[Neutrophil plasticity: A new key in the understanding of onco-immunology]. / La plasticité des neutrophiles : nouvel élément de compréhension en onco-immunologie.

Lung cancer remains the leading cause of cancer mortality in France. Research has shown that immune cells play a major role in tumor growth, angiogenesis and promotion of metastasis. While the density of intra-tumoral adaptive immune cell infiltrate is associated with a favorable prognosis, the presence of polynuclear neutrophils (innate immune cells) is associated in different types of cancer with a poor prognosis. The reviewed studies underline the abundance of intra-tumoral neutrophils involved in tumor progression by their immunosuppressive activity. More specifically, it has been shown that the neutrophil/lymphocyte (N/L) ratio is a prognostic marker. Different mechanisms promoting tumor progression have been identified, particularly the pro-angiogenic and immunosuppressive activities of neutrophils. However, under certain conditions, they can also exert effective anti-tumor activity through their interactions with the adaptive immune system. The complexity of the role of neutrophils in oncology resides in the diversity of subpopulations and their plasticity under the influence of the tumor environment. In this review, we will discuss the different properties of neutrophils not only as pro- and anti-tumor effector cells, but also as immunomodulatory cells, and we will conclude by considering therapeutic perspectives in lung cancer.

Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

[Rapid outpatient diagnostic pathways for lung cancer: Evaluation after one year]. / Parcours de diagnostic rapide du cancer du poumon : évaluation à un an.

INTRODUCTION: The introduction of coordinated care pathways for lung cancer diagnosis and treatment is a complex process. The purpose of the French Cancer Plan 2014-2019 was to improve referral to treatment waiting times in people with suspected malignancy. The aim of this study was to assess a rapid outpatient diagnostic program for lung cancer established in 2016. METHOD: This retrospective study was carried out in the Pulmonology Department at Tenon Hospital, Paris, France between May 2016 and May 2017. RESULTS: During this period, 118 patients (60%) of patients in the pathway were diagnosed with lung cancer. The median waiting time to first consultation (D1) was 4 (2-7) days. The median waiting time between diagnosis and treatment decision (D4) was 4 (0-8) days. The median waiting time to the first treatment (D5) was 10 (4-15) days for chemotherapy and 27 (16-34) days for surgery. The median waiting time between the first abnormal chest X-ray and the first treatment (D6) was 49 days (34-70). CONCLUSION: Referral to treatment waiting times was consistent with international recommendations. Coordinating nurses improved care pathways in lung cancer patients.

Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+ double positive T cell density in locally advanced N2 non-small-cell lung carcinoma.

BACKGROUND: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. PATIENTS AND METHODS: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. RESULTS: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99-3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11-3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT. CONCLUSIONS: Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy.

Proposals for managing patients with thoracic malignancies during COVID-19 pandemic.

The objective of this document is to formalize a degraded mode management for patients with thoracic cancers in the context of the COVID-19 pandemic. The proposals are based on those of the French High Council for Public Health, on published data outside the context of COVID-19, and on a concerted analysis of the risk-benefit ratio for our patients by a panel of experts specialized on thoracic oncology under the aegis of the French-Language Society of Pulmonology (SPLF)/French-language oncology group. These proposals are evolving (10 April 2020) according to the situations encountered, which will enrich it, and are to be adapted to our institutional organisations and to the evolution of resources during the COVID-19 epidemic. Patients with symptoms and/or COVID-19+ are not discussed in this document and are managed within the framework of specific channels.

Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

Nivolumab-refractory patients with advanced non-small-cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity. METHODS: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015. RESULTS: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p < 0.0001), shorter duration of treatment before nivolumab (p = 0.028) and had dramatically shorter nivolumab overall survival (p < 0.0001) than patients who did not present with refractory disease. CONCLUSION: Nivolumab-refractory disease can affect up to 20% of patients treated with nivolumab for advanced NSCLC with dramatically shortened survival rates. Further studies are needed to understand the precise mechanisms leading to refractory disease as well as its management.

[Biomarkers predictive of PD1/PD-L1 immunotherapy in non-small cell lung cancer]. / Biomarqueurs prédictifs de l'immunothérapie anti-PD1/PD-L1 dans le cancer broncho-pulmonaire non à petites cellules.

