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Objectives Immunohistochemistry (IHC) is considered as a screening method for ALK rearrangement thanks to its excellent sensitivity. Strong marking on immunohistochemistry give the go-ahead to start ALK tyrosine kinase inhibitors (ALK TKI). Lack of therapeutic response may then lead to the suspicion of molecular alterations other than ALK rearrangements. Methods We present a patient with strong ALK and PD-L1 positive IHC expression lung sarcomatoid carcinoma with initial life-threatening disease progression after beginning ALK TKI. We also review the literature to summarize ALK amplification clinical features and therapeutic management in lung cancers. Results Fluorescence in situ Hybridization (FISH) revealed ALK amplification on the initial anatomopathological samples. Lack of ALK rearrangement and strong PD-L1 positive IHC expression led to the initiation of immune checkpoint inhibitor (ICI) as a second line of treatment, with an excellent response. Conclusion We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy.

Introduction KRAS mutations are detected in 20% to 30% of NSCLC. However, KRAS mutation subtypes may differently influence the outcome of patients with advanced NSCLC. Methods In the Biomarkers France study, 4894 KRAS mutations (26.2%) were detected in 4634 patients from the 17,664 enrolled patients with NSCLC. Survival and treatment data on noncurative stage III to IV NSCLC were available for 901 patients. First- and second-line treatment effects on progression-free survival and overall survival were analyzed according to the KRAS mutations subtype. Results Over 95% of patients with KRAS mutation were smokers or former smokers who were white (99.5%), presenting with adenocarcinoma (82.5%). The most common KRAS mutation subtype was G12C (374 patients; 41.5%), followed by G12V (168; 18.6%), G12D (131; 14.5%), G12A (62; 6.9%), G13C (45; 5.0%), G13D (31; 3.4%), and others (10; 1%). Approximately 21% of patients had transition mutation and 68.2% had a transversion mutation. G12D and transition mutations were predominant in never-smokers. The median overall survival for patients with KRAS-mutated NSCLC was 8.1 months (95% confidence interval [CI]: 7.5–9.5), without any differences according to the different KRAS subtypes mutations. The median progression-free survival was 4.6 months (95% CI: 4.2–5.1) for first-line treatment and 4.8 months (95% CI: 4.3–6.8) for second-line treatment, without any differences according to the different KRAS subtypes mutations. Conclusions KRAS mutation subtypes influenced neither treatment responses nor outcomes. The KRAS G12C mutation was detected in 41.5% of patients, who are now eligible for potent and specific G12C inhibitors.

Introduction Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the efficacy of ICI in SC. Methods All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed death-ligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase. Results Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8–79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3–45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0–100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1+ and 0% in the one patient with PD-L1- (p = 0.44). The median TMB was 18 (4–39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p = 0.2). Conclusions Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.

International audience; Immune checkpoint inhibitor-related pneumonitis (ICI-P) during cancer treatment is rarely observed (

International audience; Calpain 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.

International audience; Non–small-cell lung cancer (NSCLC) is the most common non-acquired immune deficiency syndrome-related malignancy responsible for death. Mutational status is crucial for choosing treatment of advanced NSCLC, yet no data is available on the frequency of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations and their impact on NSCLC in human immunodeficiency virus (HIV)-infected patients (HIV-NSCLC).All consecutive HIV-NSCLC patients diagnosed between June 1996 and August 2013 at two Paris university hospitals were reviewed, with tumor samples analyzed for EGFR and KRAS mutational status.Overall, 63 tumor samples were analyzed out of 73HIV-NSCLC cases, with 63% of advanced NSCLC. There were 60 non-squamous and nine squamous cell carcinomas, with EGFR and KRAS mutations identified in two (3.3%) and seven (11.5%) tumors, respectively. The proportion of KRAS mutations was 29% if solely the more sensitive molecular techniques were considered. The two patients with advanced adenocarcinoma harboring EGFR mutations exhibited lasting partial response to EGFR-tyrosine kinase inhibitors. Overall survival for patients with advanced NSCLC were >30 months for those with EGFR mutations

