Management Of Non-small Cell Lung Cancer Research Articles

PC04.02 CON: ICI Is Enough

PC04.02 CON: ICI Is Enough

MA22.05 Assessment of Gender Differences in the Psychosocial and Economic Impact on Patients with Stage IV Non-Small Cell Lung Cancer

Incidence of lung cancer in women is rising overtime reporting evident gender-based differences in epidemiology, biology, and treatment outcome. However, little is known about gender-differences regarding psychological, economic and social aspects. The objectives of this prospective study are to evaluate the psychosocial and economic impact of metastatic non-small cell lung cancer (NSCLC), according to gender. Additionally, to assess the emotional burden and the economic impact of the disease on the primary caregiver from a gender perspective Multicenter, prospective, observational, study of two cohorts of patients with metastatic NSCLC (male and female) in Oncology departments of 20 Spanish hospitals. The following measurement tools were used: the APGAR questionnaire (family functionality: adaptability, partnership, growth, affection, and resolve), the Relationship impact scale, the DUKE-UNC scale (perceived socio-affective support), the patient and the caregiver economic impact scale and the Zarit scale (caregiver burden). All questionnaires were performed at the first visit, repeated 4 months later and following the first and second disease progression. Of the 333 pts included, 104 were females and 229 male, of whom 63% and 97%, respectively, were smokers/ex-smokers (p=0.0001). More women than men (85% vs 70%) had adenocarcinomas . The median overall survival was longer in women but did not reach statistical significance [17.1 vs 11.0 months, HR 0.732 (95% CI 0.534 to 1.005), p=0.0524]. Most families considered themselves functional (high score in APGAR questionnaire) with no changes in their partner relationship and social support was evaluated as optimal for majority of patients. Around a quarter of interviewed patients said their economic situation was a little worse after the lung cancer diagnosis, without remarkable differences by gender. Statistically significant differences were found between both groups regarding the caregiveŕs relationship to the patient (more parents were the caregiver in females than in males) (p <0.0001) and the caregiver’s employment situation (more employed caregivers in females) (p<0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden. No remarkable differences by gender were found between the different variables across the study. This study provides a preliminary insight into gender-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a gender perspective

Les nouveautés en chirurgie thoracique: chirurgie mini-invasive, infra-lobaire, Fast-Track

With 28 000 deaths per year, primary lung cancer is the leading cause of death related to cancer in France. Gold standard curative treatment for non-small cell lung cancer (NSCLC) remains surgical resction. In this article, we’ll review the latest breakthroughs in surgical management of NSCLC. Indications for curative surgical resections have been updated with the 8th classification for NSCLC and the new pathology classification for lung adenocarcinoma. We witness an increase in sublobar resections, especially lung segmentectomies.Each surgical approache at the surgeon’s disposal present its own benefits and disadvantages. Over the years, thoracic surgeons have gone from conventional thoracotomies to muscle-sparing thoracotomies and finally minimally-invasive surgical approaches, represented by video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS). In order to decrease post-operative morbi-mortality, hospital stay and fasten recovery, surgeons include their patients in fast-track protocols.

Liquid Biopsy for the Detection of Resistance Mechanisms in NSCLC: Comparison of Different Blood Biomarkers.

The use of targeted agents and immunotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) has made it mandatory to characterize tumor tissue for patient selection. Moreover, the development of agents that are active against specific resistance mechanisms arising during treatment make it equally important to characterize the tumor tissue at progression by performing tissue re-biopsy. Given that tumor tissue is not always available for molecular characterization due to the paucity of diagnostic specimens or problems relating to the carrying out of invasive procedures, the use of liquid biopsy represents a valid approach to overcoming these difficulties. The most common material used for liquid biopsy in this setting is plasma-derived cell free DNA (cfDNA), which originates from cells undergoing apoptosis or necrosis. However, other sources of tumor material can be considered, such as extracellular vesicle (EV)-derived nucleic acids, which are actively secreted from living cells and closely correspond to tumor dynamics. In this review, we discuss the role of liquid biopsy in the therapeutic management of NSCLC with particular regard to targeted therapy and immunotherapy, and analyze the pros and cons of the different types of samples used in this context.

