Pulmonary adenocarcinoma with enteric differentiation (PAED) without TTF-1 expression is a very rare subtype with limited treatment options and poor prognosis.

Introduction: Pulmonary adenocarcinoma with enteric differentiation (PAED) without thyroid transcription factor-1 (TTF-1)- expression is an extremely rare variant of lung cancer. Due to its rarity, few clinicopathological and molecular studies have been performed on PAED, particularly in Caucasian patients. Therefore, it is necessary to obtain clinicopathological data of Caucasian PAED patients without TTF-1 expression, their systemic therapy options and the efficacy of their systemic treatment.

Methods: We examined the clinicopathological features of 121 cases of TTF-1 negative pulmonary adenocarcinoma at a certified German lung cancer center including 79 cases without a PAED and 42 cases with a PAED, compared these subgroups and investigated patients` response to chemotherapy and immunotherapy as first-line treatment. By using endoscopy and/or a PET-CT, a primary adenocarcinoma of the digestive tract was excluded in all PAED patients.

Results: A comparison of clinicopathological data of TTF-1- negative PAED and non-PAED patients revealed a significantly lower frequency of high Programmed Death receptor Ligand 1 (PD-L1) expression in PAED resulting in the lack of single-agent immunotherapy (p=0.032) in this subgroup. Frequencies of an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation were high in both groups (46.7 % and 50.0% ), but G12C gene mutations were seldomly noted (in 6.7% and 18.5% of patients with evaluable data). Median overall survival (OS) was poor in both groups (10 and 12 months). The majority of PAED patients received platinum-based and taxane-containing chemotherapy or chemo-/immunotherapy with an objective response rate (ORR) of 31.6 % and a disease control rate (DCR) of 57.9%. Median progression-free survival (PFS) and OS of PAED patients with systemic therapy was very poor (3.9 months and 5.9 months).

Conclusions: Caucasian patients with TTF-1 negative PAED have a poor prognosis with a reduced ORR to standard first-line systemic therapy and short survival times (PFS and OS).