Relationship between thyroid transcription factor 1 and prognosis in locally advanced lung adenocarcinoma

Authors

Abstract

AimStage 3 lung cancers are usually treated with chemoradiotherapy. Thyroid transcription factor 1 (TTF-1) is a transcription protein and is positive in 70% of lung adenocarcinomas. Recent studies have reported that TTF-1 is not only a diagnostic marker but also a prognostic marker. However, to the best of our knowledge, there is no study in the literature showing the relationship between prognosis and TTF-1 in stage 3 patients receiving chemoradiotherapy. For this reason, we retrospectively analyzed the relationship between TTF-1 and prognosis in patients with lung adenocarcinoma who received chemoradiotherapy for the first time in the literature.
MethodsMedical data of n = 108 patients in Manisa State Hospital between 2009 and 2022 were retrospectively analyzed.
ResultsMedian overall survival was 32.69 (95% CI, 26.61-38.77) months in the TTF-1 positive group versus 15.28 (95% CI, 11.02-19.54) months in the TTF-1 negative group. Median progression-free survival was 19.68 (95% CI, 16.48-22.88) months in the TTF-1 positive group versus 10.91 (95% CI, 10.08-11.73) months in the TTF-1 negative group. In multivariate analyses, both OS and PFS were associated with ECOG performance score (p=0.023, p=0.005), TTF-1 (p=0.001, p=0.01), stage (p=0.008, p=0.009), and albumin (p=0.038, p=0.007) level at diagnosis.
ConclusionTTF-1 is both a diagnostic and prognostic marker in lung adenocarcinoma. TTF-1 can be used as an easy and inexpensive biomarker to determine prognosis in patients receiving chemoradiotherapy diagnosed with stage 3 lung adenocarcinoma.

Keywords

Introduction

Lung adenocarcinoma (LAC) is the most common cancer of the lung, accounting for approximately 40% of all lung cancer cases.¹ 40% of patients diagnosed with non-small cell lung cancer (NSCLC) are locally advanced stage III patients.² As a standard, surgery is recommended for all eligible patients in the early stage, while cytotoxic chemotherapy, repeated targeted therapy, or immunotherapy is recommended for stage 4 patients. In stage 3 disease, surgery is recommended only in operable stage 3a disease, while chemoradiotherapy is recommended as standard for other stage 3 diseases.³
Although some clinical and laboratory findings such as age, sex, performance score, albumin, hemoglobin, and lactate dehydrogenase (LDH) levels are associated with prognosis in patients with stage 3 disease, the most important standard prognostic indicator is still stage.⁴ Because even if patients have the same stage and the same clinical and laboratory findings, they may show different characteristics in daily practice and their prognosis may be different. Therefore, other prognostic markers are needed.
Thyroid transcription factor 1 (TTF-1) is a transcription protein with both oncogenic and anti-oncogenic properties required for lung differentiation and morphogenesis.⁵ It is used in daily routine practice in the diagnosis of lung adenocarcinoma and in differentiating lung adenocarcinoma from other cancers. TTF-1 is positive in 70% of lung adenocarcinomas.⁶ Recent studies have reported that TTF-1 is not only a diagnostic marker but also a prognostic marker. Studies have shown that TTF-1 positive, early-stage, surgery patients have a better prognosis, and stage 4 patients have better responses to chemotherapy, targeted therapy, and immunotherapy.^{7,8,9,10,11,12}
However, to the best of our knowledge, there is no study in the literature showing the relationship between prognosis and TTF-1 in stage 3 patients receiving chemoradiotherapy. For this reason, in our center, we retrospectively analyzed the relationship between TTF-1 and prognosis in patients with lung adenocarcinoma who received chemoradiotherapy for the first time in the literature.

Materials and Methods

Study PopulationMedical data of n = 108 patients who received chemoradiotherapy with the diagnosis of stage 3 lung adenocarcinoma in Manisa State Hospital between 2009 and 2022 were retrospectively analyzed. Patients who were ≥ 18 years of age at the time of diagnosis, had stage 3 disease, were not suitable for surgery, had undergone immunohistochemical staining with TTF-1, and had lung adenocarcinoma histology were included. Patients who were < 18 years, did not have lung adenocarcinoma histology, did not undergo immunohistochemical staining with TTF-1, had a stage other than stage 3 or had stage 3 but did not receive chemoradiotherapy, or had more than one primary tumor were excluded. The stage of the disease was determined using PET and MRI.
Data CollectionPatients’ demographic characteristics such as age and sex, ECOG performance scores, smoking history, TTF-1 results, stage, and their relationship with survival were examined. Patients were divided into groups according to ECOG performance score (<2 and ≥2), TTF-1 (positive, negative), and stage (3A, 3B). Survival time was calculated from the date of chemotherapy to death or last follow-up for survivors. Progression-free survival (PFS) was calculated as the time from initiation of first treatment to clinical or radiological progression or death from any cause. The primary endpoint was PFS and OS, and the secondary endpoint was factors affecting PFS and OS.
Ethical ApprovalThe study was conducted in accordance with the principles of the Declaration of Helsinki and reviewed and approved by the Health Sciences Ethics Committee of Manisa Celal Bayar University (Decision no: 05.02.2020 Date: 20.478.486).
Statistical AnalysisDescriptive statistics were presented as mean ± SD, median, minimum–maximum values for numerical variables, and as numbers and percentages for categorical variables. Survival analyses were performed using the Kaplan-Meier method. Factors affecting survival were examined using Cox regression. p<0.05 was considered significant in all statistical analyses.
Ethical ApprovalEthics Committee approval for the study was obtained.