Summary Background Despite recent progress, non-small cell lung cancer (NSCLC) first-line treatment remains a platinum-based doublet in most cases. No guidelines exist beyond third line. Chemotherapy rechallenge is an option, but little data is available in NSCLC. Our study aims to describe patients who underwent chemotherapy rechallenge while assessing its efficacy and safety. Methods Consecutive patients with advanced-stage NSCLC receiving first-line treatment in Tenon hospital in 2011 were included, with a 5-year follow-up. Patients were analyzed according to chemotherapy rechallenge or not. Chemotherapy rechallenge was defined as re-initiation of a previously administered chemotherapy agent at any point in the treatment sequence, with at least one treatment regimen between first use and rechallenge. Results Of 149 patients, 18 underwent chemotherapy rechallenge (12%). They were younger (56 vs. 61 years, P = 0.04), mostly women (61% vs. 30%, P = 0.02), with lepidic adenocarcinoma (23% vs. 3.5%, P = 0.03), a better general state of health (100% performance status 0–1 vs. 74%, P = 0.04), and fewer cardiovascular comorbidities (16% vs. 42%, P = 0.04). They were more likely to have received a receptor tyrosine kinase inhibitor treatment (89% vs. 43%, P = 0.0003). Progression-free survival was longer at first use than at rechallenge (median 9.2 vs. 2.7 months, P = 0.002). No increased toxicity was observed at rechallenge compared to first use. Finally, a subsequent line of treatment was given after rechallenge in 61% of the patients. Conclusion Patients eligible for chemotherapy rechallenge were those with good prognostic factors. Chemotherapy rechallenge may provide a well-tolerated additional line of treatment, with decreased efficacy compared to its first application.

Introduction MNNG HOS transforming gene (MET) abnormalities such as amplification and exon 14 mutations may be responsive to targeted therapies. They are prevalent in lung sarcomatoid carcinomas (LSCs) and must be diagnosed as efficiently as possible. Hypothetically, c-MET overexpression by immunohistochemistry (IHC) may prove effective as a screening test for MET abnormalities. Methods Tissue samples were obtained from consecutive patients with a resected LSC in four oncologic centers. IHC was performed using the SP44 antibody (Ventana, Tucson, Arizona) and evaluated using the MetMab score and H-score. Fluorescence in situ hybridization was applied with the dual color probe set from Zytovision (Clinisciences, Nanterre, France). True MET amplification was diagnosed when MET gene copy number was 5 or greater and the ratio between MET gene copy number and chromosome 7 number was greater than 2. All MET exon 14 alterations including those affecting splice sites occurring within splice donor and acceptor sites were detected in the routine molecular testing on genetic platforms. Results A total of 81 LSCs were included. Fourteen (17%) exhibited positive IHC using the MetMab score and 15 (18.5%) using the H-score. MET amplification was detected in six tumors (8.5%) and MET exon 14 mutation in five (6%). A weak positive correlation between IHC and fluorescence in situ hybridization was found (r = 0.27, p = 0.0001). IHC sensitivity for MET amplification was 50%, with a specificity of 83%, positive predictive value of 21.4%, and negative predictive value of 94.7%. IHC sensitivity for MET exon 14 mutations was 20%, with a specificity of 83%, positive predictive value of 7%, and negative predictive value of 94%. Conclusion IHC is not a relevant screening tool for MET abnormalities in LSC.

Anaplastic lymphoma kinase (ALK) translocations are a validated molecular target in non-small cell lung cancer (NSCLC). ALK translocations result in the expression of a chimeric protein, exhibiting a constitutive ALK kinase activation, involved in cell proliferation, invasion and loss of apoptosis (1). ALK translocations are found in 4–7% of NSCLC, particularly in adenocarcinomas and in non-smokers (1). According to FDA and EMEA, standard first-line therapy for advanced ALK translocated NSCLC is crizotinib, a multi-target MET, ALK and ROS1 inhibitor (1,2). The use of second generation ALK inhibitors, such as ceritinib or alectinib, was initially validated at progression (3-5). More recently, these second generation ALK inhibitors were evaluated in first-line treatment. This year, ceritinib received FDA and EMEA approval in the first-line treatment for advanced ALK translocated NSCLC after the results of a phase III trial comparing ceritinib to platinum - pemetrexed chemotherapy with a benefit on progression-free survival of 16.6 vs. 8.1 months (6). Several clinical trials are underway comparing head to head different ALK inhibitors in phase III trials in ALK naive patients, as brigatinib vs. crizotinib (NCT02737501) or lorlatinib vs. crizotinib (NCT03052608).

Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non–small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup. Experimental Design: Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0–1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m2) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages. Results: In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7–7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0–8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae. Conclusions: The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases. Clin Cancer Res; 21(8); 1896–903. ©2015 AACR.

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.

International audience; Platinum-based perioperative chemotherapy is actually the standard of care in stage II–IIIa non-small cell lung cancer (NSCLC). A benefit may also be seen in stage IB NSCLC with tumors of more than 4 cm of diameter. Perioperative chemotherapy improves 5-year survival of 4 to 15%. This benefit is mainly proved by postoperative chemotherapy trials. Nevertheless, preoperative chemotherapy has advantages: a better tolerance, an estimation of tumor chemosensibility, without an increased postoperative morbimortality. However, pTNM and pathological tumor analyses are modified. Indications of postoperative radiotherapy are limited. In early stage NSCLC (stage I-II), radiotherapy worsens survival. Radiotherapy is routinely achieved in NSCLC with parietal tumor invasion and incomplete tumor resection. Indications of immunotherapy and targeted therapies in case of oncogenic addiction remain to be established in resected NSCLC. Several biomarkers are studied to better describe the indications of perioperative chemotherapy: recognize groups of patients with a worse prognosis and distinguish chemosensibility of the tumor.; Une chimiothérapie à base de platine administrée en périopératoire a démontré un bénéfice sur la survie dans le traitement des cancers bronchiques non à petites cellules (CBNPC) de stades II, IIIA et peut être IB (tumeur de plus de 4 cm de diamètre). Ce gain de survie varie entre 4 et 15 % selon les études. Le niveau de preuve est plus élevé pour la chimiothérapie adjuvante que néo-adjuvante. La chimiothérapie néo-adjuvante présente cependant certains avantages : une meilleure adhésion au traitement et une évaluation de la chimiosensibilité de la tumeur. Néanmoins, l’analyse précise anatomopathologique et le pTNM sont modifiés. La place de la radiothérapie postopératoire est restreinte. Dans les stades précoces (stades I-II), elle est délétère sur la survie. Elle est réalisée en routine en cas d’atteinte pariétale avec résection incomplète. La place de l’immunothérapie ou des thérapies ciblées en situation d’addiction oncogéniques reste à déterminer dans les CBNPC réséqués. Plusieurs marqueurs biologiques sont étudiés pour mieux définir les indications à un traitement médical périopératoire afin de déterminer les groupes de patients ayant un pronostic péjoratif et identifier les patients ayant une tumeur chimiosensible.

Pulmonary sarcomatoid carcinomas are a rare group of tumors accounting for about 1 % of non-small cell lung carcinoma (NSCLC). In 2004, World Health Organization classification united under this name all the carcinomas with sarcomatous or sarcomatous-like component with spindle cell or giant cell appearance. There are five subtypes: spindle cell carcinoma, giant cell carcinoma, pleomorphic carcinoma, carcino-sarcoma and pulmonary blastoma. Clinical characteristics are not specific from the others subtypes of NSCLC. Epithelial to mesenchymal transition pathway may play a key role. Patients are frequently symptomatic. Tumors are voluminous more often peripherical than central, with strong fixation on FDG TEP CT. Distant metastasis are frequent with atypical locations such as peritoneal or retroperitoneal sites. These tumors have poorer prognosis than the other NSCLC subtypes because of great aggressivity, and frequent chemoresistance. Here, we present a review of litterature in order to better describe these tumors.