Update on liquid biopsy in clinical management of non-small cell lung cancer.

Lung cancer, a leading cause of cancer-related mortality, has a low rate of early diagnosis and a poor prognosis for advanced stages. Recent advances in further mastery of the biology of tumors promote the diagnosis and therapy, especially for non-small cell lung cancer (NSCLC). However, tumor tissue-based information is often not available in most cases due to the invasive and high risk nature of the tumor biopsy procedures. Liquid biopsy, based on the multiple liquid samples including circulating tumor cells (CTC), circulating tumor DNA (ctDNA), and tumor-derived exosome obtained from blood or urine as well as other body fluids, can also provide valuable tumor-related information, playing an important role in management of NSCLC in clinical practice. It is widely believed that concordance of detection for tumor by liquid samples in comparison with tissue biopsy for both early and advanced stage NSCLC patients is optimistic. We herein review the current and future clinical application of liquid biopsy, including early diagnosis and management of precise personalized treatment in lung cancer. The future directions of development for liquid biopsy are also discussed in this review.

Non-Small Cell Lung Cancer Patients Harboring HER2 Mutations: Clinical Characteristics and Management in a Real-Life Setting. Cohort HER2 EXPLORE GFPC 02-14.

BackgroundMutation of human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) is a rare event, found in approximately 1% non-small cell lung cancers (NSCLC). The objective was to investigate the clinical characteristics and management of HER2-mutated NSCLCs in a real-life setting.MethodsThis multicenter study described NSCLCs harboring HER2 mutations diagnosed between January 2012 and December 2014, according their clinical characteristics, management, and outcomes: response rate (RR), progression-free survival (PFS), and overall survival (OS).ResultsThirty patients were included: 66.7% women; median age 65.2 ± 12 years; never or former smokers 73.3%. Of the stage IV patients (n = 23), 86% received first-line platin doublet chemotherapy: RR 61.5% and PFS 6.7 (95% CI 5.9–9.5) months; 52.1% received a second-line therapy: RR 18.2% and PFS 4.9 (95% CI 2.5–11.9) months. Median OS of stage IV was 10.7 months and 2-year OS was 27.2% (95% CI 11.7–63.2). All patients with stage I–III NSCLCs were alive at 2 years.ConclusionThe rarity of HER2-mutated NSCLCs requires specific studies.

Advanced Non-Small Cell Lung Cancer: Sequencing Agents in the EGFR-Mutated/ALK-Rearranged Populations.

Personalized therapy based on actionable molecular markers has completely transformed the therapeutic landscape in advanced non-small cell lung cancer (NSCLC). In less than 15 years, multiple molecular targets, led by EGFR and anaplastic lymphoma kinase (ALK), have been identified, and myriad oral tyrosine kinase inhibitors (TKIs) are now available to target these oncogenic drivers, with the expectation that the majority of patients will respond to treatment and that progression-free survival (PFS) will exceed 10 to 30 months, far better than we observed historically with chemotherapy alone. As a result, prognosis has improved dramatically in this subset of patients. Osimertinib has largely displaced first- and second-generation EGFR TKIs, including gefitinib, erlotinib, and afatinib, in the management of EGFR-mutated NSCLC. PFS now exceeds 18 months, and central nervous system penetrance is enhanced. Dacomitinib has the distinction of being the first EGFR TKI to demonstrate a survival advantage compared with older TKIs. Recent data suggest therapeutic additivity, if not synergy, for the concurrent use of chemotherapy, as well as monoclonal antibodies targeting angiogenesis, with EGFR TKIs. Alectinib and brigatinib, very specific ALK inhibitors, have proven superior to the erstwhile standard crizotinib in treatment-naive ALK+ NSCLC; PFS now routinely exceeds 2 to 3 years. In addition, these newer agents have far superior central nervous system penetration. As a result, many patients with ALK+ advanced NSCLC with brain metastases, even some who are symptomatic, can defer or indefinitely avoid brain irradiation. Mechanisms of resistance in ALK are complicated, with multiple new agents being developed in this arena. Although many patients with molecular targets can reasonably expect to live 5 years or more, the emergence of molecular resistance is virtually inevitable. In this regard, systemic platinum-based chemotherapy is the final common therapeutic pathway for virtually all patients with oncogenic drivers. Standard regimens include pemetrexed and carboplatin, as well as the E4599 regimen, combination solvent-based paclitaxel, carboplatin, and bevacizumab. Checkpoint inhibitors, as single agents, have not yielded much benefit, even in those with high levels of PD-L1 expression. However, in a subanalysis of patients with ALK and EGFR mutations enrolled in IMpower150, the addition of atezolizumab to the E4599 regimen led to a major overall survival benefit (hazard ratio < 0.40). In the absence of systemic chemotherapy, combining checkpoint inhibitors with TKIs in this setting remains investigational; several studies have demonstrated untoward pulmonary and hepatic toxicity.

