• CBC-derived inflammatory parameters
• COPD
• histology
• inflammation
• lung cancer
• smoking

• Lung cancer
• Prognosis
• Single nucleotide polymorphism
• TYMS
• rs3819102

• Mendelian randomization
• RNA-seq
• SIRPG
• immune infiltration
• squamous cell carcinoma of the lung

• Biologically Effective Dose
• Early-stage Lung Adenocarcinoma and Squamous Cell Carcinoma
• Stereotactic Body Radiation Therapy
• The Hypofractionated Treatment Effects in the Clinic (HyTEC)
• Tumor control probability

• Humans
• Lung Neoplasms/radiotherapy
• Lung Neoplasms/pathology
• Carcinoma, Squamous Cell/radiotherapy
• Carcinoma, Squamous Cell/pathology
• Radiation Dose Hypofractionation
• Radiosurgery/methods
• Neoplasm Staging
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Carcinoma, Non-Small-Cell Lung/pathology
• Adenocarcinoma of Lung/radiotherapy
• Adenocarcinoma of Lung/pathology
• Male
• Dose Fractionation, Radiation
• Female

• KL2 TR001421 NCATS NIH HHS

• Checkpoint inhibitors
• Clinical trial
• NSCLC
• Predictive biomarker

• Humans
• Adenocarcinoma/drug therapy
• Adenocarcinoma of Lung/drug therapy
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carboplatin
• Carcinoma, Non-Small-Cell Lung/pathology
• Lung Neoplasms/pathology
• Pemetrexed/therapeutic use
• Platinum/therapeutic use
• Retrospective Studies
• Thyroid Nuclear Factor 1

• carcinoma
• clinical trial
• irinotecan
• non-small cell lung
• phase II

• Humans
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/etiology
• Epithelial Cells
• Irinotecan
• Japan
• Lung Neoplasms/etiology
• Neoplasm Recurrence, Local/drug therapy
• Neoplasm Recurrence, Local/etiology

• DNA ploidy
• NSCLC
• adjuvant therapy
• disease-free survival
• nucleotyping

• 81871860 and 82003155 National Nature Science Foundation of China

• adenocarcinoma
• local neoplasm recurrence
• non-small-cell lung cancer
• squamous cell carcinoma
• stereotactic body radiotherapy

• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics
• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm/genetics
• Folic Acid/metabolism
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Methotrexate/pharmacology
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Tetrahydrofolates/metabolism

• T32 GM007287 NIGMS NIH HHS
• P30 CA014051 NCI NIH HHS
• R01 CA201276 NCI NIH HHS
• R35 CA242379 NCI NIH HHS
• Howard Hughes Medical Institute

• molecular targeting agent
• platinum
• refractory
• salvage chemotherapy
• thymic carcinoma

• adjuvant chemotherapy
• excision repair cross-complementation 1
• messenger RNA
• non-small-cell lung cancer
• pharmacogenomics
• thymidylate synthase

• Neuroendocrine
• carcinoma
• diagnosis
• immuno-oncology
• immunohistochemistry
• intratumor heterogeneity
• lung
• marker
• personalized medicine
• precision medicine
• prediction
• prognosis
• tumor

Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT.

Published datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TS^HIGH and TS^LOW. Metastasis was assayed in a syngeneic mouse model.

TS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo.

These results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.

The chemotherapy agent pemetrexed is currently considered in combination with other therapies for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) in patients negative for gene mutations/rearrangements. The aim of this review was to highlight data from clinical studies with pemetrexed in patients with advanced nonsquamous NSCLC positive for gene mutations/rearrangements. The results of the review suggest that pemetrexed could be a treatment option in patients with advanced nonsquamous NSCLC positive for certain gene mutations/rearrangements.

Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in patients with Kirsten rat sarcoma (KRAS) virus proto-oncogene mutations or WTD, although the available studies were limited. For Erb-b2 receptor tyrosine kinase 2 (ERRB2) mutations, first-line pemetrexed showed outcomes similar to those for EGFR and KRAS alterations. Data on pemetrexed in patients with KRAS mutations or MNNG HOS-transforming (MET) expression were limited. Pemetrexed could be an option for first- and second-line treatment for TKI failure in nonsquamous advanced NSCLC with select targetable driver mutations.