Background and objective: Only a small proportion of patients with advanced non-small cell lung cancer (NSCLC) have a life expectancy greater than 2 years. The aim of this study was to identify the factors associated with long-term survival of patients with advanced NSCLC. Methods: Patients who had received chemotherapy for stage IIIb or IV NSCLC that was not amenable to radiotherapy were studied retrospectively. Data were gathered prospectively from a comprehensive database. Long-term survivors (>2 years) were compared with the other patients, with respect to clinical, biological and tumour–node–metastasis criteria. Results: Data for 245 consecutive patients were collected. Thirty nine patients (15.9%) survived for more than 2 years. Long-term survivors were more likely to have had metastases at fewer sites (P = 0.008), an absence of bone metastases (P = 0.01), a performance status (PS) of 0–1 at first progression of the tumour (P = 0.002), a tumour that was controlled with first (P 3 months (P 110 g/L at first progression of the tumour (P = 0.02). In multivariate analysis, surgery, maintenance treatment, time to first progression of the tumour of >3 months, a PS of 0–1 at first progression, the number of chemotherapy agents received, and LDH levels, were significant predictors of long-term survival. Conclusions: Assessment of these factors, and the use of maintenance therapy, when possible, may identify a population of patients with NSCLC that is likely to have a prolonged life expectancy.

Introduction: Pemetrexed is approved to treat non-small cell lung cancer and has an overall favorable toxicity profile. A case of pemetrexed-induced cutaneous adverse events (CAE), i.e., periorbital edema with conjunctivitis and edema of the limbs, leading to severe fluid retention, was diagnosed in our unit. The aim of this study was to evaluate the incidence and risk factors for CAEs. Methods: Patients treated with pemetrexed were identified from a prospective cohort. To detect pemetrexed-associated CAEs, questionnaires were answered by patients and the referring oncologist. Results: Included were 107 patients treated with four cycles or more of pemetrexed. Pemetrexed-induced CAEs were observed in 37 of 107 (35%) total patients (TPs) and 25 of 47 (53%) alive patients (APs). Conjunctivitis was the most frequent CAE: 27 of 107 (25%) in TPs and 21 of 47 (44%) in APs. Periorbital edema occurred in 16 of 107 (15%) TPs and 14 of 47 (30%) APs. Limb edema was present in 14 of 107 (13%) TPs and 12 of 47 (25%) APs. Only two cases of CAE influenced pemetrexed treatment. No significant differences in age, body surface area, smoking status, and performance status were detected. Patients with CAE had more cycles of pemetrexed (7 versus 5.5; p = 0.028). In univariate and multivariate analyses, gender ratio was statistically different ( p = 0.031): 48% (12/25) of women in the CAE group versus only 18% (4/18) in the control group. Conclusion: Pemetrexed induces frequent conjunctivitis, peripheral edema, and edema of the limbs. Female gender seems to be an independent risk for CAE. CAEs are frequently disabling and symptomatic treatment should be proposed.

Introduction Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort. Methods We investigated 106 frozen tumors from surgically resected NSCLC patients. Genes copy number of MET and EGFR were assessed by quantitative relative real-time polymerase chain reaction and K-Ras mutations by sequencing. Results MET is amplified in 22 cases (21%) and deleted in nine cases (8.5%). EGFR is amplified in 31 cases (29%). K-Ras is mutated in 11 cases (10.5%). As observed for EGFR amplification, MET amplification is never associated with K-Ras mutation. MET amplification could be associated with EGFR amplification. MET amplification is not related to clinical and pathologic features. MET amplification and EGFR amplification showed a trend toward poor prognosis in adenocarcinomas. Conclusion In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