Bevacizumab in EGFR-positive NSCLC: time to change first-line treatment?

The first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with a common EGFR mutation is EGFR tyrosine kinase inhibitor (TKI) monotherapy. Once patients have disease progression and continuing treatment is deemed inappropriate, patients with EGFR Thr790Met resistance mutations are switched to osimertinib, 1 Yang JC Ahn MJ Kim DW et al. Osimertinib in pre-treated T790M positive advanced NSCLC: AURA study phase II extension cohort. J Clin Oncol. 2017; 35: 1288-1296 Google Scholar or to pemetrexed and cisplatin if osimertinib was the first-line treatment. Subsequent treatment after disease progression following second-line treatment is more complicated and should be personalised according to clinical manifestations and genomic tumour alterations. Recent clinical trials have shown that median overall survival for patients with EGFR-positive NSCLC ranges between 3 and 5 years. 2 Hsu WH Yang JC Mok TS Loong HH Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol. 2018; 29: i3-i9 Google Scholar Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trialThe results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. Full-Text PDF

Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice

PurposeImmune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.MethodsWe examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.ResultsThe median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent ≥ 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4–31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893–4.21) and 10.25 (95% CI 5.39–15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.ConclusionsThe real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients’ different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.

Safety and Efficacy of Lattice Radiotherapy in Voluminous Non-small Cell Lung Cancer.

ObjectiveLattice radiotherapy (LRT) is a novel technique of delivering heterogeneous doses of radiation to voluminous tumors not amenable to surgery. Built from the conventional two-dimensional grid, LRT utilizes the power of new technology, three-dimensional radiation allowing the delivery of higher doses of radiation to small spheres, also called vertices, inside bulky tumors while limiting exposure to surrounding healthy tissue. The main goals of the study were the evaluation of tumor response and the overall safety of LRT in this cohort of patients with bulky non-small cell lung cancer.Materials and methodsDuring a seven-year period, 10 patients with non-small cell lung cancer (NSCLC), who presented with bulky, unresectable tumors, were treated using a single fraction of LRT followed by conventionally fractionated radiation. Patients received one initial LRT fraction of 18 Gy in the vertices and 3 Gy in the periphery. After the LRT, all patients continued with conventional radiation: 25 to 29 daily fractions of 1.8 Gy to 2 Gy.ResultsWith a median follow-up of six months (range: one to 71 months), the mean decrease in tumor volume was 42%. The overall survival of the entire group ranged from four to 86 months (mean 22, median 16). There was no mortality related to LRT. No significant acute or chronic toxicity was noted.ConclusionIn this small cohort, LRT appears to be a safe and effective modality to treat bulky NSCLC. Further research is needed to establish its efficacy in the management of voluminous NSCLC.

The Value of Liquid Biopsies for Guiding Therapy Decisions in Non-small Cell Lung Cancer.

Targeted therapies have allowed for an individualized treatment approach in non-small-cell lung cancer (NSCLC). The initial therapeutic decisions and success of targeted therapy depend on genetic identification of personal tumor profiles. Tissue biopsy is the gold standard for molecular analysis, but non-invasive or minimally invasive liquid biopsy methods are also now used in clinical practice, allowing for later monitoring and optimization of the cancer treatment. The inclusion of liquid biopsy in the management of NSCLC provides strong evidence on early treatment response, which becomes a basis for determining disease progression and the need for changes in treatment. Liquid biopsies can drive the decision making for treatment strategies to achieve better patient outcomes. Cell-free DNA and circulating tumor cells obtained from the blood are promising markers for determining patient status. They may improve cancer treatments, allow for better treatment control, enable early interventions, and change decision making from reactive actions toward more predictive early interventions. This review aimed to present current knowledge on and the usefulness of liquid biopsy studies in NSCLC from the perspective of how it has allowed individualized treatments according to gene profiling and how the method may alter the treatment decisions in the future.

