Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer.

In developed countries, lung cancer is the leading cause of cancer-related death in both sexes. Although cigarette smoking represents the principal risk factor for lung cancer in females, the higher proportion of this neoplasm among non-smoking women as compared with non-smoking men implies distinctive biological aspects between the two sexes. Gender differences depend not only on genetic, environmental, and hormonal factors but also on the immune system, and all these aspects are closely interconnected. In the last few years, it has been confirmed that the immune system plays a fundamental role in cancer evolution and response to oncological treatments, specifically immunotherapy, with documented distinctions between men and women. Consequently, in order to correctly assess cancer responses and disease control, considering only age and reproductive status, the results of studies conducted in female patients would probably not categorically apply to male patients and vice versa. The aim of this article is to review recent data about gender disparities in both healthy subjects' immune system and lung cancer patients; furthermore, studies concerning gender differences in response to lung cancer immunotherapy are examined.

An examination of two dichotomies: Women with lung cancer and living with lung cancer as a chronic disease.

Lung cancer remains the leading cause of cancer death globally, yet with many recent advances in the diagnosis and treatment of lung cancer, the face of the disease is shifting. Historically, lung cancer is often thought of as a predominantly male disease with more than twice as many men as women being diagnosed worldwide-mostly due to the influence of smoking as the leading risk factor. However, lung cancer is also the second leading cause of cancer death in women and there is a growing population of young women who have never smoked and are being diagnosed. The past decade has seen groundbreaking innovations in both the early detection and treatment of lung cancer. In this new era, survival rates are beginning to increase and many of those diagnosed are finding themselves in a new situation-living long term with a deadly cancer. Here, we review pertinent aspects of women and lung cancer as well as the concept of living with lung cancer as a chronic disease to give a new perspective on the changing face of lung cancer treatment and care.

Peritoneal carcinomatosis in non-small-cell lung cancer: retrospective multicentric analysis and literature review.

AIM: We investigated outcomes in patients with advanced non-small-cell lung cancer (NSCLC) and peritoneal involvement. PATIENTS & METHODS: NSCLC patients with peritoneal carcinomatosis (PC) were included. We evaluated mOS1 (overall survival [OS] from NSCLC diagnosis) and mOS2 (OS from diagnosis of PC). RESULTS: In total, 60 NSCLC patients were diagnosed with PC, 12 (20%) patients had a diagnosis of NSCLC and synchronous PC with a median OS of 9 months. Smokers had a shorter mOS1 and mOS2 compared with never-smokers; EGFR-mutated patients on tyrosine kinase inhibitors had longer mOS1 and mOS2 than EGFR wild-type patients. CONCLUSION: Metachronous PC is correlated to a short survival, irrespective of treatment line. Never-smokers and EGFR-mutated patients had improved mOS1 and mOS2 when compared with smokers and EGFR wild-type population.

Adjuvant Therapy of Resected Non-small Cell Lung Cancer: can We Move Forward?

OPINION STATEMENT: Twenty years ago, an individual patient data meta-analysis of eight cisplatin-based adjuvant chemotherapy (AC) studies in completely resected early stage non-small cell lung cancer (NSCLC) demonstrated a 13 % reduction of the risk of death favoring chemotherapy that was of borderline statistical significance (p = 0.08). This marginal benefit boosted a new generation of randomized trials to evaluate the role of modern platinum-based regimens in resectable stages of NSCLC and, although individual studies generated conflicting results, overall they contributed to confirm the role of AC which is now recommended for completely resected stage II and III NSCLC, mostly 4 cycles, while subset analyses suggested a benefit in patients with large IB tumors. Cisplatin-based therapy was the core regimen of those adjuvant clinical trials and even if a substitution with other platinum-derived was also suggested, mainly based on extrapolated data from studies in advanced disease, cisplatin was confirmed to be slightly superior to carboplatin and is still the drug of choice in the adjuvant setting. Currently, any attempt to improve efficacy of cisplatin-based chemotherapy through antiangiogenic drugs association or pharmacogenomics approaches have failed, while results of additional studies are eagerly awaited. In the context of promising targeted therapies, even if several randomized trials in the advanced setting evaluated tyrosine kinase inhibitors (TKis) versus platinum-based chemotherapy and showed impressive results, clinical experience with TKIs in the adjuvant setting is still limited and most of the trials have not required patients to be molecularly tested for the drug-specific molecular predictive factor. At the present time, the role of targeted agents as adjuvant approaches remains largely not investigated. Finally, with the negative experience of the use of vaccines in this setting, the integration of immunotherapy (mainly immunocheckpoint inhibitors) in platinum-based schedules has just started to be evaluated, representing a potential future clinical option, but still far from clinical practice.

