for immunological phenotypic markers because for all the results p < 0.05.

Mentions: Biological markers are more difficult to compare, because for most of these markers only one or two reports are published. We grouped the biological markers according to their function and we ended up with 5 groups, namely cell cycle, karyotype, immunological, blood products and the remaining biological markers which couldn't be classified in one of the other groups. The results from the biological markers are shown in Tables 5, 6, 7, 8 and 9. The correlation between patient number and statistical significance of the outcome for the five groups is shown in Figures 3. We show that there is no correlation between the patient number and the statistical significance of the outcome. It appears that ki67, an S-phase cell cycle biomarker, may be a biomarker of cell activity in the tumour that significantly correlates with outcome. The mechanism for the activation of cell cycle appears unclear, but is presumably driven by other factors other that EWS-FLI1 translocation. Loss of function of cell cycle dependent kinases (p16, p14, p21) and other regulators of the cell cycle through the p53 pathway (MDM2, p53), also appear deregulate in a proportion of tumours and potentially are useful prognostic markers. Importantly, activity of telomerase appears significantly correlated with outcome as occurs in many other tumours. There appears much interest in secondary copy number changes and mutations in Ewing sarcoma, and in particular, chromosome 1 (Table 6). For example, recent evidence points to gain of 1q and alteration in abundance of a gene product called CDt2 involved in ubiquitination [7]. It is however difficult to objectively say anything about the other reported markers because they may influence each other. This appears most clear for tumour size and metastases, where bigger tumours may correlate with a higher chance of having metastases. For biological markers it is probably the same issue, but less clear because we don't really know their true experimental influence on tumour genesis. For example, LDH levels are probably a reflection of cell turnover in larger tumours, and may be an indirect measure of bulk of disease (comparing Table 2 versus Table 9). It is also more difficult to say anything about biological markers because they haven't been tested as extensively as phenotypic markers, and certainly they have not often been validated independently. Results for most of these markers are only reported in 1 or 2 articles with sometimes small numbers of patients and no statistical validation. To improve this situation it would important to capture high quality clinical material and clinical outcome to develop a bio-bank. We may be able to test the most promising biomarkers from previously run studies and so define their significance. Either a multivariate analysis or data mining analysis should be done to evaluate the way biomarkers affect each other. The easiest way to achieve this objective is by collecting material and outcome data from large phase III trials. It is also important to standardize the way material is collected and how the biomarkers are compared. For example, the phenotypic marker tumour site is the most often tested marker with results published in 26 articles (data not shown). However it is not possible to say anything about these results since different tumour sites are compared in the reports. This is also true for the marker age in which different age groups are compared with each other, for example some articles compare patients < 18 years vs > 18 years, others < 30 years vs > 30 years (data not shown).


The clinical use of biomarkers as prognostic factors in Ewing sarcoma.

van Maldegem AM, Hogendoorn PC, Hassan AB - Clin Sarcoma Res (2012)

Distribution of p related to patient number for the biological markers related to cell cycle, karyotype, immunological, blood products and remaining markers. The red line shows the cut-off point of p = 0.05. Note, there is no line for immunological phenotypic markers because for all the results p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351700&req=5