Circular RNA circ_0026134 regulates non-small cell lung cancer cell proliferation and invasion via sponging miR-1256 and miR-1287

Non-small cell lung cancer (NSCLC) is the major type of lung malignancy with increasing incidence worldwide. Despite progression in diagnosis and management of NSCLC, the patients’ survival rate is still unfavorable. Accumulating data have shown that circular RNAs (circRNAs) act as key roles in oncogenesis. In this project, circ_0026134 expression in NSCLC tissue specimens and cells was measured by RT-qPCR. The functional roles (cell growth, apoptosis, migration, and invasion) of circ_0026134 were investigated by gain and loss-of-function assays. In addition, luciferase reporter assay was used to uncover the mechanisms of circ_0026134. Circ_0026134 was frequently upregulated in NSCLC samples and cell lines. Furthermore, we observed that downregulation of circ_0026134 attenuated NSCLC cell proliferation and metastatic properties and induced cell apoptosis. The overexpression of circ_0026134 in NSCLC cells caused the opposite effect. For the part of mechanism exploration, miR-1256 and miR-1287 were proved to be sponged by circ_0026134. Rescue experiments further indicated that the oncogenic role of circ_0026134 was dependent on its regulation of miR-1256 and miR-1287. Taken together, this study may provide a new insight and treatment target for NSCLC.

Current and Future Oncology Management in the United States.

The cost of treating cancer patients is high and rising in the United States. Payers are exposed to cost through doctor visits, laboratory tests, imaging tests, radiation treatment, drugs, hospital stays, surgery, home care, transportation and travel, and caregiving. This study focuses on the cost of medication from the viewpoint of U.S. payers. Although new tools for managing these costs have been gaining attention, prices continue to rise, and challenges to managing costs remain high. Innovative tools are necessary for controlling the cost of care in oncology, but their effectiveness is still unclear. To (a) gauge payer perceptions of current and future cost management of innovative oncology drugs and (b) predict which management tools will increase in prevalence by 2020-2022. A literature search of cost and management of oncology created the foundation for developing a survey for U.S. payers. The mobile survey was completed on devices such as smart phones or tablets. Payers were asked about general oncology product management, use of specific management tools today, management challenges, and expected use of specific management tools in 2020-2022. Management tools were segmented into traditional (used across many therapeutic categories), oncology-specific (used in oncology but not routinely used in other disease areas), and systemic (not product-specific but that affect the way services are provided and funded). Specific questions for managing the cost of care in non-small cell lung cancer (NSCLC) and chronic lymphocytic leukemia (CLL) were included in the survey. NSCLC and CLL were chosen because of their diverse clinical characteristics and the level of innovation in these disease areas. The survey was fielded from May 31, 2017, to June 15, 2017. Results consisted of simple descriptive statistical analysis weighted by the payer's reported organizational covered lives. Payers were concerned with the high cost and budget impact of oncology drugs and considered these a high priority for management. However, they continue to use traditional management tools such as manage to FDA label, quantity limits, step edits, and reauthorizations, which are ineffective in controlling cost. More innovative management tools such as pathways of care are available but are not yet widely adopted. Payers hope to better control oncology cost in the future; however, specific questions pertaining to the management of NSCLC and CLL indicate that minimal changes in cost management will occur by 2020-2022. Despite an increasing number of innovative cost management tools, challenges remain for managing oncology medication costs. New incentives are being generated, but barriers to their implementation will continue to restrict use through 2020-2022. No outside funding supported this study. The authors are employed by MKO Global Partners, which is a consulting firm that focuses on payer strategy and market access in the pharmaceutical and biotech markets. Some initial results from this research were published as part of a comparative poster at ISPOR European Conference; November 4-8, 2017; Glasgow, Scotland, UK.

