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

Thyroid transcription factor 1 (TTF-1)-negative lung adenocarcinoma is a poorly described entity. Analyzing 741 patients with stage IV adenocarcinoma, a distinct TTF-1enegative phenotype with the predominance of male sex, a worse Eastern Cooperative Oncology Group performance status, and more adrenal metastases was identified. These patients had improved survival with pemetrexed-free platinum regimens. Thus, incorporation of TTF-1 expression may be a helpful tool when choosing an appropriate therapy regimen. Introduction: Thyroid transcription factor 1 (TTF-1) is a prognostic biomarker in lung adenocarcinoma; however, TTF-1 epositive patients also display more favorable factors like actionable target mutations. In contrast, TTF-1enegative cancer is a poorly described entity. Weperformed a retrospective study to characterize a TTF-1enegative 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 matchingmodel, depending on the platinum doublet chemotherapy's incorporating pemetrexed or not, with subsequentCox regression. Results: TTF-1 negativity implied a distinct cancer phenotype with the predominance ofmale sex, worse Eastern Cooperative Oncology Group performance status, greatermetastatic 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-1epositive 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. (C) 2020 Elsevier Inc. All rights reserved.