ATF2 contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway.

ATF2 is a transcription factor involved in stress and DNA damage. A correlation between ATF2 JNK-mediated activation and resistance to damaging agents has already been reported. The purpose of the present study was to investigate whether ATF2 may have a role in acquired resistance to cisplatin in non-small cell lung cancer (NSCLC). mRNA and protein analysis on matched cancer and corresponding normal tissues from surgically resected NSCLC have been performed. Furthermore, in NSCLC cell lines, ATF2 expression levels were evaluated and correlated to platinum (CDDP) resistance. Celastrol-mediated ATF2/cJUN activity was measured. High expression levels of both ATF2 transcript and proteins were observed in lung cancer specimens (p << 0.01, Log2 (FC) = +4.7). CDDP-resistant NSCLC cell lines expressed high levels of ATF2 protein. By contrast, Celastrol-mediated ATF2/cJUN functional inhibition restored the response to CDDP. Moreover, ATF2 protein activation correlates with worse outcome in advanced CDDP-treated patients. For the first time, it has been shown NSCLC ATF2 upregulation at both mRNA/protein levels in NSCLC. In addition, we reported that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Altogether, our results indicate a potential increase in CDDP sensitivity, on Celastrol-mediated ATF2/cJUN inhibition. These data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance.

Safety and diagnostic performance of image-guided lung biopsy in the targeted therapy era.

OBJECTIVE OF THE STUDY: To identify risk factors for the adverse events and determine the diagnostic yield of a large series of image-guided thoracic biopsies performed in a single institution. MATERIALS AND METHODS: We reviewed a consecutive series of 811 patients (546 males; average age: 68 years.) who underwent 824 image-guided biopsies of pulmonary lesions performed between 2009 and 2013. Indications for biopsy were always evaluated by a multidisciplinary board. All complications were registered. The diagnostic accuracy was calculated on the basis of histology after surgery, response to medical therapy, or outcome at imaging follow-up. Safety and accuracy was correlated with patient-related and lesion-related factors. RESULTS: 61 biopsies were performed under US-guidance, 750 under CT-guidance, and 13 under combined guidance. The average lesion size was 36.4 mm (6-150 mm). FNAB was exclusively performed in 247 patients, whereas 577 patients underwent also or only core biopsy (CB). 40 (4.8 %) major complications and 172 (20.8 %) minor complications occurred. US-guidance, absence of perilesional emphysema and minor depth of the target lesion from the skin resulted as favorable predictors against major complications. According to the gold standard criteria, we demonstrated 497 true positives, 72 true negatives, 18 false negatives, 0 false positives. Sensitivity, specificity and diagnostic accuracy were 96.5, 100 and 97 %. No predictors for accuracy were found, but the number of samples largely related to the pathologist on site. CONCLUSIONS: Image-guided lung biopsy is safe and highly accurate for diagnosing thoracic lesions. In the targeted therapy era, CB with larger needles can be safely applied when the need for larger amounts of tumor tissue is presumed.

Sotorasib in KRASp.G12C mutated advanced NSCLC: Real-world data from the Italian expanded access program.

BACKGROUND: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP). METHODS: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed. RESULTS: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases. CONCLUSION: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.

Focal nodular hyperplasia after oxaliplatin-based chemotherapy: A diagnostic challenge.

