RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion

Chemotherapy; Non–small cell lung cancer; RET inhibitorsQuimioteràpia; Càncer de pulmó de cèl·lules no petites; Inhibidors de RETQuimioterapia; Cáncer de pulmón de células no pequeñas; Inhibidores de RETIntroduction Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. Methods This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. Results For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). Conclusions Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.Writing assistance was provided by Mrs. Sarah Mackenzie. Dr. Marinello was the recipient for the grant for DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie). Dr. Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health); Ayuda de la Acción Estratégica en Salud-ISCIII FIS 2021 (PI21/01653); Ayuda SEOM-Juan Rodés 2020. Dr. Cortellini acknowledges the support from the National Institute for Health Research Imperial Biomedical Research Centre. Dr. Pinato acknowledges the support from the Wellcome Trust Strategic Fund (PS3416), Associazione Italiana per la Ricerca sul Cancro (Associazione Italiana per la Ricerca sul Cancro MFAG Grant ID 25697), National Institute for Health Research Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and the Imperial College Tissue Bank

Etude de la concordance de la réponse radiologique des tumeurs primitives et métastases de cancers bronchiques non à petites cellules traités par inhibiteurs de tyrosine kinase du récepteur de l'Epidermal Growth Factor

LYON1-BU Santé (693882101) / SudocSudocFranceF

Biomarqueurs prédictifs de l’efficacité des inhibiteurs de checkpoint immunitaire dans le traitement des cancers

International audienceThe remarkable efficacy of PD-1/PD-L1 and CTLA4 immune checkpoint inhibitors has led to numerous approvals in melanoma, non-small cell lung cancer, kidney cancer and several other cancers. Nevertheless, a response is observed in a variable proportion of patients, emphasizing the need for predictive biomarkers of efficacy of immune checkpoint inhibitors effectiveness. Several predictive biomarkers of efficacy are of interest: companion tests such PD-L1 immunohistochemistry, the mutational load, the immune status of the tumor and its molecular profile. They do not allow a perfect selection of the patients, but standardization procedures for certain techniques are ongoing. Moreover the emergence of new approaches, such as the multiplex in situ techniques and the microbiote analysis, may offer the opportunity to better select patients who really benefit from immunotherapy. The goal of this article is to discuss available and promising predictive biomarkers of efficacy for immunotherapy strategies.La remarquable efficacité des inhibiteurs de checkpoint immunitaire PD-1/PD-L1 et CTLA4 a mené à de nombreuses autorisations de mise sur le marché dans les mélanomes, les cancers du poumon, les cancers du rein et d’autres cancers. Cependant, le bénéfice de ces traitements se restreint à une part variable de patients, soulignant la nécessité de disposer de biomarqueurs prédictifs de leur efficacité. Plusieurs paramètres prédictifs de réponse se dessinent : les tests compagnons, tel que l’immunohistochimie PD-L1, la charge mutationnelle, le statut immunitaire de la tumeur et son profil moléculaire. Ils ne permettent pas de sélection parfaite, mais une stratégie de standardisation de certains tests se met progressivement en place. Par ailleurs, la complémentarité de certaines méthodes et l’émergence de nouvelles approches, telles que les techniques in situ multiparamétriques et l’étude du microbiote intestinal offrent l’opportunité de rationaliser encore plus les patients susceptibles de bénéficier de l’immunothérapie. Cet article a pour but de décrire les facteurs prédictifs validés ou potentiels de réponse à l’immunothérapie

Pro-tumoural CXCL10/CXCR3-A autocrine loop in invasive mucinous lung adenocarcinoma

International audienceInvasive mucinous adenocarcinoma (IMA) is a mucinous variant of lepidic predominant lung adenocarcinoma (LPA) and associated with a worse prognosis. We postulated that cytokine expression would enable us to differentiate IMA from LPA in terms of prognosis and acquisition of pro-tumoural capacities. A 30-cytokine panel was assessed in bronchoalveolar lavage fluids (BALF) from IMA (n=38), LPA (n=25) and control samples (n=7). We investigated the expression of differentially expressed cytokines and splice variants of their receptors in surgical samples. The presence of EGFR and KRAS mutations were determined. We also examined the expression of cytokines and splice variants of their receptors in different cell lines, exploring their functional impact on signalling pathways, proliferation and migration. Only C-X-C motif chemokine 10 (CXCL10) was differentially expressed, namely overexpressed in IMA BALF compared with LPA. CXCL10 overexpression in BALF was linked to a worse prognosis. In surgical samples, CXCL10 and its receptor C-X-C motif chemokine receptor 3 (CXCR3) were overexpressed in IMA compared to LPA. A pro-tumoural CXCR3-A splice variant was overexpressed in IMA, suggesting a CXCL10/CXCR3-A autocrine loop in IMA. CXCL10 and CXCR3 expression were not correlated with EGFR or KRAS status. CXCL10 up-regulated CXCR3-A expression, Erk1/2 phosphorylation and enhanced migration in the mucinous H2228 cell line. CXCL10/CXCR3-A may play a pro-tumoural role in IMA via an autocrine mechanism

Lung cancer surgical treatment after solid organ transplantation: A single center 30-year experience

