Annals of Oncology Advance Access originally published online on September 15, 2006
Annals of Oncology 2006 17(11):1673-1676; doi:10.1093/annonc/mdl287
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© 2006 European Society for Medical Oncology
lung cancer |
Thyroid transcription factor 1—a new prognostic factor in lung cancer: a meta-analysis
1 Department of Intensive Care and Thoracic Oncology, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Belgium
2 Data Centre, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Belgium
3 Department of Pathology, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Belgium
4 Chest Department, Centre Hospitalier Universitaire Calmette, Lille, France
*Correspondence to: Dr T. Berghmans, Institut Jules Bordet, rue Héger-Bordet, 1, B-1000 Brussels, Belgium. Tel: +32-2-541-31-91; Fax: +32-2-534-37-56; E-mail: thierry.berghmans{at}bordet.be
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Abstract |
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Background: The aim of this study was to determine the prognostic role for survival of thyroid transcription factor 1 (TTF-1) in lung cancer.
Methods: Studies evaluating survival and TTF-1 in lung cancer patients, published until August 2005, were assessed with a methodological scoring system. The required data for estimation of individual hazard ratios (HRs) for survival were extracted from the publications and a combined HR was calculated.
Results: We identified 10 eligible papers, all dealing with non-small-cell lung cancer (NSCLC). Eight were meta-analysed (evaluable studies). Seven studies included patients with local and/or locoregional diseases and three dealt only with adenocarcinoma. Median methodological quality score was 65.9% (range = 31.8%–70.5%). TTF-1 positivity was associated with statistically significant reduced or improved survival in one and four studies, respectively. Combined HR for the eight evaluable studies was 0.64 [95% confidence interval (CI) = 0.41–1.00]. In the subgroup of adenocarcinoma, the combined HR was 0.53 (95% CI = 0.29–0.95).
Conclusion: TTF-1 is a good prognostic factor for survival in NSCLC. Its effect appears also significant when the analysis is restricted to patients with adenocarcinoma. This study supports the fact that TTF-1 could be included in further prospective trials studying prognostic factors in NSCLC.
Key words: lung cancer, meta-analysis, prognostic factor, survival, systematic review, thyroid transcription factor 1
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introduction |
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TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
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Non-small-cell lung cancer (NSCLC) is a major cause of death in developed countries. Overall, survival is poor for the majority of patients. Yet, in early stages, cure is obtained in <60% of the cases [1]. Advances have been obtained with neo-adjuvant chemotherapy in surgical stages [2], with increased survival associated with these treatments. Nevertheless, chemotherapy is associated with significant morbidity and mortality needing for a better definition of the patients who will most benefit from such an approach. In this setting, prognostic factors could be of potential value. Some clinical independent prognostic factors for survival have already been identified: performance status (PS), stage and, with lower impact, age, sex and weight loss [3, 4]. Some of these factors are useful when choosing the treatment on an individual basis, principally disease stage, but for most of the potential prognostic markers, their discriminant value is insufficient to allow an individual decision.
In recent years, research has focused on the potential role of new biological factors involved in the carcinogenic process, as prognostic markers for survival in patients with lung cancer. Results were frequently conflicting among the studies or studies lacked statistical power. In order to answer this question, the methodological group of the European Lung Cancer Working Party (ELCWP) has carried out various meta-analyses. We showed that vascular endothelial growth factor [5], higher microvessel density [6], Epidermal Growth Factor Receptor (EGFR) [7], HER-2/Neu [8], Ki-67 [9], K-Ras [10] and p53 [11] are probable negative prognostic factors, while Bcl-2 positivity [12] is associated with a better survival.
The thyroid transcription factor 1 (TTF-1), also known as Nkx2.1 or thyroid-specific enhancer-binding protein, is a 38-kDa nuclear protein encoded by a gene located on chromosome 14q13. TTF-1 is expressed in the thyroid, the lung and the diencephalum during embryogenesis. It plays a physiologic role in the development and the morphogenesis of the thyroid and the lung during embryogenesis. The role of TTF-1 in lung carcinogenesis remains largely unexplained. It was suggested that TTF-1 could promote cancerisation by regulating the activity of proliferating cells and the formation of new vessels, at least in adenocarcinoma [13], and by increasing the rate of cell proliferation [14].
In lung cancer, TTF-1 is more frequently expressed in adenocarcinoma and small-cell lung cancer than in squamous cell carcinoma. The prognostic role of TTF-1 for survival in lung cancer was assessed in few studies, mainly incorporating NSCLC at local or locoregional stages. Their results are conflicting and do not allow the drawing of definitive conclusions. The aim of this study was to assess the possible role of TTF-1 as prognostic factor for survival in lung cancer by carrying out a systematic review of the literature followed by a meta-analysis.