Chemotherapy could induce benign liver alterations presenting as diffuse or focal lesions mimicking metastases. Oxaliplatin-induced vascular liver injury is described in literature, but the association with FNH-like lesions has been reported in a limited number of cases. We herewith describe the case of a 67-year-old male, who had laparoscopic right-sided hemicolectomy, 8 years ago, because of colonic adenocarcinoma (pT3N0M0) and subsequent adjuvant chemotherapy (capecitabine + oxaliplatin), who referred to the ultrasound service of our Radiology Unit because of abdominal pain. Five-years follow-up was negative for metastases. Ultrasound examination showed 2 small hypoechoic hepatic nodules, in segment VIII and VII, confirmed at CT, suspected for metastases. FDG-PET was negative, and blood tumor markers were within normal ranges. For further evaluation we performed gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI that showed hyperintensity of the nodules in the hepatobiliary phase with central small hypointensity due to a central scar. Considering the previous oxaliplatin-based chemotherapy the findings were compatible with FNHlike lesions and the diagnostic suspicion was confirmed at ultrasound-guided core needle biopsy. Knowledge of the possible occurrence of FNH-like lesions in oncologic setting, along with the detection of typical MRI appearance, is important for appropriate management and may avoid unnecessary biopsy or surgery and reduce patients' anxiety.

Molecular profiling of advanced non-small cell lung cancer in the era of immunotherapy approach: a multicenter Italian observational prospective study of biomarker screening in daily clinical practice.

AIMS: Heterogeneous implementation of molecular tests in current diagnostic algorithm at a European and international level is emerging as a major issue for efficient lung cancer molecular profiling. METHODS: From May 2017 until October 2017, N=1612 patients referring to 13 Italian institutions were selected, at advanced stage non-small cell lung cancer (NSCLC), and prospectively evaluated. Principal endpoints were: the percentage of diagnoses performed on cytological and histological material, the proportion of requests for epidermal growth factor receptor (EGFR) mutational status, and resistance mutations detected on tissue and/or liquid biopsy samples after first-generation or second-generation tyrosine kinase inhibitors, the proportion of requests for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS proto-oncogene 1 (ROS1) and Kirsten Rat Sarcoma (KRAS) determinations, the proportion of requests for programmed death-ligand1 (PD-L1) evaluation and, finally, the different assays used for the detection of EGFR mutations, ALK and ROS1 gene rearrangements and PD-L1 expression. RESULTS: Of 1325 patients finally included, only 50.8% requests were related to driver mutations with target agents already available in first-line at that preplanned time, while 49.2% were associated with PD-L1, ROS1, KRAS and others. Multiplex genomic assays (such as next-generation sequencing) were considered by all participating centres. CONCLUSIONS: To the best of our knowledge, this is the first study in a 'real-life daily practice' involving both pathologists and oncologists evaluating routinely workflow and trends towards improvements in molecular requests. Collected data aim to describe the applied algorithms and evolution of molecular screening for stage IV NSCLC in clinical practice.

The Genomics of Young Lung Cancer: Comprehensive Tissue Genomic Analysis in Patients Under 40 With Lung Cancer.

INTRODUCTION: Lung adenocarcinomas in young patients (<40 y) are more likely to harbor targetable genomic alterations. This study aimed to determine whether the prevalence of targetable alterations is greater in young adults with lung carcinoma than in the overall lung cancer population. To reach this rare patient population, a web-based platform was used to recruit and enroll patients remotely. METHODS: In this prospective study, patients less than 40 years old at the time of primary lung cancer diagnosis with confirmed lung carcinoma were recruited from four global sites and remotely by means of a website. Genotyping data were collected, if available, or obtained by means of next-generation sequencing using the FoundationOne platform. The prevalence of targetable alterations was quantified across patients with advanced adenocarcinoma. RESULTS: Overall, 133 patients across five continents were included, 41% of whom enrolled online. The mean (SD) age at diagnosis was 34 (5.2) years; 79% had stage IV disease at diagnosis. Among patients with adenocarcinoma (n = 115), 112 entered the study with previous genomic testing results and 86 (77%) had targetable alterations in EGFR, ALK, ROS1, MET, ERBB2, or RET. Among those without targetable alterations, 14 received further testing and a targetable alteration was identified in eight (57%). CONCLUSIONS: This study revealed the feasibility of using a web-based platform to recruit young patients with lung cancer and revealed that 94 of 112 (84%) with adenocarcinoma at any stage had targetable genomic alterations. Among patients with stage IV adenocarcinoma, 85% had a targetable alteration, which is higher than historical expectations for the general population.

Anaplastic lymphoma kinase tyrosine kinase inhibitors in non-small cell lung cancer.

Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3-7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Lung cancer and women.