Immune checkpoint inhibitors (ICI), targeting the PD1/PD-L1 axis has shown their efficacy in lung cancer but only in a restricted population of patients, thus it is mandatory to identify biomarkers predicting the clinical benefit. In this article we will describe and analyzed biomarkers already published, from protein, to RNA and at last DNA markers, discussing each markers feasibility and interest. In the future, combined analysis of several markers will probably be proposed, particularly with the increasing complexity of therapy schema with molecules association.

[IHC, FISH, CISH, NGS in non-small cell lung cancer: What changes in the biomarker era?] / IHC, FISH, CISH, NGS dans les cancers bronchiques non à petites cellules : quelles évolutions dans l'ère des biomarqueurs ?

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.

[IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. / Inhibiteurs du check-point immunitaire en néo-adjuvant dans les cancers bronchiques non à petites cellules localisés : essai IoNESCO.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) is a checkpoint receptor that facilitates immune evasion by tumor cells, through interaction with programmed cell death-1 (PD-1), a receptor expressed by T-cells. Durvalumab is an anti-PD-L1 monoclonal antibody that blocks PD-L1 interaction with PD-1 on T-cells, countering the tumor's immune-evading tactics. Phase I/II studies demonstrated durable responses and manageable tolerability in heavily pre-treated patients with non-small cell lung cancer (NSCLC). METHODS: This phase II study is designed to administrate three durvalumab IV infusions (10mg/kg at day 1, 15, 29) before surgery, to patients with pathologically confirmed NSCLC, clinical stage IB (>4cm) or stage II, ≥18 years of age, WHO performans status 0-1, without selection on PD-L1 expression. Preoperative chemotherapy and radiation therapy are not permitted. The primary objective is feasibility of complete surgical resection. Major pathological response on surgical tissue, defined as 10% or less remaining tumor cells, will be a secondary objective. Additional secondary objectives include tolerance, adverse effects, delay between start of treatment and surgery, response rate (RECIST 1.1), metabolic response rate, postoperative adverse events, disease-free survival and overall survival. A rate of complete resection<85% (P0) is considered unacceptable. P1 hypothesis is of 95%, and with a study power of 90% and an alpha risk of 5% (two-steps Fleming's procedure), 81 patients are required. EXPECTED RESULTS: To establish whether neoadjuvant immunotherapy is feasible and could improve the survival of patients with early-stage NSCLC.

[MET exon 14 splicing sites mutations: A new therapeutic opportunity in lung cancer]. / Les mutations des sites d'épissage de l'exon 14 de MET. Une nouvelle opportunité thérapeutique dans le cancer du poumon.

The mutations leading to MET exon 14 skipping represent a new class of molecular alterations described in various cancers. These alterations are observed in 2 to 3 % of cases of non-small cell lung cancer (NSCLC). Several cases of NSCLC carrying such alterations and achieving objective response to MET tyrosine kinase inhibitorshave recently been published. This review summarizes the molecular mechanisms responsible for MET exon 14 skipping as well as the consequences of the loss of this exon on receptor activity. We also describe the clinical characteristics of patients with METΔ14 mutations. Finally, we address the issues related to the detection of these mutations in lung cancer, and the need to anticipate resistance to MET inhibitors.

Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities.

BACKGROUND: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13). PATIENTS AND METHODS: Whole-exome sequencing was carried out in 15 SC patients and on data from 10 previously published cases. Hierarchical clustering and consensus non-negative matrix factorization were carried out for samples classification based on mutational signatures. RESULTS: In the two series, SC distributed between two clusters (C): Csig4 (characterized by signature 4) and Csig2-3-13 (signatures 2, 3, and 13). Csig4 exhibited more frequent MAPK pathway mutations than Csig2-3-13 (pooled series: n = 10/14 versus 2/11, P < 0.05, respectively) and stronger PD-L1 expression (our series: n = 6/9 versus 1/6, P = 0.12). MET alterations were only found in Csig2-3-13 (pooled series: n = 5/11 versus 0/14, P = 0.009), as well as BRCA1/BRCA2 (n = 3/11 versus 0/15), EGFR (n = 1), and IDH1 (n = 1) mutations. Csig2-3-13 patients had better overall survival than Csig4 patients (median: >45 versus 7 months, respectively, P = 0.001). CONCLUSIONS: Our study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in Csig4 and specific targeted agents in Csig2-3-13. These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.

Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort.

BACKGROUND: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens. PATIENTS AND METHODS: This retrospective cohort study in European centers assessed patients with advanced non-small-cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. RESULTS: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30-87), 62.4% women, 60.4% never-smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. The median number of treatment lines was 3 (range: 1-11). The median overall survival was 24 months. Overall response rate (ORR) and the median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n = 52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab = 57, neratinib = 14, afatinib = 9, lapatinib = 5, T-DM1 = 1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. CONCLUSION: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials.

