Pemetrexed-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

doi:10.1016/j.cllc.2020.05.014

Clinical Lung Cancer

Volume 21, Issue 6, November 2020, Pages e607-e621

https://doi.org/10.1016/j.cllc.2020.05.014 Get rights and content

Abstract

Introduction

Thyroid transcription factor 1 (TTF-1) is a prognostic biomarker in lung adenocarcinoma; however, TTF-1–positive patients also display more favorable factors like actionable target mutations. In contrast, TTF-1–negative cancer is a poorly described entity. We performed a retrospective study to characterize a TTF-1–negative phenotype and to evaluate outcome depending on the chemotherapy regimen applied in the EGFR/ALK-negative population.

Patients and Methods

Phenotypic traits were analyzed in 741 patients with evaluable TTF-1 expression status, among them 529 patients with platinum-based first-line chemotherapy, with disease diagnosed between 2009 and 2016 at a tertiary referral university hospital. The influence of TTF-1 and several cofactors on progression-free survival and overall survival (OS) were analyzed using a 1:1 propensity score matching model, depending on the platinum doublet chemotherapy’s incorporating pemetrexed or not, with subsequent Cox regression.

Results

TTF-1 negativity implied a distinct cancer phenotype with the predominance of male sex, worse Eastern Cooperative Oncology Group performance status, greater metastatic burden at primary diagnosis, and more adrenal gland metastases. These patients had improved progression-free survival (hazard ratio, 0.42; P = .001) and OS (hazard ratio, 0.40; P < .001) when gemcitabine-, taxane-, or vinorelbine-based regimens were provided instead of pemetrexed. None of the regimens was superior in TTF-1–positive patients with regard to OS. Overall, TTF-1 expression was strongly prognostic with a substantial increase in progression-free survival (hazard ratio, 0.54; P < .001) and OS (hazard ratio, 0.53; P < .001).

Conclusion

TTF-1 negativity is associated with a distinct cancer phenotype. Incorporation of this biomarker may be helpful when choosing an appropriate therapy regimen.

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.

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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

Abstract

Introduction

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patients and Methods

Results

Discussion

Conclusion

Disclosure

Lung Cancer

Ann Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

J Biol Chem

J Biol Chem

Clin Chim Acta

Lung Cancer

J Thorac Oncol

J Thorac Oncol

J Thorac Oncol

Mod Pathol

Lung Cancer

Eur J Cancer

J Thorac Oncol

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Int J Cancer

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Int J Cancer

Original Study
Pemetrexed-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