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material and methods |
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To be eligible for the systematic review, a study had to fulfil the following criteria: to deal with lung cancer only (any stage or histology), to assess the relationship between TTF-1 and survival and to have been published as a full paper in the English, Dutch or French language. Abstracts were excluded due to insufficient data to evaluate the methodological quality of the trial and/or to carry out meta-analysis. Studies were identified by an electronic search on Medline data bank using the following key words: ‘lung neoplasms’, ‘TTF-1’ and ‘thyroid transcription factor 1’. The references reported in all the identified studies were used to complete this search which ended in August 2005.
To assess the methodological quality of the publications, each study was read independently by seven investigators according to the ELCWP scale previously published [11] and applied in other meta-analyses [5–10, 12]. Each item was assessed using an ordinal scale (possible values = 2, 1, 0). As the assessed items were objective ones, a consensus was always obtained on each value. All items were separated into four categories, each scored on a maximum of 10 points: the scientific design, the description of the laboratory methods, the generalisability of the results and the analysis of the study data. The final scores were expressed as percentages, ranging from 0% to 100%, higher values reflecting better methodological quality. Studies included in the systematic review were called ‘eligible’ and those providing sufficient data for the meta-analysis ‘evaluable’.
statistical methods
A study was considered as significant if the P value for the statistical test comparing survival distributions between the groups with and without TTF-1 expression was <0.05. A study was called ‘positive’ or ‘negative’ when TTF-1 positivity was identified as a significant favourable or unfavourable prognostic factor for survival, respectively. These studies were further called ‘significant’ ones. Finally, a study was called ‘not significant’ if no statistically significant difference between the two groups was detected.
The association between two continuous variables was measured by the Spearman's rank correlation coefficient. Non-parametric tests were used to compare the distribution of the quality scores according to the value of a discrete variable (Mann–Whitney tests for dichotomic variables or Kruskal–Wallis tests for multiple class variables).
For the quantitative aggregation of the survival results, we measured the impact of TTF-1 positivity on survival by hazard ratio (HR) between the two survival distributions. For each trial, this HR was estimated by a method depending on the data provided in the publication. The most accurate method consisted of calculating the estimated HR and its standard error from the reported results or to calculate them directly using two of the following parameters: the O – E statistic (difference between numbers of observed and expected events), the confidence interval (CI) for the HR and the log-rank statistic or its P value. If these were not available, the total numbers of events, the number of patients at risk in each group and the log-rank statistic or its P value were used to allow for an approximation of the HR estimate. Finally, if the only exploitable data were in the form of graphical representations of the survival distributions, survival rates at some specified times were extracted in order to reconstruct the HR estimate and its variance, with the assumption that the rate of patients censored was constant during the study follow-up [15]. If this last method was used, three independent persons read the curves to reduce the inaccuracy in the extracted survival rates. The individual HR estimates were combined into an overall HR using Peto's method [16]. If homogeneity among the studies was confirmed by carrying out a chi-square test for heterogeneity, we used a fixed-effect model; otherwise, we used a random-effect model. By convention, an observed HR <1 implied a better survival for the group with TTF-1 expression and was considered statistically significant if the 95% CI did not overlap 1.
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results |
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Ten publications, published between 1999 and 2005, were eligible for the systematic review [13, 14, 17–24]. All these publications concerned different cohorts of patients. The total number of included patients was 1101, ranging from 50 to 284 patients per study (median = 93). The main characteristics of the 10 eligible publications are reported in Table 1. TTF-1 expression was always detected by immunohistochemistry. The same mAb was used except by Puglisi et al. [14]. There was a doubt for Shah et al. [22] who used an antibody furnished by Dako (Carpinteria, CA) which was the producer of the majority of mouse mAb 8G7G3/1 employed by the other authors. Two studies were not included in the meta-analysis due to a lack of data in the publications, not allowing the HR calculation.
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Half of the studies were significant (all evaluable for meta-analysis) of which only one identified TTF-1 as a poor prognostic factor for survival; four studies demonstrated that TTF-1 positivity is associated with better survival. The five others showed no statistically significant impact of TTF-1 on survival (three evaluable for meta-analysis).
The overall quality score for the 10 eligible studies ranged from 31.8% to 70.5% with a median of 65.9%. The individual results of the quality scores are reported in Table 1.
meta-analysis
The individual HR of the eight evaluable studies (652 patients) [13, 14, 18–22, 24] was calculated as follows: three studies allowed to directly calculate the estimated HR; in two studies, HR was approximated by the total number of events and the log-rank statistic; for the three remaining ones, HR had to be extrapolated from the graphical representation of the survival distributions. The test for heterogeneity including the eight evaluable studies was highly significant (P <0.001). We used a random-effect model in calculating the overall HR which was 0.64 (95% CI = 0.41–1.00) (Figure 1). The heterogeneity was mainly attributed to the study of Puglisi et al. [14]. We secondly carried out the same meta-analysis without this publication (564 patients). The HR (random model) was then 0.56 (95% CI = 0.34–0.90).