Figure 3: Distribution of p related to patient number for the biological markers related to cell cycle, karyotype, immunological, blood products and remaining markers. The red line shows the cut-off point of p = 0.05. Note, there is no line for immunological phenotypic markers because for all the results p < 0.05.
Mentions: Biological markers are more difficult to compare, because for most of these markers only one or two reports are published. We grouped the biological markers according to their function and we ended up with 5 groups, namely cell cycle, karyotype, immunological, blood products and the remaining biological markers which couldn't be classified in one of the other groups. The results from the biological markers are shown in Tables 5, 6, 7, 8 and 9. The correlation between patient number and statistical significance of the outcome for the five groups is shown in Figures 3. We show that there is no correlation between the patient number and the statistical significance of the outcome. It appears that ki67, an S-phase cell cycle biomarker, may be a biomarker of cell activity in the tumour that significantly correlates with outcome. The mechanism for the activation of cell cycle appears unclear, but is presumably driven by other factors other that EWS-FLI1 translocation. Loss of function of cell cycle dependent kinases (p16, p14, p21) and other regulators of the cell cycle through the p53 pathway (MDM2, p53), also appear deregulate in a proportion of tumours and potentially are useful prognostic markers. Importantly, activity of telomerase appears significantly correlated with outcome as occurs in many other tumours. There appears much interest in secondary copy number changes and mutations in Ewing sarcoma, and in particular, chromosome 1 (Table 6). For example, recent evidence points to gain of 1q and alteration in abundance of a gene product called CDt2 involved in ubiquitination [7]. It is however difficult to objectively say anything about the other reported markers because they may influence each other. This appears most clear for tumour size and metastases, where bigger tumours may correlate with a higher chance of having metastases. For biological markers it is probably the same issue, but less clear because we don't really know their true experimental influence on tumour genesis. For example, LDH levels are probably a reflection of cell turnover in larger tumours, and may be an indirect measure of bulk of disease (comparing Table 2 versus Table 9). It is also more difficult to say anything about biological markers because they haven't been tested as extensively as phenotypic markers, and certainly they have not often been validated independently. Results for most of these markers are only reported in 1 or 2 articles with sometimes small numbers of patients and no statistical validation. To improve this situation it would important to capture high quality clinical material and clinical outcome to develop a bio-bank. We may be able to test the most promising biomarkers from previously run studies and so define their significance. Either a multivariate analysis or data mining analysis should be done to evaluate the way biomarkers affect each other. The easiest way to achieve this objective is by collecting material and outcome data from large phase III trials. It is also important to standardize the way material is collected and how the biomarkers are compared. For example, the phenotypic marker tumour site is the most often tested marker with results published in 26 articles (data not shown). However it is not possible to say anything about these results since different tumour sites are compared in the reports. This is also true for the marker age in which different age groups are compared with each other, for example some articles compare patients < 18 years vs > 18 years, others < 30 years vs > 30 years (data not shown).

Bottom Line: Good histological response (necrosis > 90%) after treatment appeared a significant predictor for a positive outcome.Our recommendation is that we can stratify patients according to their stage and using the phenotypic features of metastases, tumour size and histological response.For biological biomarkers, we suggest a number of validating studies including markers for 9p21 locus, heat shock proteins, telomerase related markers, interleukins, tumour necrosis factors, VEGF pathway, lymphocyte count, and a number of other markers including Ki-67.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology University of Oxford, Oxford, OX3 7LJ, UK. bass.hassan@path.ox.ac.uk.

ABSTRACT
Ewing Sarcoma is the second most common primary bone sarcoma with 900 new diagnoses per year in Europe (EU27). It has a poor survival rate in the face of metastatic disease, with no more than 10% survival of the 35% who develop recurrence. Despite the remaining majority having localised disease, approximately 30% still relapse and die despite salvage therapies. Prognostic factors may identify patients at higher risk that might require differential therapeutic interventions. Aside from phenotypic features, quantitative biomarkers based on biological measurements may help identify tumours that are more aggressive. We audited the research which has been done to identify prognostic biomarkers for Ewing sarcoma in the past 15 years. We identified 86 articles were identified using defined search criteria. A total of 11,625 patients were reported, although this number reflects reanalysis of several cohorts. For phenotypic markers, independent reports suggest that tumour size > 8 cm and the presence of metastasis appeared strong predictors of negative outcome. Good histological response (necrosis > 90%) after treatment appeared a significant predictor for a positive outcome. However, data proposing biological biomarkers for practical clinical use remain un-validated with only one secondary report published. Our recommendation is that we can stratify patients according to their stage and using the phenotypic features of metastases, tumour size and histological response. For biological biomarkers, we suggest a number of validating studies including markers for 9p21 locus, heat shock proteins, telomerase related markers, interleukins, tumour necrosis factors, VEGF pathway, lymphocyte count, and a number of other markers including Ki-67.

No MeSH data available.


Related in: MedlinePlus