International audience; Introduction : Chemoresistance is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). As the Sonic Hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.Materials and Methods : From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n=36). Shh activation was evaluated through Gli1 and Gli2 expression by immunohistochemistry (IHC) (quantitative score). In vitro treatment studies with cisplatin, vismodegib (Shh-pathway inhibitor) or both were performed on NSCLC cell lines (H322 and A549) and on primary cultures from patients with sarcomatoid carcinoma (n=4).Results : Twelve patients were refractory to chemotherapy (r-patients, 33.3%) and 24 had controlled disease (c-patients). Gli1 expression did not differ between the r- and c-patients (p=0.35). Gli2 expression was more often positive in the r-patients (41.7% versus 8.3%, p=0.02). Progression-free survival (PFS) and overall survival (OS) in patients with Gli2-positive score were 2.1 and 8.0 months, respectively, versus 6.7 and 18.0 months in patients with Gli2-negative score (p=0.03; p=0.002). In multivariate analysis, Gli2 score was independently correlated with PFS (hazard ratio [HR]=2.64; 95% confidence interval [CI]: 1.05-6.63; p=0.04) and OS (HR=4.36; 95% CI: 1.67-11.36; p=0.003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than the H838 and A549 cell lines. The cisplatin - vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro.Conclusion : The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.

Central nervous system (CNS) metastases are common in patients with non-small cell lung cancer (NSCLC), particularly in adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. In single brain metastasis, surgery or stereotactic radiosurgery should be discussed. Whole-brain radiation therapy is necessary in case of multiple symptomatic metastases. Systemic treatment remains a challenge. Preclinical data and case series confirm the efficacy of EGFR tyrosine kinase inhibitor (TKI) on EGFR-mutated NSCLC CNS metastases. Detecting EGFR mutations in the brain is difficult, as a surgical specimen is needed. In leptomeningeal metastases, molecular analysis in the cerebrospinal fluid is a reliable method to detect EGFR mutations. In patients with mutated NSCLC, brain metastases present usually the same mutation as the primary tumor. In EGFR-mutated NSCLC, objective response rates of EGFR-TKIs were between 43% and 89%, with a progression-free survival of more than 6 months and an overall survival of more than 12 months. As CNS penetration of EGFR-TKIs is limited, dose escalation may be an option. The higher serum concentration of erlotinib compared to gefitinib may lead to higher cerebrospinal fluid concentration, and erlotinib may be more effective in CNS metastases as gefitinib. Data of EGFR-TKI efficacy in brain metastases of patients with EGFR wild-type NSCLC are scarce. Response rates seem disappointing. However, as TKIs are good radiosensitizers, several clinical trials are in progress to evaluate the efficacy of adding a TKI during whole-brain radiation therapy in NSCLC brain metastases.

Objectives Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management. Materials and methods From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR , KRAS , HER2 , BRAF , PIK3CA , and MET genes mutations (PCR). Results Seventy-seven patients were included. Median age was 61 years (53–69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS , PIK3CA , EGFR , and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size p =0.011), no lymph-node metastasis (HR=3.25 [1.68–6.31], p p =0.002), no BVI (HR=1.22 [1.06–1.40], p =0.005), and no squamous component (HR=3.17 [1.48–6.79], p =0.01) were associated with longer OS. Biomarkers did not influence OS. Conclusion Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.

International audience; Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI) are a therapeutic option as second-line therapy in non-small-cell lung carcinoma (NSCLC), regardless of the EGFR gene status. Identifying patients with early progression during EGFR-TKI treatment will help clinicians to choose the best regimen, TKI or chemotherapy. From a prospective database, all patients treated with gefitinib or erlotinib between 2001 and 2010 were retrospectively reviewed. Patients were classified into two groups according to their tumor response by RECIST after 45 days of treatment, progressive disease (PD) or controlled disease (CD). Two hundred and sixty-eight patients were treated with EGFR-TKI, among whom 239 were classified as PD (n = 75) and CD (n = 164). Median overall survival was 77 days (95% CI 61–109) for PD and 385 days (95% CI 267–481) for CD. Patients with PD were of younger age (P = 0.004) and more frequently current smokers (P = 0.001) had more frequently a performance status ≥2 (P = 0.012), a weight loss ≥10% (P = 0.025), a shorter time since diagnosis (P < 0.0001), a pathological classification as non-otherwise-specified NSCLC (P = 0.01), and the presence of abdominal metasta-ses (P = 0.008). In multivariate analysis, abdominal metastases were the only factor associated with early progression (odds ratio (OR) 2.17, 95% CI [1.12– 4.19]; P = 0.021). Wild-type EGFR versus mutated EGFR was associated with early progression. The presence of abdominal metastasis was independently associated with early progression in metastatic NSCLC receiving EGFR-TKI.

