Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rb^inap) or the absence of very intense p53 staining (p53^inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16^high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rb^inap (63% vs. 42%, p = 0.025) and p16^high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11–15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.

Background: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers.Methods: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers.Results: We identified 99 SRG adult variant carriers (SFTPA1(n=18),SFTPA2(n=31),SFTPC(n=24),ABCA3(n=14) andNKX2-1(n=12)), including 20 (20.2%) with lung cancer (SFTPA1(n=7),SFTPA2(n=8),SFTPC(n=3),NKX2-1(n=2) andABCA3(n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01–1.08), smoking (OR 20.7, 95% CI 6.60–76.2) andSFTPA1/SFTPA2variants (OR 3.97, 95% CI 1.39–13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patientsversusTRG patients was 18.1 (95% CI 7.1–44.7).Conclusions: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

It has become more and more evident that the BCL-2 family proteins mediate a wide range of non-apoptotic functions. The pro-apoptotic BAX protein has been reported in interphasic nuclei. Whether the nuclear form of BAX could be involved in non-apoptotic function is still unknown. Our study showed for the first time that BAX was associated with chromatin in vitro. Next, we used gain and loss of function approaches to decipher the potential role of nuclear BAX in non-apoptotic cells. In vitro, nuclear BAX promoted cell proliferation in lung epithelial cells and primary human lung fibroblasts by modulating CDKN1A expression. Interestingly, BAX occupancy of CDKN1A promoter was specifically enriched close to the transcription-starting site. Nuclear BAX also modulated the basal myofibroblastic differentiation and migration of primary human lung fibroblasts. Finally, BAX nuclear localization was associated in vivo with the remodelling of lung parenchyma during development, tumorigenesis as well as fibrosis compared to control adult human lungs. Hence, our study established for the first time, a strong link between the nuclear localization of the pro-apoptotic BAX protein and key basic cellular functions in the non-apoptotic setting.

The high prevalence of lung cancer in patients with idiopathic pulmonary fibrosis (3–30%) has been confirmed by several studies, pointing to specific diagnostic and therapeutic issues. The co-occurrence is associated with worse survival than with each disease alone [1]. Because cigarette smoking is a risk factor for both diseases, smoking is an ideal culprit for their co-occurrence, despite several common pathogenic mechanisms such as common genetic risk factors.

Nivolumab appears efficacious in highly PD-L1-expressing NSCLC with poor PS, resulting in Lazarus syndromehttp://ow.ly/X92e30coTsB