• chemotherapy
• gain of function mutation
• non-small-cell lung cancer
• pemetrexed
• progression-free survival

In recent years, multitarget drugs for neurological diseases such as Alzheimer’s disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that targets c-MET, ROS1, and ALK. Alectinib is known as an ALK inhibitor but also targets LTK, CHEK2, FLT3, PHKG2, and RET. Sorafenib is a tyrosine kinase inhibitor that targets RAF kinase, KIT, VEGFR, PDGFR1β, FLT3, and RET. Nintedanib is a multiple tyrosine kinase inhibitor that targets FGFR, PDGFR, and VEGFR. In this review, we summarize the mechanisms of action of multitarget therapies and report the results of the latest clinical trials.

• ALK inhibitors
• angiogenesis inhibitors
• multitarget
• pemetrexed

• Pemetrexed
• Squamous cell lung cancer
• Thymidylate synthase

Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth.

In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins.

In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.

• Cancer
• Chemoresistance
• Epithelial-to-mesenchymal transition
• Pyrimidine metabolism

• Non-small cell lung cancer
• Pemetrexed
• Predictive biomarkers
• Protein reversion less 3-like
• Thymidylate synthase

Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen’s efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients ≤75 years with performance status ≤1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m² oral S-1 from days 1–14. The starting docetaxel dose was 45 mg/m² and this was escalated to a maximum of 70 mg/m². In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m² docetaxel (day 1) and 80 mg/m² S-1 (days 1–14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6–20.9%), and median PFS and OS were 18.0 weeks (95% CI; 11.3–22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m² docetaxel plus 80 mg/m² oral S-1 had a lower response rate than anticipated; however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population.

• S-1
• chemotherapy
• docetaxel
• non-small cell lung cancer
• phase I/II trial
• previously treated patients

Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G₁ phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.

• EML4-ALK rearrangement
• afatinib
• drug resistance
• lung cancer
• pemetrexed

• Afatinib/pharmacology
• Antineoplastic Agents
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Drug Resistance, Neoplasm/drug effects
• Gene Rearrangement
• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Oncogene Proteins, Fusion/genetics
• Pemetrexed/pharmacology
• Protein Kinase Inhibitors/pharmacology
• RNA Interference
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism

• Antiangiogenic
• NSCLC
• checkpoint inhibitors
• immunotherapy
• nintedanib
• nonsquamous
• ramucirumab
• regimen
• resistance

• ACTH
• Adrenocorticotropic hormone-producing lung carcinoid
• Cushing syndrome
• Ki67 index
• Prognostic factors

• Adrenocorticotropic Hormone/metabolism
• Adult
• Aged
• Carcinoid Tumor/metabolism
• Carcinoid Tumor/pathology
• Cushing Syndrome/metabolism
• Cushing Syndrome/pathology
• Female
• Humans
• Lung/metabolism
• Lung/pathology
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Prognosis
• Retrospective Studies
• Survival Rate

• lung adenocarcinoma
• lung squamous cell carcinoma
• mRNA
• microRNAs
• transcriptome signature

• Adenocarcinoma of Lung
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Squamous Cell
• Humans
• Lung Neoplasms
• MicroRNAs
• Y-Box-Binding Protein 1

• Lung cancer
• pemetrexed
• phase I/II, sirolimus
• thymidylate synthase (TS)

Palliative pemetrexed-based chemotherapy remains a standard of care treatment for the majority of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Currently, no predictive markers for pemetrexed treatment are available.

Resected tumour samples from pemetrexed-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to pemetrexed classified predicted responders (60%) and non-responders (40%) based on differentially expressed genes encoding for pemetrexed target enzymes. Genes showing a strong correlation with these target genes were selected for measurement of corresponding protein expressions by immunohistochemical (IHC) staining. A semi-quantitative IHC scoring method was applied to construct a prediction model for response to pemetrexed. A retrospective cohort of patients with advanced NSCLC treated with first-line pemetrexed-based chemotherapy was used for external validation.

