Original StudyPemetrexed-Based Chemotherapy Is Inferior to Pemetrexed-Free Regimens in Thyroid Transcription Factor 1 (TTF-1)-Negative, EGFR/ALK-Negative Lung Adenocarcinoma: A Propensity Score Matched Pairs Analysis
Introduction
Lung cancer is the leading cause of cancer deaths worldwide, accounting for up to one third of malignancy-related mortality.1, 2, 3 Rates of adenocarcinoma have risen continuously for decades and today represent more than 50% of all lung cancer cases.4,5 In addition to stratification according to phenotypic traits, like performance status,6 sex,7 disease stage, and number of metastatic sites affected,8, 9, 10, 11 cancer-specific factors of lung adenocarcinoma, like subtyping, grading,12, 13, 14 and identifying targetable molecular alterations, have gained importance.15 Modern cancer-specific therapies have increasingly focused on identifying distinct tumor-specific patterns, thus ideally leading to tailored therapies with an individually improved outcome. Astonishingly, other than the identification of actionable target mutations and programmed death ligand 1 (PD-L1) expression, none of the aforementioned (histopathologic) patterns has gained any importance in the therapeutic management of lung adenocarcinoma.
Thyroid transcription factor 1 (TTF-1) is expressed by the surfactant-producing type 2 pneumocytes,16 and it can also be detected in most small-cell17 and approximately 60% to 80% of lung adenocarcinomas.18 The 38 kDa nuclear protein, known as Nkx2.1, is encoded by a gene located on chromosome 14q13. It is crucial in lung, thyroid, and diencephalic embryogenesis.19 It may represent a gain-of-function oncogene, but its role in carcinogenesis remains unclear.20 With regard to its frequent expression in lung adenocarcinoma, it is routinely tested to distinguish primary lung metastases from metastases of extrapulmonary adenocarcinoma. A prognostic role of TTF-1 expression has been shown in nonmetastatic and advanced disease.21,22 However, the observed differences in survival may be biased by (prognostic) cofactors. For example, patients expressing TTF-1 show a substantially higher proportion of sensitizing EGFR mutations and a better Eastern Cooperative Oncology Group performance status (ECOG PS) at primary diagnosis.22,23 In contrast, TTF-1–negative cancer is poorly defined. Furthermore, data are scarce on the predictive value of TTF-1 expression with regard to the chemotherapy regimens provided. Pemetrexed-based first-line chemotherapy is an established regimen in EGFR/ALK-negative lung adenocarcinoma,24,25 but whether this is an appropriate regimen irrespective of TTF-1 expression status remains an unanswered question.
We therefore performed the present study to evaluate whether the worse prognosis in TTF-1–negative patients resulted from a specific cancer phenotype with distinct cancer- and patient-specific parameters; and whether positive and negative patients derived a different benefit from platinum-based chemotherapy applied as first-line palliative treatment.
Section snippets
Patients and Methods
For this single-center retrospective study, all patients presenting with metastatic adenocarcinoma of the lung, diagnosed during the period of validity of the 7th edition of the tumor, node, metastasis classification system (TNM; from January 1, 2009, until December 31, 2016), were evaluated. TTF-1–negative tumors were counted as of pulmonary origin after performing thorough diagnostics and finding no evidence of another potential primary cancer. In case of a TTF-1–negative tumor, nonpulmonary
Results
If not otherwise specified, results are reported for TTF-1–positive patients first, then TTF-1–negative patients.
From January 2007 to December 2016, a total of 949 patients were diagnosed with stage IV lung adenocarcinoma. TTF-1 status was available for 858 patients; 741 were EGFR/ALK negative (cohort 1A). Nearly all EGFR mutations and numerically more ALK rearrangements were observed in the TTF-1–positive group (17.0% vs. 1.4%, P < .001; and 5.8% vs. 2.7%, P = .28, respectively). All baseline
Discussion
The present investigation provides what is to our knowledge the most comprehensive analysis of a distinct cancer phenotype in TTF-1–negative patients. Our first main finding was the correlation of male sex, worse ECOG PS, adrenal metastases, and higher metastatic burden at primary diagnosis with TTF-1 negativity. In this setting, lack of TTF-1 expression had a predictive value, as negative patients derived a substantially improved PFS and OS when they received pemetrexed-free regimens. Survival
Conclusion
We identified a distinct TTF-1–negative phenotype and a potential predictive role of TTF-1 negativity. Our data provide a clinical rationale for the integration of additional parameters in the choice of an appropriate therapy regimen.
Disclosure
The authors have stated that they have no conflict of interest.
References (41)
- et al.
International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women
Lung Cancer
(2014) - et al.
The influence of sex and histology on outcomes in non–small-cell lung cancer: a pooled analysis of five randomized trials
Ann Oncol
(2010) - et al.
The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th Edition of the TNM Classification for Lung Cancer
J Thorac Oncol
(2015) - et al.
The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM Classification of Lung Cancer
J Thorac Oncol
(2015) - et al.
The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM Classification for Lung Cancer
J Thorac Oncol
(2016) - et al.
Does lung adenocarcinoma subtype predict patient survival? A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification
J Thorac Oncol
(2011) - et al.
Prognostic impact and clinicopathological correlations of the cribriform pattern in pulmonary adenocarcinoma
J Thorac Oncol
(2015) - et al.
Lung cell–specific expression of the murine surfactant protein A (SP-A) gene is mediated by interactions between the SP-A promoter and thyroid transcription factor-1
J Biol Chem
(1995) The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities
J Biol Chem
(2013)- et al.
Prognostic value of TTF-1 expression in patients with non–small cell lung cancer: a meta-analysis
Clin Chim Acta
(2015)
Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas
Lung Cancer
Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non–small cell lung cancer treated with pemetrexed-based chemotherapy
J Thorac Oncol
Associations between TS, TTF-1, FR-alpha, FPGS, and overall survival in patients with advanced non–small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy
J Thorac Oncol
International Association for the Study of Lung Cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma
J Thorac Oncol
Ciliated adenocarcinomas of the lung: a tumor of non-terminal respiratory unit origin
Mod Pathol
Treatment outcomes by histology in REVEL: a randomized phase III trial of ramucirumab plus docetaxel for advanced non–small cell lung cancer
Lung Cancer
Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non–small cell lung cancer: results from a population-based study
Eur J Cancer
The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification
J Thorac Oncol
Cancer Incidence in five continents: inclusion criteria, highlights from Volume X and the global status of cancer registration
Int J Cancer
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int J Cancer
Cited by (30)
Prognostic implications of synaptophysin, CD56, thyroid transcription factor-1, and Ki-67 in pulmonary high-grade neuroendocrine carcinomas
2024, Annals of Diagnostic PathologyTTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading
2024, European Journal of CancerTTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study
2023, JTO Clinical and Research Reports