Sylvie Lantuejoul

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)

BACKGROUNDnThe molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute.nnnMETHODSnThis study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582.nnnFINDINGSn18,679 molecular analyses of 17,664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18-98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7-16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17,706 analyses for which data were available, HER2 mutations in 98 (1%) of 11,723, KRAS mutations in 4894 (29%) of 17,001, BRAF mutations in 262 (2%) of 13,906, and PIK3CA mutations in 252 (2%) of 10,678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8-25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7-38·2] for presence of a genetic alteration vs 33% [29·5-35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0-18·8] vs 9% [6·7-11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2-10·7] vs 7·1 months [6·1-7·9]; p<0·0001) and overall survival (16·5 months [15·0-18·3] vs 11·8 months [10·1-13·5]; p<0·0001) compared with absence of a genetic alteration.nnnINTERPRETATIONnRoutine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit.nnnFUNDINGnFrench National Cancer Institute (INCa).

CD74-NRG1 fusions in lung adenocarcinoma

UNLABELLEDnWe discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.nnnSIGNIFICANCEnCD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease.

Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection

PURPOSEnThe classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern-lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT).nnnPATIENTS AND METHODSnOf 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis.nnnRESULTSnA total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01).nnnCONCLUSIONnThe new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.

Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis

Lung carcinoma with a basaloid pattern (BC) is classified as either a basaloid variant of squamous cell carcinoma (SCC) or as variant of large cell carcinoma (LCC) depending on the presence of a squamous component. In a previous study of 37 cases, the present authors showed that BC presented with a shorter median and overall survival. In order to confirm its clinical significance in a larger series, 90 BC, including 46 basaloid variants of LCC and 44 basaloid variants of SCC, were compared with 1,328 other nonsmall cell lung carcinoma (NSCLC) with regard to clinical features and survival. The survival of basaloid variants of LCC and SCC was comparable. Median and overall survival were significantly lower for BC than for NSCLC in stage I–II patients, with a median survival of 29 and 49u2005months, respectively, and 5-yr survival rates of 27 and 44% for BC and NSCLC. When disease-specific survival was considered, BC had a shorter survival than both NSCLC and SCC. Basaloid pattern confers a poor prognosis in nonsmall cell lung carcinoma, especially in stage I–II patients, suggesting that lung carcinoma with a basaloid pattern is not only a variant of squamous cell carcinoma or large cell carcinoma, but is a unique entity with a significantly poor prognosis.

Comorbidities and Charlson score in resected stage I nonsmall cell lung cancer.

Patients with nonsmall cell lung cancer (NSCLC) have been shown to have a higher prevalence of comorbidity associated with age and tobacco consumption. The objective of the present study was to determine the impact of comorbidity on survival after surgery of stage I NSCLC. In total, 588 consecutive patients operated on for a pathological stage I NSCLC between January 1, 1979 and December 31, 2003 were studied. Comorbidities were analysed individually. Overall comorbidity was assessed using the Charlson index of comorbidity (CCI). Survival data were collected for each patient from the date of operation, with a median duration of follow-up of 104 months. Survival analyses and Cox proportional hazards model analyses were used. The mean age of patients was 62.7u2005yrs, and 529 (89%) patients were male. The distribution of overall comorbidity severity was as follows. CCI grade 0: 47.1%; grade 1–2: 43.7%; grade 3–4: 8.3%; and grade ≥5: 0.8%. The 2, 3 and 5u2005yrs survival were 69, 62 and 50%, respectively. Multivariable analysis showed that T stage, age, a concomitant history of moderate-to-severe liver disease, a past history of cured cancer, cerebrovascular disease and CCI were independent predictors of survival (Hazard Ratio for CCI grade >2: 1.81; 95% confidence interval 1.25–2.63). In conclusion, comorbidity has a significant impact on survival after surgical resection of patients with stage I nonsmall cell lung cancer. The use of a validated index of comorbidity in prognostic analyses of resected nonsmall cell lung cancer is recommended.

34βE12 expression along the whole spectrum of neuroendocrine proliferations of the lung, from neuroendocrine cell hyperplasia to small cell carcinoma

Aims:u2002 Monoclonal antibody 34βE12 (Ck34βE12) recognizes a set of cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous epithelium. We have recently reported its expression in squamous cell carcinoma and basaloid carcinoma, in contrast to large cell neuroendocrine carcinoma, an entity with overlapping morphological features with basaloid carcinoma. We have now examined the role of Ck34βE12 in discriminating between neuroendocrine and non‐neuroendocrine proliferations.

Statin-induced fibrotic nonspecific interstitial pneumonia

Statins inhibit the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, reduce the serum level of low-density lipoprotein cholesterol, and are extensively prescribed to prevent cardiovascular mortality and morbidity. Few systemic adverse effects, such as pseudopolymyositis, lupus-like syndromes, and anecdotal hypersensitivity pneumonitis, have been reported. A simvastatin-induced diffuse interstitial pneumonia associated with a nonspecific interstitial pneumonia pattern at histological analysis is repoted here. Ultrastructural analysis showed a diffuse cytoplasmic accumulation of intralysosomial lamellar inclusions in type II pneumonocytes, histiocytes and endothelial cells, suggesting a shared pathogenesis with amphiphilic drug-induced toxic lung injury. Because statins are increasingly prescribed, statin-induced interstitial lung disorders may be more frequently observed and early recognition will be required.

Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer.

PURPOSEnTumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer.nnnPATIENTS AND METHODSnA discovery set (one trial, n = 824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non-small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set.nnnRESULTSnDiscovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points).nnnCONCLUSIONnIntense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non-small-cell lung cancer.

Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis

Multifocal alveolar hyperplasia associated with pulmonary lymphangioleiomyomatosis is reported in a 21‐year‐old woman with tuberous sclerosis. Beside the cystic lesions of lymphangioleiomyomatosis, the tomography showed nodules up to 8u2003mm in both upper lobes. A proliferation of type II pneumonocytes and Clara cells lining the alveolar walls in an adenoma‐like pattern was observed. Nuclear atypia, mitoses and necrosis were not observed, providing evidence against multicentric bronchioloalveolar carcinoma or micronodular atypical alveolar adenomatous hyperplasia. Whereas the lymphangioleiomyomatosis lesions showed strong positivity for HMB45 and expressed oestrogen and progesterone receptors, the alveolar hyperplasia was negative for these markers as it was for carcinoembryonic antigen, p53 and MIB1 antibodies. Multifocal alveolar hyperplasia in tuberous sclerosis is probably a benign hamartomatous lesion in our case without progression on a 2‐year follow‐up. Its histogenesis is unknown, but is possibly related to chromosome instability.