Results

A total of n = 108 patients, including 91 (84.3%) males and 17 (15.7%) females were examined. Their mean age was 63.69 ± 9.61 years. TTF-1 was positive in 76 (70.4%) patients and TTF-1 was negative in 32 (29.6%) patients. There were 87 (80.6%) smokers (Table 1). Median cigarettes smoked was 45 (0-150) pack/year.
The median albumin level was 3.2 (2.0-4.6) g/dL, the median LDH level was 268 (105-4046) U/L, the median platelet count was 288 (141-585) 10³/μL, the median lymphocyte count was 1.7 (0.5-2.8) 10³/μL, the median neutrophil count was 5.7 (2.6-1.6) 10³/μL and the mean hemoglobin level was 12.66 ± 1.88 g/dL.
The median overall survival was 27.83 (95% CI, 23.67-31.98) months, and the median PFS was 17.08 (95% CI, 13.79-20.24) months in all patients.
Stage, ECOG performance score, TTF-1 and albumin level at diagnosis were related to both OS and PFS in univariate and multivariate analyses (Table 2 and Table 3).
The survival rates of the patients were respectively 94% at 12 months, 81% at 24 months, 51% at 36 months, 29% at 48 months, and 13% at 60 months in stage 3A disease. In the group with stage 3B disease, the survival rates of the patients were respectively 57% at 12 months, 36% at 24 months, 13% at 36 months, 7% at 48 months, and 3% at 60 months in stage 3B.
The median overall survival was 32.69 (95% CI, 26.61-38.77) months in the TTF-1 positive group versus 15.28 (95% CI, 11.02-19.54) months in the TTF-1 negative group. Median progression-free survival was 19.68 (95% CI, 16.48-22.88) months in the TTF-1 positive group versus 10.91 (95% CI, 10.08-11.73) months in the TTF-1 negative group (Figure 1).
During follow-up, after chemoradiotherapy, local recurrence 51 (47.2%), lung metastasis 41 (38%), brain metastasis 19 (17.6%), bone metastasis 37 (34.3%), adrenal metastasis 25 (23.1%), liver metastasis 13 (12%) were detected.

Discussion

In this study, we retrospectively examined stage 3 patients who received chemoradiotherapy and found that prognosis was related to TTF-1, ECOG, stage, and albumin level.
According to SEER data, when all lung cancers are considered, the 5-year life expectancy is still around 22.9%.¹³ Approximately 15-20% of patients are in the early stage, 50-60% are metastatic, and the rest are at locally advanced stages.¹³ Surgery in the early stages is the standard, while systemic treatment is recommended in advanced stages. Chemoradiotherapy is recommended for stage 3A and stage 3B patients who are not suitable for surgery.³
Although previous studies showed a relationship between stage, albumin, ECOG performance score, and prognosis, there is still no standard prognostic marker other than stage in daily practice.⁴ Patients with similar ECOG scores, albumin levels, and stages may have different prognoses. Therefore, additional prognostic markers are needed. In our study, unlike the literature, we examined the relationship between TTF-1 and prognosis in patients who received chemoradiotherapy for the first time. As a result, we found a significant relationship between TTF-1 and prognosis for the first time in the literature.
TTF-1 is expressed in type II pneumocytes and Clara cells and regulates surfactant and Clara cell secretory protein gene expression to maintain normal lung functions.¹⁴ TTF-1 is a homeodomain nuclear transcription protein of the NKX2 gene family. By binding to specific gene sequences, TTF-1 modulates transcriptional activation of target genes.¹⁵ The NKX2-1 locus, which encodes TTF-1, is frequently amplified in the lung cancer genome.¹⁵ TTF-1 could be important for the survival of a subset of patients with lung adenocarcinomas expressing TTF-1 based on the lineage-specific dependency model.¹⁶ Therefore, TTF-1 may be important in the diagnosis and prognosis of lung adenocarcinoma.
In previous meta-analyses, TTF-1 was reported to be associated with prognosis in both early and advanced stages.⁸ Subsequent studies reported a relationship between chemotherapy response and TTF-1, and later between targeted therapies and TTF-1.^10,11,12 In addition, TTF-1 positive patients receiving immunotherapy were reported to have a better prognosis with or without chemotherapy.^17,18 This may be due to the fact that TTF-1 inhibits cell migration and invasion, Ki-67 proliferation index is lower in TTF-1 positive patients, EGFR mutations are higher in TTF-1 positive patients, whereas KRAS mutations are more common in TTF-1 negative patients.^19,20,21
The relationship between radiotherapy and chemoradiotherapy with TTF-1 is unknown. To our knowledge, there is no study examining this relationship. For this reason, in our study we found a significant relationship between disease stage, TTF-1, ECOG performance score, and OS and PFS in both univariate and multivariate analyses.
Although the limitations of our study are that it was retrospective, included a small number of patients, and driver mutations were not known, this study is important as it is the first to show the relationship between prognosis and TTF-1 in stage 3 lung adenocarcinoma patients receiving chemoradiotherapy at the time of diagnosis.

Conclusion

TTF-1 is both a diagnostic and prognostic marker in lung adenocarcinoma. TTF-1 can be used as an easy and inexpensive biomarker to determine the prognosis in patients receiving chemoradiotherapy with the diagnosis of stage 3 lung adenocarcinoma.

Declarations

References

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About This Article

Received:

February 1, 2023

Accepted:

March 12, 2023

Published Online:

March 19, 2023

Printed:

March 25, 2023