Is routine dissection of lymph node station 4L clinically significant in left lung NSCLC?

I read with special interest the article entitled “Clinical significance of 4L lymph node dissection in left lung cancer” published in Journal of Clinical Oncology in October 2018 (1). The authors did a retrospective analysis of their patients who underwent lung parenchyma resection for non-small cell lung cancer (NSCLC) of the left lung during the 5-year period 2005–2009. The main conclusions of their study were that dissection of the 4L lymph node station revealed a quite high rate of involvement by the tumor (20.9%), while 4L lymph node dissection was found to be an independent prognostic factor for improved disease-free survival (DFS) and overall survival (OS) in left lung NSCLC. In case the above-mentioned results will be reproduced in future studies, dissection of the 4L lymph node station will be definitely considered an essential step in the surgical management of left lung NSCLC which will affect the clinical practice and the guidelines for lymph node dissection of left lung NSCLC.

Nanoparticle albumin bound-paclitaxel for treatment of advanced non-small cell lung cancer: an evaluation of the clinical evidence

ABSTRACTIntroduction: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a microtubule inhibitor, has demonstrated clinical efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) either as monotherapy or in combination. Nab-paclitaxel was developed to reduce the toxicities associated with solvent-bound paclitaxel (sb-paclitaxel).Areas covered: This review first focuses on the clinical trials evaluating the efficacy and tolerability of nab-paclitaxel in NSCLC at different settings. The approval of nab-paclitaxel in combination with carboplatin at the front-line setting for advanced NSCLC was based on the key phase III study, which showed that nab-paclitaxel/carboplatin was associated with superior overall response rate and favorable toxicity profile compared to sb-paclitaxel/carboplatin. The review also addresses the nab-paclitaxel pharmacology, other combinations (e.g. immunotherapy with PD-1/PD-L1 inhibitors), potential biomarkers (e.g. caveolin-1), and special subgroups (e.g. the elderly, squamous histology).Expert opinion: Existing data has established the role of nab-paclitaxel in the management of advanced NSCLC. Emerging evidence, such as preliminary results from Keynote-407 and IMpower 131 studies, indicates that novel combinations of nab-paclitaxel/carboplatin and PD-1/PD-L1 inhibitors could further improve clinical benefits with manageable toxicity. Nevertheless, in order to better position nab-paclitaxel and to improve patient selection, future studies are warranted to further understand its mechanism of action, predictive biomarkers, and potential synergism with other agents.

CircABCB10 promotes nonsmall cell lung cancer cell proliferation and migration by regulating the miR-1252/FOXR2 axis.

Circular RNA (circRNA) is a key regulator in the development and progression of human cancers. Previous studies confirmed circRNA‐0008717 (circABCB10) as an oncogene in osteosarcoma, but the regulatory effect of circABCB10 in nonsmall cell lung cancer (NSCLC) is still unclear. In the current study, we examined the expression of circABCB10 in different NSCLC cell lines. Bioinformatics analysis, Cell Counting Kit‐8 assays, Transwell migration, fluorescein reporting experiments, and xenografts in mice were used to detect the effect of circABCB10 on NSCLC cell proliferation and migration in vitro and tumor growth in vivo. The results showed that the expression of circABCB10 in NSCLC cell lines was increased. Downregulation of circABCB10 suppressed NSCLC cell proliferation and migration by promoting microRNA miR‐1252 expression and suppressing Forkhead box 2 (FOXR2). Fluorescein reporting experiments confirmed that circABCB10 expression increased FOXR2 levels by sponging miR‐1252, and in vivo experiments found that knockdown of circABCB10 decreased tumor growth. These data suggested that circABCB10 acted as a tumor promoter through a novel miR‐1252/FOXR2 axis, providing potential biomarkers and therapeutic targets for the management of NSCLC.

Therapeutic bronchoscopy in the era of genotype directed lung cancer management.