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According to the literature, TTF-1 is mainly expressed in adenocarcinoma. We looked at the prognostic role of TTF-1 in this subgroup of patients. Four studies (281 patients) included adenocarcinomas only [13, 18, 21] or reported separate data for those patients [19]. The combined HR for the four evaluable studies (random-effect model) was 0.53 (95% CI = 0.29–0.95).
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discussion |
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We carried out a systematic review of the French and English language literature to determine the impact of TTF-1 on survival in patients with lung cancer. We observe a significant role of TTF-1 in NSCLC and in the subgroup of adenocarcinomas. TTF-1 should be considered as a good prognostic factor for survival in NSCLC.
Prognostic factors have been extensively studied in lung cancer [25]. Some clinical and biological parameters have been identified, mainly stage and PS [3, 4]. Some of them have a direct impact on the therapeutic strategy, essentially disease stage. However, with similar disease extent, prognosis could be dissimilar. Stages are not homogeneous and it is difficult, with the currently available prognostic factors, to determine which patients will survive and who will die despite identical treatments. There is a need for new prognostic factors. In this way, recent knowledge in the lung cancer biology prompted lung cancer specialists to assess the prognostic role of new biological factors in this population. Unfortunately, these are frequently small size studies with limited statistical power. Therefore, meta-analyses are needed to answer the question, as our group published these last years [5–12].
TTF-1 is an interesting marker, currently used in routine clinical practice to distinguish lung adenocarcinoma from adenocarcinoma metastatic to the lung. Moreover, TTF-1 is also expressed in lung squamous carcinoma. The role of TTF-1 in lung carcinogenesis remains unclear, although different explanations are proposed [13, 14]. Ten studies assessing the relationship between TTF-1 and survival (Table 1) have been so far published [13, 14, 17–24]. Four demonstrated a positive impact of TTF-1 on survival, one observed a detrimental effect of TTF-1 and in the last five studies, no survival difference was found between TTF-1-positive and -negative tumours. Once more, the conflicting results of the literature with underpowered studies require carrying out a quantitative aggregation of the individual results (meta-analysis).
We found that TTF-1 positivity was associated with better survival in NSCLC. This effect is essentially demonstrated in early and locally advanced diseases (stages I–III) as there is only one study incorporating stage IV NSCLC without separate results in this group of patients. Also, the positive impact of TTF-1 is demonstrated in adenocarcinoma but the lack of data in other NSCLC histologies does not allow the drawing of definite conclusions. Randomised trials of neo-adjuvant chemotherapy demonstrated that an approach combining surgery and medical treatment increased absolute cure rates by 5%–10%. However, all the patients do not benefit from these treatments, needing to better delineate those who need to be treated. In this setting, it could be hypothesised that new biological factors are of potential usefulness. On the basis of our results, TTF-1 could be selected for a prospective study with multivariate analysis including the most known prognostic factors in NSCLC such as stage and PS.
Our analysis had to deal with problems of heterogeneity. There was a significant heterogeneity among the eight evaluable studies included in the meta-analysis. Heterogeneity is principally related to the study of Puglisi et al. [14] in which the results were opposite to those found in the other publications. One explanation could be related to the immunohistochemistry techniques. Most importantly, all the authors used the same mouse mAb (8G7G3/1) except Puglisi et al. [14], who employed an antiserum raised in rabbits. The exclusion of this study from the analysis decreased only partially the heterogeneity for which there is different explanations either related to the immunohistochemistry techniques (various definitions of threshold positivity, use of the mAb at different concentrations and dissimilar staining protocols) or related to the patients' characteristics (type of patients, disease characteristics). More precisely, the cut-off definition of TTF-1 positivity was at least one positive cells, >5% or >10% in two, three and one studies, respectively. A complex score was used in two other studies and no clear definition was used in the last two studies.
Some other biases could have occurred. We carried out a methodological assessment of the studies to avoid some selection biases, as we carried out in prior studies about biological prognostic factors in lung cancer reported by our team [11]. There were no obvious methodological differences between significant and non-significant and between evaluable and non-evaluable studies. Nevertheless, the limited number of studies in each group did not allow us to perform meaningful statistical comparisons. However, this approach does not prevent all potential biases. Publication bias, choice of language, selection of fully published studies only, method of extrapolation of HR, validity of a meta-analysis based on systematic review of the literature as compared with those based on individual data were already discussed in our previous papers [5–12].
In conclusion, we observe that TTF-1 positivity is associated with better survival in NSCLC, mainly in early and locally advanced stages and in adenocarcinomas. Our present results and those from previous meta-analyses carried out by our group could serve to set up a prospective trial aiming at better delineating the patients who will most benefit from neo-adjuvant chemotherapy in surgical stage lung cancers. This trial must include, in a multivariate analysis, the classical well-defined prognostic factors in lung cancer and the new biological prognostic markers that have been identified.
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CM is supported by a fellowship from the National Fund for Scientific Research.
Received for publication April 3, 2006. Revision received June 30, 2006. Accepted for publication July 3, 2006.
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References |
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