Activating mutation in exons 19 or 21 of epidermal growth factor receptor (EGFR) in non-small-cell lung cancers (NSCLC) are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib. Cancer patients harboring activating EGFR mutations benefit from first-line TKI therapy. Yet 10% of patients present a primary TKI resistance, while 50% of the others develop a secondary resistance within 9-12 months after starting TKI. The RECIST's definition of progression appears flawed when applied to EGFR-mutated NSCLC patients. Most often, tumor volume shrinking widely exceeds 30% during TKI response and kinetics of growth is low during relapse. At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial-mesenchymal transition or transdifferentiation to small-cell cancer. The best strategy for secondary resistance is not well-defined: maintaining TKI therapy, switching to chemotherapy, combining both treatments, or using new therapies targeting other signaling pathways.

Cisplatin is a pivotal drug in combined chemotherapy for non-small cell and small-cell lung cancers (NSCLC or SCLC), but its renal toxicity limits its use. Current guidelines recommend 24 h hydration: thus hospitalization is required. The aim of this retrospective study was to confirm the safety of short hydration before giving an intermediate-to-high dose of cisplatin in an outpatient clinic.Patients eligible had NSCLC or SCLC and were being treated with a chemotherapy regimen that included cisplatin ≥ 75 mg/m(2). They were given the same short hydration protocol for 1 day. Nephrotoxicity was defined as ≥ grade 1 according to NCIC common toxicity criteria. Predictive factors for nephrotoxicity were analyzed.Three hundred and fifty-seven consecutive patients (median age 58 years, range: 25-81) were reviewed. Twenty-one patients (6%) had ≥ grade 1 nephrotoxicity and all except one had grade 1 toxicity according to NCIC criteria for common toxicity (SC1,5 N). Predictive factors independently associated with nephrotoxicity included associated co-morbid conditions (hypertension, diabetes, heart disease) (OR = 4.97 CI 95% [1.8-13.7] P = 0.002), initial serum creatinine ≥ 100 μmol/L (OR = 8.3 CI 95% [2.55-27.4] P = 0.0005), and dose cycle of cisplatin ≥ 100 mg/m(2) (OR = 10.8 CI 95% [3.6-32.5] P0.0001).Rapid outpatient administration of a single dose of cisplatin at ≥ 75 mg/m(2) is feasible without a high risk of nephrotoxicity.

International audience; Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P

A 34-year-old woman, heavy smoker, noticed after horseback riding, flushing and sweating exclusively of the left side of her face (Figure 1A). Following this she developed progressive right shoulder pain radiating to the medial side of the forearm in addition to ipsilateral ptosis, miosis, and enophtalmos (Figure 1B). She was then referred to our department for investigations. Chest radiograph showed an ill-defined opacity of the right apex and computed tomography-scan (Figure 2) confirmed a 5 cm tumor of the superior sulcus invading the thoracic inlet, including the subclavian vessels, the stellate ganglion, and the lower nerve roots of the brachial plexus, best shown on T1-weighted sagittal magnetic resonance imaging. Bronchoscopy was normal and the diagnosis of adenocarcinoma was obtained by computed tomography guided transthoracic fine needle biopsy. Concurrent chemotherapy with cisplatin—vinorelbine (four courses) and radiation therapy (46 Grays), were performed. A partial response was obtained and the patient underwent an en bloc resection (right upper lobectomy), extended to the first two ribs and to the lower roots of the brachial plexus. Described separately by Tobias in 1931 and Henry Pancoast in 1932, these tumors arise in the superior sulcus of the apex. They are situated in the costovertebral gutter and may be responsible for the following symptoms: (i) shoulder pain radiating to the ulnar aspect of the forearm with decreased strength, atrophy of small muscles of the hand by invasion of C8 and T1 roots of the brachial plexus, (ii) Horner syndrome characterized by miosis, enophtalmos, ptosis, and anhidrosis ipsilateral to the tumor by invasion of the paravertebral sympathetic chain and the inferior cervical stellate ganglion, (iii) pain in the posterior upper ribs due to chest invasion. Intervertebral foraminal invasion, as well as medullar compression and paraplegia may occur.1 This report shows originality through the presence of hemifacial sweating and flushing with Horner syndrome, known as Harlequin sign and also ipsilateral anhidrosis which was the first symptom noticed by the patient, who then took a picture of this classic but seldom seen clinical sign. Service de *Pneumologie, †Radiologie, and ‡Chirurgie thoracique, Nouvel Hopital Civil, Hopitaux Universitaires, 67091 Strasbourg cedex, France. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Elisabeth Quoix, MD, Service de Pneumologie, Hopitaux Universitaires, 1 place de l’hopital, 67091 Strasbourg cedex, France 67091. E-mail: elisabeth.quoix@chru-strasbourg.fr Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0402-0240 FIGURE 1. A, An assymetrical coloring of the face, right anidrosis. B, Horner syndrome characterized by mild ptosis, miosis, and enophtalmos of the right side of the face.