Lung cancer is the leading cause of cancer related deaths. Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers. Our understanding of driver mutations and genotype directed therapy has revolutionized the management of advanced NSCLC. Commonly described mutations include mutations in epidermal growth factor (EGFR) & BRAF and translocations in anaplastic lymphoma kinase (ALK) & rat osteosarcoma (ROS1). Drugs directed against these translocations have significantly improved progression free survival individually and have shown a survival benefit when studied in the Lung Cancer Mutation Consortium (median survival 3.5 vs. 2.4 years compared to standard therapy). In a related yet parallel universe, the number of bronchoscopic ablative modalities available for management of cancer related airway obstruction have increased exponentially over the past decade. A wealth of literature has given us a better understanding of the technical aspects, benefits and risks associated with these procedures. While they all show benefits in terms of relieving airway obstruction, symptom control, quality of life and lung function testing, their complication rates vary based on the modality. The overall complication rate was ~4% in the AQuIRE registry. Bronchoscopic therapeutic modalities include rigid bronchoscopy with mechanical debulking, laser, thermo-coagulation [electrocautery & argon plasma coagulation (APC)], cryotherapy, endobronchial brachytherapy (EBT), photodynamic therapy (PDT), intratumoral chemotherapy (ITC) and transbronchial needle injection (TBNI) of chemotherapy. Intuitively, one would assume that the science of driver mutations would crisscross with the science of bronchoscopic ablation as they overlap in the same patient population. Sadly, this is not the case and there is a paucity of literature looking at these fields together. This results in several unanswered questions about the interplay between these two therapies.

The evolving role of pemetrexed disodium for the treatment of non-small cell lung cancer

ABSTRACTIntroduction: Non-small cell lung cancer (NSCLC) remains one of the big cancer killers, despite the introduction of a number of approved therapeutics in recent times. Pemetrexed is a multi-target folate inhibitor, which is currently available to patients affected by advanced non-squamous NSCLC in combination with a platinum derivate in first-line therapy and as a single agent in second-line therapy.Areas covered: This review covers presents the use pemetrexed in the management of NSCLC by exploring the data available from clinical trials and meta-analyses. Data from a phase III trial confirmed its role in the first-line setting in combination with immune checkpoint inhibitors (ICIs). Furthermore, data suggested a role for pemetrexed in local and advanced NSCLC.Expert opinion: To date, in spite of the introduction of novel anti-neoplastic agents, pemetrexed still represents a cornerstone in the management of non-squamous NSCLC. Furthermore, recently published data support its role in innovative combinations including together with chemotherapy and immunotherapy.

PMD156 - NEXT GENERATION SEQUENCING: BENEFIT ANALYSIS TO SUPPORT A STRATEGIC ADOPTION MODEL IN THE ITALIAN NHS

The study aims to assess current testing procedures for NGS and hotspot single gene tests in terms of impact on hospital organization, patient and disease management. The analysis focuses on advanced non-small-cell lung cancer (NSCLC) and unresectable metastatic colon-rectal cancer (mCRC), for patients treated in Italian hospitals. A set of decisional and operational recommendations on clinical practice, defined by an expert panel, is provided. The study is based on a decision model, designed to compare NGS with single gene tests, along the whole testing process. The model assesses the impact of testing alternatives on hospital organization and outcomes, in terms of: activities to be performed, professionals and resources absorbed, time to treatment, access rate to personalized medicine, testing invasiveness. The assessment of current gene testing path has been conducted in Italian advanced Oncological Hospitals. The data and information collected on current clinical practice, organization, resources and economics were integrated with published data. Results are articulated into a present scenario, based on current diagnostic practice and associated gene testing and a future scenario defined as the set of genes that an expert panel would recommend to test in order to deploy the best test strategy in the perspective of the Italian NHS. The study provides strategic recommendations on NGS use to maximize its associated benefits. The study measures also the potential impact of NGS adoption for patients, hospitals and NHS in terms of: time to treatment, costs, number of biopsy and associated adverse events. NGS might enable oncologist to profile the patients and define the most suitable treatment path. Such benefits still need to be further investigated. The strategic use of NGS as an alternative to single gene tests, allows hospitals and the NHS to capture significant organization, clinical and economic benefits in the management of advanced NSCLC and unresectable mCRC.

MA06.07 Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer

Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear. The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes. Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.