High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets.

BACKGROUND: Pulmonary sarcomatoid carcinomas (SC) are tumors characterized by poor prognosis and resistance to conventional platinum-based chemotherapy. This study sought to describe the mutational profile of SC using high-throughput genotyping technology. PATIENTS AND METHODS: We used mass spectrometry to test 114 surgical biopsies from 81 patients with SC for 214 mutations affecting 26 oncogenes and tumor suppressor genes. RESULTS: In total, 75 (92.6%) patients were smokers. Within the total 81 tumors, 67 distinct somatic alterations were identified, with 56 tumors (69.1%) harboring at least one mutation. The most frequent mutations were KRAS (27.2%), EGFR (22.2%), TP53 (22.2%), STK11 (7.4%), NOTCH1 (4.9%), NRAS (4.9%), and PI3KCA (4.9%). The EGFR mutations were almost always rare mutations (89%). In 32 tumors (39.5%), two or more mutations co-existed, with up to four mutations in a single case. In six different cases, comparative genetic analysis of different histological areas from the same tumor (giant, spindle, or epithelial component) revealed a 61% concordance rate for all the mutations with a 10% detection threshold, compared with 91.7% with a 20% detection threshold. CONCLUSION: Our results demonstrated a high mutation rate and frequent co-mutations. Despite SC tumors exhibiting a high histological heterogeneity, some intratumoral molecular homogeneity was found. Now with newly developed targeted therapies, SC patients may be eligible for new target mutations, and can now therefore be screened for clinical trials.

[Role of the Sonic Hedgehog pathway in thoracic cancers]. / Rôle de la voie Sonic Hedgehog dans les cancers thoraciques.

INTRODUCTION: Sonic Hedgehog (Shh) pathway is physiologically activated during embryogenesis and development. It plays a role in idiopathic lung fibrosis and is also activated in several solid cancers. STATE OF THE ART: Shh pathway is reactivated in thoracic cancers, as small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma. Shh pathway is associated with cancer stem cells and seems to have a crucial role in tumor proliferation, aggressiveness and chemoresistance in these cancers. This review describes the activation mode of Shh pathway in thoracic cancers and its role in small cell lung carcinoma, non-small cell lung carcinoma and malignant pleural mesothelioma, using in vitro and in vivo models. Notably, data from literature show that inhibition of Shh pathway has an antitumor action and sensitizes to chemotherapy. PERSPECTIVES: These results incite to develop targeted therapies against Shh pathway in the treatment of thoracic cancers.

2014 update on non-small cell lung cancer (excluding diagnosis).

Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has changed with an increased incidence in non-smokers and women. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011, and they are now the most frequent histological subtype. More than half the cases of LC are diagnosed at the metastatic stage. Biopsies must provide tissue samples that are quantitatively large enough and of a good enough quality for diagnosis and to search for biomarkers. When the cancer seems to be localized, precise staging must be obtained. Treatment is based on the TNM classification. In localized stages, lobectomy associated with lymph node dissection is the standard therapy. Intraoperative chemotherapy improves survival in case of lymph node infiltration. Stereotactic radiation therapy and radiofrequency can be considered as specific cases. In cases with local progression, treatment is more controversial. In the presence of metastases, the goal is not a cure, but improving survival and quality of life. Numerous advances have been made with personalized treatment, (in particular in relation to the histological type and oncogenic addiction in tumors, access to new drugs, and improved management). Clinical research in thoracic cancer is very active. The fight against tobacco should remain a priority.

[Lung cancer and HIV infection]. / Cancer du poumon et infection par le Virus de l'Immunodéficience Humaine.

AIDS was the cause of the majority of deaths from HIV infection before 1996 but since the introduction of antiretroviral therapies the causes of mortality have changed considerably. In 2010, 75 % of deaths were due to diseases other than AIDS, the majority being cancers. Lung cancer is the most common in terms of both incidence and mortality. It shows specific features when compared to the general population: there is an excess risk due to heavy smoking but also probably due to immunosuppression. The age of onset is younger and the prognosis worse than in the general population. Management is difficult, partly due to the aggressive nature of the tumor and partly to co-morbidities and potential interactions between anticancer and antiretroviral therapies. A phase II therapeutic trial (IFCT-CHIVA 1001) is under way nationally.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.