e18025 Background: Pemetrexed is approved to treat non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), and has an overall favorable toxicity profile. A case of pemetrexed-i...

CASE REPORT A 44-year-old woman a former smoker, presented with a 2-month history of progressive dyspnea. Computed tomography (CT)-scan showed diffuse alveolar opacities and micronodules in both lungs. Bronchoscopy was macroscopically normal, and bronchial biospsies were negative. Bronchioloalveolar lavage displayed revealed many TTF1 positive adenocarcinomatous cells harboring an exon 19 deletion (E746-A750) of endothelial growth factor receptor (EGFR) gene by sequencing. No extrathoracic metastases were detected on brain CT-scan or positron emission tomography scan. A first-line chemotherapy with carboplatin (area under the curve = 6), paclitaxel (175 mg/ m) and bevacizumab (15 mg/kg) every 3 weeks was started in December 2009. After stabilization at three cyles, the patient presented a pulmonary progression at six cycles. Erlotinib (150 mg/day) was started in June 2010 (Fig. 1A). After a partial

10507 Background: The EGFR exon 19 deletion and exon 21 L858R mutation are associated with response to EGFR-TKI. However, the correlation with response to EGFR-TKI remains unclear for rare exon 18 and 20 EGFR mutations. We investigated the clinical features of NSCLC patients with exon 18 and exon 20 EGFR mutations, analyzed response to EGFR-TKI and patient's survival. Methods: Between 2005 and 2011, all rare exon 18 and 20 EGFR mutations were collected from 10117 cases of NSCLC in 15 of 28 French NCI molecular genetic laboratories. Results: During the study period, EGFR mutations were identified in 1048 (10.35%) out of the 10117 performed tests and 108 rare mutations (10.3%) were identified in 103 patients, including 25 never identified mutations. Among them, 48 mutations were localized at exon 18 and 60 at exon 20, with 3 out of the 4 identified T790M exon 20 mutations associated with L858R mutation. Only 5 other rare mutations were associated with EGFR 19 or 21 mutations. 38 patients received EGFR-TKI (erlotinib, n=32; gefitinib, n=6). Among the 36 evaluable patients, best response on TKI was progression in 18 patients (50%), stabilization in 11 (30.5%) and partial response in 7 (19.4%). Tumor control rate observed in exon 18 mutations was 61% (8/13) and 50% (13/26) in exon 20 mutations. For the EGFR-TKI treated patients, the median PFS was 6 months (2-53). Median OS was 15 months (1-92), with no difference between the EGFR-TKI treated patients or not. Conclusions: Prevalence of rare EGFR mutations was 1.06% of all tested NSCLC and 10.35% of all EGFR mutations. Tumor control on TKI was observed in half of the patients. Reports of NSCLC harboring rare mutations are important to help the decision-making process in this subset of patients.