International audienceObjectives: Solid organ transplantation is an accepted treatment for end-stage organ failure. Long-lasting immunosuppressive therapy may increase the risk of de novo malignancies in transplant recipients. Increased risk of bronchogenic carcinoma in this population is controversial but prolonged transplant recipients' survival (obtained in modern transplantation era) may increase the need for lung cancer surgical resection in immunosuppressed patients. Our aim was to assess morbidity, mortality and long-term survival after lung cancer surgical treatment in this population.Materials and methods: In an observational study, the medical charts of all consecutive patients who had undergone surgical treatment for lung cancer after solid organ transplantation were reviewed. These medical records were extracted from the University of Lyon (France) Transplantation database and Thoracic Surgery database. From 1986-2016, 61 patients underwent a surgical treatment for lung cancer after solid organ transplantation.Results: The surgical procedures consisted of 52 lobectomies, 7 pneumonectomies and 2 wedge-resections. 90-day post-operative complications, most of which were pneumonias, affected 31 patients (50.8 %). 90-day postoperative mortality was 9.8 %. Overall survival was 40.6 % at 5 years and 18 % at 10 years.Conclusion: Despite a higher rate of infectious complications and 90-day postoperative mortality, surgical treatment for lung cancer must be offered to these patients as it offers a chance to cure earlier-stage disease. Long-term survival rate is satisfactory and similar to that of the general population. In transplant recipients with former smoking history, close follow-up is mandatory to increase early lung cancer diagnosis

Calpain 1 in bronchoalveolar lavage fluid is associated with poor prognosis in lepidic predominant pulmonary adenocarcinoma

International audienceCalpain 1 is a proinflammatory calcium-activated cysteine protease, which can be partly externalized. Extracellular calpains limit inflammatory processes and promote tissue repair, through cell proliferation and migration. Toll like receptor (TLR) 2 has been identified as a target of extracellular calpains in lymphocytes. The aim was to investigate the externalization of calpain 1 and the release of soluble TLR2 during tumor progression of pulmonary lepidic predominant adenocarcinoma (LPA). Extracellular calpain 1, soluble fragment of TLR2 and cytokines were analyzed by ELISA in bronchoalveolar lavage fluid (BALF) supernatants from patients with LPA (n = 68). Source of calpain was analyzed by immunohistochemistry and soluble TLR2 by flow cytometry on polymorphonuclear neutrophils (PMN) and human lung cancer cell lines. Extracellular calpain 1, secreted by tumor cells, was associated to tumor progression, neutrophilic inflammation, with a poor prognostic factor on survival (P = 0.003). TLR2 was expressed on PMN and tumor cells and decreased after calpain exposure. Soluble fragment of TLR2 in BALF supernatants was correlated to the extracellular calpain 1 concentration (r = 0.624; P < 0.001), and its high level was associated with tumor progression and a pro-inflammatory environment. Extracellular calpain 1 secreted by tumor cells, could participate in inflammatory microenvironment and tumor progression through TLR2 in LPA

Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers

International audienceObjectives: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers.Materials and methods: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n = 25) or LPA (n = 27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements.Results: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n = 11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n = 14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression.Conclusions: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes

Patients with advanced lung cancer harboring oncogenic mutations should be admitted to intensive care units

International audienc

Chemotherapy Effectiveness After First-Line Gefitinib Treatment for Advanced Lepidic Predominant Adenocarcinoma (Formerly Advanced Bronchioloalveolar Carcinoma): Exploratory Analysis of the IFCT-0401 Trial.

International audienceHYPOTHESIS:: This study explored whether chemotherapy after first-line gefitinib was effective in patients with advanced lepidic predominant adenocarcinoma (LPA), formerly advanced bronchioloalveolar carcinoma, who were enrolled in the Intergroupe Francophone de Cancérologie Thoracique (IFCT)-0401 trial. METHODS:: Overall, 88 patients presenting advanced LPA were enrolled in the IFCT-0401 trial, receiving gefitinib as first-line therapy. No predefined second-line treatment was mandatory in the case of progression or limiting toxicity under gefitinib. However, the carboplatin plus paclitaxel regimen was recommended for patients with a performance status (PS) 0 or 1 and gemcitabine monotherapy for those with a PS 2. For these patients, data concerning treatment efficacy was collected from the IFCT-0401 trial database. RESULTS:: In total, 47 patients (53%) received second-line treatment after the failure of gefitinib, with 43 having PS 0 or 1. Regarding treatment, 43 were treated with chemotherapy, with 38 receiving a platinum-doublet regimen (taxane-based, n = 29; gemcitabine-based, n = 9) and five receiving monotherapy (gemcitabine, n = 3; pemetrexed, n = 2). The overall response rate (ORR) to chemotherapy was 21% (95% confidence interval [CI]: 10-36), disease control rate 56% (95% CI: 40-71), and median progression-free survival (PFS) 3.0 months (95% CI: 2.4-4.9). For patients receiving a platinum doublet (n = 38), ORR was 21% (95% CI: 10-37), with disease control rate being 55% (95% CI: 38-71), and median PFS 2.9 months (95% CI: 2.4-4.4). For patients receiving taxane-based regimen (n = 29) and gemcitabine-based regimen (n = 12), ORR was 28% and 0%, respectively, with a median PFS of 3.3 and 2.0 months, respectively, (p = 0.0243). The two patients receiving pemetrexed experienced a prolonged response. Multivariate Cox model analysis revealed that only the use of taxane-based chemotherapy or pemetrexed was related to PFS. CONCLUSION:: Platinum-doublet chemotherapy showed some effectiveness in treating advanced LPA patients after first-line gefitinib. Our findings also suggest that taxane-based chemotherapy and pemetrexed should be investigated further in future clinical trials