Different pathways to lung cancer diagnosis in a real-life setting.

BACKGROUND: Most lung cancers are diagnosed at an advanced stage and therefore have a poor prognosis. One major challenge is to choose the most adapted sampling technique to obtain a rapid pathological diagnosis so as to start treatment as early as possible. A growing number of techniques have been developed in recent years. This study sought to assess the diagnostic efficiency of each, along with the respective duration of the diagnostic pathways. METHODS: This retrospective, bicentric, observational study enrolled patients with inoperable lung cancer (stage III or IV) diagnosed in 2018-2019. Diagnostic efficiency was assessed based on the different examinations performed to achieve a precise diagnosis (pathology, immunohistochemistry, and/or molecular biology). The time between the first medical contact and treatment initiation was also assessed. RESULTS: Overall, 625 patients were included (median age 67 years; men 67 %; adenocarcinoma 55 %). The most frequent examinations were bronchial endoscopy (n = 469, 75 %), followed by metastasis biopsy (n = 137, 21.9 %) and guided transthoracic core-needle biopsy (TCNB) (n = 116, 18.6 %). 372 patients had only one procedure (59.5 %), mainly bronchial endoscopy (n = 217, 34.7 %) and metastasis biopsy (n = 71, 11 %). The most efficient examination was thoracic surgery (surgical pleural biopsy, (n = 32, 100 %); mediastinoscopy (n = 26, 96.3 %); surgical pulmonary biopsy (n = 14, 93.3 %). The second most efficient examination was metastasis biopsy (n = 126, 94 %) followed by guided TCNB (n = 108, 93.1 %). The median time from first medical contact to first examination was 4 days (interquartile range 25 %-75 % 1-8). The median time from first medical contact to pathological result was 17 days (10-34). The median time from first medical contact to treatment start was 48 days (30-69). CONCLUSIONS: In order to make an accurate and rapid diagnosis of lung cancer, it is crucial to choose the most appropriate technique. Bronchial endoscopy remains the first-line examination for central lesions, as it is efficient and easily accessible. Guided TCNB and metastasis biopsy are the preferred techniques for peripheral lesions. The choice of the diagnostic technique should be part of a multidisciplinary approach and a dedicated pathway to optimize initial management.

PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.

Despite initial high response rates to first-line EGFR TKI, all non-small-cell lung cancer (NSCLC) with EGFR-activating mutation will ultimately develop resistance to treatment. Identification of resistance mechanisms is critical to adapt treatment and improve patient outcomes. Here, we show that a PPP3CB transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of PPP3CB by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

FDG PET and CT radiomics in diagnosis and prognosis of non-small-cell lung cancer.

Background: 18F-FDG PET and CT radiomics has been the object of a wide research for over 20 years but its contribution to clinical practice remains not yet well established. We have investigated its impact versus that of only histo-clinical data, for the routine management of non-small-cell lung cancer (NSCLC). Methods: Our patients were retrospectively considered. They all had a FDG PET-CT and immuno-histo-chemistry (IHC) to assess PD-L1 expression at the beginning of the disease. A prognosis univariate and multivariate Cox survival analyses was performed for overall survival (OS) and progression free survival (PFS) prediction, including a training/testing procedure. Two sets of 47 PET and 47 CT radiomics features (RFs) were extracted. Difference between RFs according to PD-L1 expression, the histology status and the stage level were tested using suited non parametric statistical tests and the receiver operating characteristics (ROC) curve and the area under curve (AUC). Results: From 2017 to 2019, 212 NSCLC patients treated in our institution were included. The main conventional prognostic variables were stage and gender with a low added prognostic value in the models including PET and CT RFs. Neither PET nor CT RFs were significant to separate the different levels of PD-L1 expression. Several RFs differ between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumours and a large number of PET and CT RFs are significantly linked to patient stage. Conclusions: In our population, PET and CT RFs show their intrinsic power to predict survival but do not significantly improve OS and PFS prediction in the different multivariate models, in comparison to conventional data. It would seem necessary to carry out one's own survival analysis before determining a radiomics signature.