In the early 1900s, lung cancer was a rare malignancy in women, but starting from the 1960s it has progressively reached epidemic proportions, surpassing breast cancer in 1987 and becoming the leading cause of cancer deaths in many countries. Retrospective data show that the 5-year survival rate for women who have lung cancer is 15.6%, compared with 12.5% for men, and this improved survival could have important implications in the design and interpretation of lung cancer trials. Women have major responses to therapy regardless of stage, therapeutic modalities or histology. The increase of lung cancer incidence among women is reflected in their clinical trial participation, causing a survival improvement and suggesting the need of stratification by sex in future studies. No specific drugs for women with lung cancer are currently available, but researchers are devoting energies in this area in order to better understand the implication of gender differences in epidemiology, pathogenesis, prognosis and tumor response.

Alectinib in the treatment of ALK-positive non-small cell lung cancer: an update on its properties, efficacy, safety and place in therapy.

Anaplastic lymphoma kinase (ALK) rearrangement is identified in 3-7% of advanced non-small cell lung cancer (NSCLC) cases, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of NSCLC patients. ALK-TKIs have been proven highly effective in ALK-rearranged advanced NSCLC patients, but after initial responses and benefit, a subsequent progression inevitably occurs. Understanding acquired-resistance mechanisms and defining an appropriate algorithm is becoming even more essential, particularly considering the availability of extremely efficacious next-generation ALK inhibitors. The aim of this review is the analysis of current data about ALK inhibition as a therapeutic strategy in ALK-rearranged NSCLC management, with a focus on a specific ALK-TKI, alectinib. Alectinib is a highly selective inhibitor of ALK and showed systemic and central nervous system (CNS) efficacy in the treatment of this particular population. The change of first-line approach, and consequently of further lines of therapy, in ALK-rearranged NSCLC patients is still a matter of debate. A summary of evidence from randomized trials evaluating alectinib will be presented in order to discuss the available clinical evidence, safety and place in therapy.

Management of Leptomeningeal Metastases in Non-oncogene Addicted Non-small Cell Lung Cancer.

Brain metastases in non-small cell lung cancer (NSCLC) patients are more often detected due to imaging modalities improvements but also emerge because of improved treatments of the primary tumor which lead to a longer survival. In this context, development of leptomeningeal metastases (LM) is a devastating complication and its prognosis remains poor despite advances in systemic and local approaches. Histology characterization of NSCLC and molecular expression influence LM management. For those with "oncogene addiction," new generation epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) were developed to strongly penetrate the blood-brain barrier (BBB) with the aim to prevent central nervous system cancer dissemination, eventually impacting on LM appearance and its subsequent management. Systemic chemotherapy, often combined with intrathecal chemotherapy (when possible), was one of common indications for lung cancer patients affected by LM, without driver mutations and a good performance status but currently, with the advent of innovative systemic approaches treatment solutions in this subgroup of patients are rapidly evolving. Whole brain radiation therapy (WBRT) is the conventional treatment for patients with brain metastases. Furthermore, modern radiation techniques, as stereotactic radiotherapy (SRT), improve outcomes in those cases with a limited number of lesions. However, LM represent a minority of CNS metastases and few literature data are available to drive the radiotherapy approach. Considering all relevant progress made in this setting, after a literature review, the aim of this paper is to discuss about recent developments and therapeutic options in LM management of non-oncogene addicted NSCLC.

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study.

BACKGROUND: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. PATIENTS AND METHODS: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. RESULTS: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. CONCLUSION: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy.

Role of afatinib in the treatment of advanced lung squamous cell carcinoma.

Lung cancer treatment has considerably changed over the last few years: the identification of druggable oncogenic alterations and innovative immunotherapic approaches granted lung cancer patients the possibility of more efficient and less toxic therapeutic options than chemotherapy. Nowadays, lung squamous cell carcinomas (SqCCs) patients have the chance to benefit from novel treatment alternatives, including immune checkpoint blockade and anti-angiogenic agents and, given positive trial results, from afatinib, a second generation tyrosine kinase inhibitor (TKI) that irreversibly antagonizes ErbB family tyrosine kinase receptors. Considering the role of the ErbB-signaling cascade in lung SqCC, it is relevant to note that ErbB1 (epidermal growth factor receptor [EGFR]) is overexpressed in 85% of non-small-cell lung carcinomas (NSCLCs), particularly in patients with squamous histology, and is associated with poor prognosis. For this reason, EGFR activity has been investigated as a therapeutic strategy in lung SqCC. Even taking into account statistically positive trial results, anti-EGFR approach still remains controversial in unselected/wild-type EGFR lung SqCC patients, as well as the optimal timing and sequencing of all available targeted therapies considering the approval of immunotherapeutic agents. This review analyzes current data about EGFR inhibition in lung SqCC with a specific focus on afatinib in order to elucidate available clinical evidence supporting EGFR targeting in this setting as well as a future management of advanced lung SqCCs in the context of new emerging immunotherapeutic drugs.