From ninety-one patients resected tumour samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers, which mRNA levels strongly correlated to pemetrexed target genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOP2A. Of 63 (69%) patients IHC staining scores of these markers were obtained, which significantly differed between predicted non-responders and responders (P < 0.05). The optimized prediction model included EZH2 (OR = 0.56, 95% CI 0.35–0.90) and TPX2 (OR = 0.55, 95% CI 0.30–1.01). The model had a sensitivity of 86.8%, specificity of 63.6% and showed a good ability to distinct between responders and non-responders (C-index 0.86).

In the external study population (N = 23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. The sensitivity decreased drastically to 33.3%, with a specificity of 82.4% and a C-index of 0.73.

Using external validation this prediction model with IHC staining of target enzyme correlated markers showed a good discrimination, but lacked sensitivity. The role of IHC markers as response predictors for pemetrexed in clinical practice remains questionable.

The online version of this article (10.1186/s12885-019-5645-x) contains supplementary material, which is available to authorized users.

• Gene-expression profiling
• Immunohistochemistry
• NSCLC
• Pemetrexed
• Response prediction

Although recent advances in molecular targeted therapy and immuno-oncology have revolutionized the landscape of lung cancer therapeutics, cytotoxic chemotherapy remains an essential component of lung cancer treatment. Extensive evidence has demonstrated the clinical benefit of chemotherapy, either alone or in combination with other treatment modalities, on survival and quality of life of patients with early and advanced lung cancer. Combinational approaches with other classes of anti-neoplastic agents and new drug-delivery systems have revealed promising data and are areas of active investigation. Chemotherapy is recommended as a standard of care in patients that have progressed after tyrosine kinase inhibitors or immune checkpoint inhibitors. Chemotherapy remains the fundamental means of lung cancer management and keeps expanding its clinical implication. This review will discuss the current position and future role of chemotherapy, and specific consideration for its clinical application in the era of precision medicine.

• Chemotherapy
• Evolution
• History
• Immunotherapy
• Lung Neoplasms
• Molecular Targeted Therapy
• Precision Medicine

• Pemetrexed
• Thymic cancer
• Thymic epithelial malignancies
• Thymoma

• Environmental factors
• Lung cancer
• Smoking
• Thymidylate synthase
• rs3819102 polymorphism

Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells. Nutlin-3A (a cis-imidazoline analogue) has been described as a potent and selective MDM2 inhibitor preventing MDM2-TP53-interaction by specific binding to the hydrophobic TP53-binding pocket of MDM2. In the present study, the effects of MDM2 inhibition in MPM via Nutlin-3A and standard platinum based chemotherapeutic agents were comparatively tested in three MPM cell lines (NCI-H2052, MSTO-211H, and NCI-H2452) showing different expression profiles of TP53, MDM2, and its physiological inhibitor of MDM2—P14/ARF. Our in vitro experiments on MPM cell lines revealed that Nutlin-3A in combination with cisplatin resulted in up to 9.75 times higher induction of senescence (p=0.0050) and up to 5 times higher apoptosis rate (p=0.0067) compared to the commonly applied cisplatin and pemetrexed regimens. Thus Nutlin-3A, a potent inhibitor of MDM2, is associated with a significant induction of senescence and apoptosis in MPM cell lines, making Nutlin-3A a promising substance for a targeted therapy in the subgroup of MPM showing MDM2 overexpression.

• Non-small-cell carcinoma of the lung
• immunotherapy
• squamous cell carcinoma
• targeted therapy

We aimed to identify predictive clinicoradiologic characteristics of thymidylate synthase (TS) expression status in advanced non-squamous non-small cell lung cancer patients. We reviewed clinicoradiologic features of 169 patients stratified into TS-negative (n = 84) and TS-positive (n = 85) groups, including quantitative CT radiomic features of both primary lung and metastatic lesions from initial CT and PET. Clinical factors including age and smoking history were significantly associated with TS as well as radiomic features. The predictive performance for dichotomizing TS expression status was slightly higher when imaging features of primary lung lesions were added compared to the model based solely on the clinical features, but without statistical significance (10-fold cross-validated AUC = 0.619 and 0.581, respectively; P = 0.425). The predictive performance of clinicoradiologic parameters slightly increased with primary lung lesions only compared to the inclusion of metastatic lesions, but without statistical significance (10-fold cross-validated AUC = 0.619 and 0.554, respectively; P = 0.203). Overall survival was prolonged in the TS-negative group compared to the TS-positive group (P = 0.001). TS-negativity is a potential prognostic biomarker, and our study presents that although CT radiomic features have potential for predicting TS expression status, clinical significance is uncertain. The addition of radiomic features to clinical factors did not show significant improvement in predicting TS-negativity.

• cisplatin
• large-cell neuroendocrine carcinoma
• pemetrexed
• pulmonary tumor

• folylpolyglutamate synthase
• pemetrexed
• personalized therapy
• pleural mesothelioma
• thymidylate synthethase

ROS1 rearrangement is a novel molecular subgroup of non-small-cell lung cancer (NSCLC). This study aimed to investigate the efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement.

A total of 2309 patients received ROS1 fusion detection and 51(2.2%) patients had ROS1 rearrangement. There was no significant difference between ROS1 fusion-positive and fusion-negative cohorts in demographic data. For the ROS1 fusion-positive patients, crizotinb-treated group had a higher overall response rate (ORR, 80.0%), disease control rate (DCR, 90.0%) and longer progression-free survival (PFS, 294 days) compared with the rates in pemetrexed-treated group (ORR, 40.8%; DCR, 71.4%; PFS, 179 days) and non-pemetrexed-treated group (ORR, 25.0%; DCR, 47.7%; PFS, 110 days). Besides, ORR, DCR and PFS were similar in three major ROS1 fusion partners. For the first-line treatment, patients received pemetrexed had a significant longer PFS than those received non-pemetrexed chemotherapy (209 vs. 146 days, P = 0.0107). In pemetrexed-treated cohorts, ROS1-positive patients with low TS expression had a statistically significant longer PFS than those with high TS expression (184 vs. 110 days, P = 0.0105).

We retrospectively identified patients with NSCLC who were screened for ROS1 fusion using multiplex reverse transcription-polymerase chain reaction (RT-PCR) from October 2013 to February 2016. The thymidylate synthase (TS) mRNA levels were tested using quantitative real-time RT-PCR.

Crizotinib was also highly active at treating Chinese NSCLC patients with ROS1 rearrangement. TS expression could predict the efficacy of pemetrexed-based therapy in ROS1 fusion-positive patients.

• ROS1 rearrangement
• crizotinib
• non-small-cell lung cancer
• pemetrexed
• thymidylate synthase

Thymidylate synthase (TS), one of the key enzymes for thymidine synthesis, is a target of pemetrexed (PEM), a key agent for the systemic therapy of malignant pleural mesothelioma (MPM) and its overexpression has been correlated to PEM-resistance. In MPM, experimental data report activation of the c-SRC tyrosine kinase suggesting it as a potential target to be further investigated.

MPM cell lines showed different sensitivity, being MSTO the most and REN the least sensitive to PEM. REN cells showed high levels of both TS and SRC: dasatinib inhibited SRC activation and suppressed TS protein expression, starting from 100 nM dose, blocking the PEM-induced up regulation of TS protein levels. Dasatinib treatment impaired cells migration, and both sequential and co-administration with PEM significantly increased apoptosis. Dasatinib pretreatment improved sensitivity to PEM, downregulated TS promoter activity and, in association with PEM, modulated the downstream PI3K-Akt-mTOR signaling.

In three MPM cell lines (MPP89, REN and MSTO), the effects of c-SRC inhibition, in correlation with TS expression and PEM sensitivity, were evaluated. PEM and dasatinib, a SRC inhibitor, were administered as single agents, in combination or sequentially. Cell viability, apoptosis and migration, as well as TS expression and SRC activation have been assessed.

These data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation.

• cell lines
• dasatinib
• malignant pleural mesothelioma
• pemetrexed
• thymidylate synthase

25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking.

Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair.

Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS).

Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001).

The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.

• DNA repair
• NanoString nCounter
• folic acid metabolism
• lung cancer
• neuroendocrine pulmonary tumors