Does Immunohistochemistry Represent a Robust Alternative Technique in Determining Drugable Predictive Gene Alterations in Non-Small Cell Lung Cancer?

Immunohistochemistry (IHC) is a widely-tested, low-cost and rapid ancillary technique available in all laboratories of pathology. This method is generally used for diagnostic purposes, but several studies have investigated the sensitivity and specificity of different immunohistochemical antibodies as a surrogate test in the determination of predictive biomarkers in non-small cell lung cancer (NSCLC), particularly for Epidermal Growth Factor Receptor (EGFR) gene mutations, Anaplastic Lymphoma Kinase (ALK) gene and ROS1 rearrangements. In this review, a critical examination of the works comparing the consistency of IHC expression and conventional molecular techniques to identify genetic alterations with predictive value in NSCLC is discussed. Summarizing, data on sensitivity and specificity of antibodies against ALK and ROS1 are very consistent and time has come to trust in IHC at least as a cost-effective screening tool to identify patients with rearranged tumors in clinical practice. On the other hand, mutant-specific antibodies against EGFR demonstrate a good specificity but a lowto- fair sensitivity, raising some cautions on their employment as robust predictive biomarkers. A brief comment on preliminary experiences with antibodies against BRAF, RET, HER2 and c-MET is also included.

Precision medicine in age-specific non-small-cell-lung-cancer patients: Integrating biomolecular results into clinical practice-A new approach to improve personalized translational research.

OBJECTIVES: Non-small-cell-lung-cancer (NSCLC) in young adults (≤45 years-old) accounts for a very small proportion, as this disease usually occurs in people at older age. The youthful NSCLC may constitute an entity with different clinical-pathologic characteristics, having predominance of adenocarcinoma histology and affecting mostly non-smoker subjects. However, without specific guidelines, it is currently considered, both clinically and biologically, as the same disease of the older counterpart, although differences have been documented. MATERIALS AND METHODS: Using formalin-fixed paraffin embedded diagnostic tissues (FFPE), targeted next-generation sequencing (NGS) technology allowed to provide insight the mutational pattern of 46 oncogenes and tumor-suppressor genes in 26 young patients (Y). Two additional populations, including a FFPE series of aged counterpart (A: 29 patients) and a group of healthy young controls (C: 21, blood provided), were also investigated to compare NGS profiles. RESULTS: Clinical features of enrolled young patients harmonized with literature data, being most of patients women (58%), never-smokers (38%) and with adenocarcinoma histology (96%). C group was adopted to filter all the non-synonymous genetic variations (NS-GVs) not-associated with malignant overt disease. This skimmed selection mostly highlighted three genes: TP53, EGFR and KRAS. TP53 NS-GVs were numerically more numerous in younger, many involving specific annotated hotspot (R248, R273, G245, R249 and R282); the majority of EGFR NS-GVs was detected in young patients, with higher allelic frequency and mostly represented by exon 19 deletions. On the contrary, KRAS NS-GVs were mainly detected in aged population, with a prevalent compact pattern involving p.G12 position and associated with adenocarcinoma histology. CONCLUSION: This retrospective study confirmed the feasibility of NGS approach for genetic characterization of NSCLC young adult patients, supporting the involvement of TP53, EGFR, and KRAS alterations in the early onset of NSCLC. Some of these GVs, or their pattern, may potentially contribute to customized targeted therapies.

BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients: Results from a multicenter Italian observational study.

OBJECTIVES: Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice. MATERIALS AND METHODS: From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs. RESULTS: 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents. CONCLUSIONS: BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting.