Virtual Library

Background:
Diagnosis of peripheral pulmonary lesions with ultrathin bronchoscopy (UTH) has fewer complications than transthoracic needle aspiration (TTNA). However, diagnostic yield with UTH is lower. Virtual bronchoscopic navigation (VBN) might increase diagnostic performance of UTH. The main objective was to compare diagnostic yield of UTH with and without VBN.

Methods:
Prospective case-control study paired 1:2 for lesion size and localization, bronchus sign, sex and final diagnosis. LungPoint (Broncus, USA) was used to plan and navigate based upon online image analysis, putting endoscopic and virtual images in correspondence. Fluoroscopy was used in all. Sampling included bronchial washing and brushing (if no direct vision) or biopsy (if lesion directly visualized). Statistical analyses R-3.2.3.

Results:
Total of 63 patients (VBN and non-VBN, 21:42). Clinical characteristics in table 1. Diagnostic yield was 75% vs 43.9% (p=0.029). Factors associated to positive diagnosis in table 2. Further diagnostic techniques were needed in 14% vs 52% (p=0.001). No differences seen in procedure duration or complications. Figure 1 Figure 2





Conclusion:
VBN significantly improves the diagnostic yield of ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions, especially those located in the utmost periphery and fluoroscopically not visible. Therefore, use of VBN reduces the need for further diagnostic procedures. Funded by La MaratóTV3-20133510, FIS-ETES PI09/90917, FUCAP and SEPAR.

Background:
Electromagnetic navigation bronchoscopy (ENB) may aid in accessing smaller, more peripheral lesions and hence facilitate earlier diagnosis. ENB may also provide a safer alternative to transthoracic biopsy, and allow adequate tissue capture for molecular testing, diagnosis, staging, and localization for surgery in a single anesthetic event. However, usage patterns, safety, and performance remain largely unexplored in a prospective, multicenter study.

Methods:
NAVIGATE is a global, prospective, multicenter study of ENB using the superDimension™ navigation system (Medtronic, Minneapolis). A pre-specified 1-month interim analysis was conducted on the first 1,000 primary cohort subjects enrolled at 29 centers in the United States and Europe. Enrollment and 2-year follow-up are ongoing.

Results:
One-month follow-up was completed in 933/1,000 subjects. Of 1,000 procedures, ENB was intended for lung biopsy in 96.4%, to place fiducial markers in 21.0%, and for dye marking in 1.7% (multiple indications in 34.9%). Lymph node biopsies were attempted in 33.4% of procedures (322/334 using linear endobronchial ultrasound [EBUS]). General anesthesia was used in 79.7% and radial EBUS in 54.3%. Among 1,129 lung lesions, fluoroscopy was used in 90.1% and rapid on-site pathology evaluation in 683/1035 (66.0%). Median lesion size was 20.0 mm (interquartile range 16.0 mm). Most lesions were in the peripheral (62.6%) or middle (30.1%) lung thirds. A bronchus sign was present in 48.4% and 6.3% were ground glass. Navigation was subjectively considered successful in 1,036 lesions (91.8%). Site-reported pathology results were read as malignant in 452 lesions (43.6%), including 38.1% with primary lung cancer. Of 247 lesions with adenocarcinoma or unspecified non-small-cell lung cancer, 70 (28.3%) were sent for molecular testing with adequate tissue in 56/70 (80.0%). Primary lung cancer clinical stage was 52.9% I; 10.7% II, 18.9% III, and 17.3% IV. Preliminary non-malignant results were obtained in 444 lesions (42.9%). An additional 140 lesions (13.5%) were read as inconclusive. Longer follow-up is required to calculate the true negative rate and diagnostic yield. ENB-related pneumothorax was 4.9% (49/1,000) overall and 3.2% Grade ≥2 based on the Common Terminology Criteria for Adverse Events scale. The ENB-related Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failures rates were 1.0% and 0.6%.

Conclusion:
Interim 1-month results suggest a low adverse event rate in the largest prospective, multicenter ENB study conducted to date. Continued enrollment and 2-year follow-up will elucidate the real-world utilization patterns, diagnostic yield, factors contributing to successful diagnosis, and the impact of ENB on lung cancer management.

Background:
Development of drugs that target molecular pathways in lung cancer has made it increasingly important for diagnostic sampling to yield sufficient material for genotyping. At the same time, minimally invasive sampling techniques such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) result in smaller volume cytological specimens. It has been shown that at least 3 EBUS-TBNA passes per lesion are sufficient for cytological subtyping. However, the number of passes needed for mutational subtyping is unclear. We sought to determine the adequacy of a single EBUS-TBNA for genotyping clinically actionable mutations.

Methods:
Patients undergoing EBUS-TBNA for diagnosis of lung cancer were prospectively recruited. Paired samples from the same target lesion were obtained. The “reference” sample was the routine diagnostic specimen consisting of ≥3 passes, whereas the “study” sample comprised a single pass. DNA was extracted from both samples and subjected to quantitative and qualitative assessment. Sequencing for EGFR, KRAS, BRAF mutations was performed in adenocarcinoma/non-small cell lung cancer not otherwise specified (NSCLC-NOS) cases.

Results:
Samples were obtain in 41 patients. Cytological diagnosis was adenocarcinoma/NSCLC-NOS in 25 (61.0%), squamous cell carcinoma in 10 (24.4%), small cell lung cancer in 5 (12.2%), and carcinoid in 1 (2.4%) case. DNA extraction yielded a mean of 4.03μg, well above the minimum required quantity for targeted sequencing of 10ng (Table 1). DNA quality measured by DNA Integrity Number could be calculated in 35 (85%) cases with a mean of 8.9, where >7 is acceptable for sequencing (Table 1). Sequencing results of adenocarcinoma/NSCLC-NOS cases show mutations in EGFR in 6, KRAS in 8, BRAF in 1 case. Wild type was demonstrated in 6 cases. Molecular analysis of the corresponding study samples is proceeding.

Table 1. DNA quantity and quality

Histological subtype	Cases, n (%)	Mean DNA quantity (μg)	Mean DNA Integrity Number (DIN)
Adenocarcinoma/NSCLC-NOS	25 (61.0)	3.83	8.8
Squamous cell carcinoma	10 (24.4)	2.65	9.0
Small cell lung carcinoma	5 (12.2)	5.28	9.0
Carcinoid	1 (2.4)	16.24	9.1
Overall	41	4.03	8.9

Conclusion:
A single EBUS-TBNA yields DNA of quantity and quality sufficient for molecular analysis, and is expected to be adequate for lung cancer genotyping.

Abstract not provided

Background:
Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk of lung cancer (LC) independent of the effect of cigarette smoking. The prognosis of IPF-associated LC (IPF-LC) is known to be worse than the lone IPF or LC mainly due to the complications accompanying LC treatment with no established or standardized consensus. However, despite recent progress in the understanding of pathogenesis and the treatment of LC in general population based on the advances in molecular genomics, the pathogenesis or molecular profiles of IPF-LC has been largely unknown to date.

Methods:
We assessed genomic profiles of IPF-LC using targeted exome-sequencing (OncoPanel version 2) in 35 matched tumor/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling were performed using GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted using CNVkit with focal events determined by GISTIC 2.0, and pathway analysis (KEGG) using DAVID.

Results:
Germline mutations in TERT (rs2736100,n=33) and CDKN1A (rs2395655,n=27) linked with IPF risk were detected in most samples. A total of 410 somatic mutations were identified with an average of 11.7 per tumor including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop, 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C→T transitions despite extensive smoking histories across most study subjects, suggesting more associations with APOBEC3B-related mutagenesis in the process of IPF-LC development, rather than smoking. TP53 (22/35,62.9%) and BRAF (6/35,17.1%) genes were found significantly mutated in IPF-LC. Recurrent focal amplifications in 3 chromosomal loci (3q26.33, 7q31.2, and 12q14.3), and 9p21.3 deletion were identified, and genes associated with JAK-STAT signaling pathway were significantly amplified in IPF-LC (P=0.012).

Conclusion:
IPF-LC is genetically characterized by the presence of somatic mutations reflecting viral and immune-related mutagenic processes in the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations.

Background:
Chronic obstructive pulmonary disease (COPD) and lung cancer are associated through tobacco. COPD is underdiagnosed in the general population. Patients with lung cancer suffer from dyspnea and hospitalization for respiratory complications, and underdiagnosis of COPD could confer worse symptoms and morbidity. Using Institute for Clinical Evaluative Sciences (ICES) data, we assessed the diagnosis of COPD in the lung cancer population in Ontario, Canada.

Methods:
Cancer registry, hospital ICD-10 codes, physician billing data, and vital statistics were abstracted in an anonymized manner from ICES. COPD was defined using the validated ICES-derived COPD cohort and spirometry use was assessed through billing codes. Cancer stage was available from cancer registry data. Analysis was conducted using ICES’s confidential, analytic virtual environment using SAS v9.3 in the population age >39 years. The local ethics board approved the study.

Results:
From 2004-2014, 90,783 individuals were diagnosed with lung cancer and 608,347 individuals diagnosed with COPD. Of individuals with lung cancer, 52.7% were male, median age at diagnosis was 65-69 years, and 82.8% have died. Of individuals with COPD, 51% were male, median age at diagnosis was 60-64 years, and 24.7% have died. The diagnosis of COPD was made at a rate of 8.7 persons per 1000 person-years. Among individuals having COPD, 48.4% underwent spirometry. 30.2% of individuals with lung cancer were also diagnosed with COPD and 60.8% underwent spirometry at any time. Among those with a diagnosis of both lung cancer and COPD, 73.6% underwent spirometry. For individuals with registry recorded stage data, 12,110 persons had stage I-II lung cancer, of whom 90.7% had spirometry and 55.9% had a diagnosis of COPD. Conversely, among 31,392 persons with stage III-IV lung cancer, 54.6% had spirometry and 46% were diagnosed with COPD (p<0.001 vs early stage for both).

Conclusion:
The diagnosis of COPD is not based on spirometry in half of cases. More patients with early stage lung cancer underwent spirometry and a higher rate of spirometry was associated with more diagnosis of COPD. Increased use of spirometry may improve the accuracy of a COPD diagnosis and may increase the diagnosis of COPD in advanced stage lung cancer, allowing improved dyspnea management in this population.

Background:
Lung cancer screening (LCS) with chest CT scans in high-risk smokers has been demonstrated to save lives. Medicare and private insurers now cover these scans for beneficiaries under specific criteria. However, most smokers will die of comorbid smoking-related diseases rather than lung cancer itself. Important information about comorbid conditions is available on screening chest CT scans, but the prevalence of these comorbidities has not been comprehensively assessed.

Methods:
COPDGene subjects from the Phase 1 visit who met USPSTF criteria for LCS (age > 55, >30 pack years smoking, current or former smokers within 15 years of smoking cessation or current smokers) were assessed for coronary calcification, emphysema, gas trapping, airway wall thickening and vertebral bone density on standard dose CT scans. A new diagnosis of emphysema, osteoporosis, or cardiovascular disease was assumed when there was no self-report of diagnosis or medication use.

Results:
In 76% of CT scans from LCS-eligible COPDGene subjects, we found abnormal emphysema (>5% low attenuation area @-950 Hounsfield units), airway wall thickening or gas trapping (>20% low attenuation area @-856 Hounsfield units). Osteoporosis was identified in 54% of all CT scans, and abnormal coronary artery calcium was present in 51%. In non-COPD smokers a new diagnosis of emphysema, osteoporosis or coronary calcification was found in 741 (48%) subjects. Overall, 75% of LCS eligible CT scans showed one or more non-cancer diagnoses.

Conclusion:
Enhanced readings of the lung cancer screening scans could identify individuals with previously undiagnosed osteoporosis, atherosclerotic heart disease, emphysema and COPD. Identification and treatment for these conditions may reduce morbidity and mortality, improve quality of life and enhance smoking cessation.

Abstract not provided

Background:
Radiation pneumonitis is a major toxicity after the thoracic radiotherapy, with no method available to accurately predict the individual risk. This was a prospective study to evaluate the exhaled nitric oxide as a predictive biomarker for radiation pneumonitis in the patients received the thoracic radiotherapy

Methods:
A total of 68 patients with lung cancer or esophageal cancer, who received the thoracic radiotherapy, were enrolled in the present study. Each patients underwent the exhaled nitric oxide measurement before the radiotherapy and at the end of radiotherapy. Pneumonitis toxicity was scored using the Common Terminology Criter

Results:
Of the 68 patients, 65 were evaluable. The pneumonitis toxicity grade were grade 3 for 6, grade 2 for 11 and grade0-1 for48. The exhaled NO measured before radiotherapy and at the end of radiotherapy were 23.05±9.59 (range 10-53) and 22.89±8.60(range 11-60) ppbs.For the exhaled NO ratio, the AUC is 0.879 (95%CI0.774-0.984). The accuracy of predicting the symptomatic patients was identified “good” according to the predictive ability criteria and the optimal cutoff value was tested as 1.305. For the exhaled at the end of RT, the AUC is 0.774 (95%CI 0.656-0.892). The accuracy of predictive the symptomatic patients was evaluated “fair” ,The optimal cutoff value was identified 19.5 ppbs.

Conclusion:
The exhaled nitric oxide ratio>1.305 or the exhaled nitric oxide at the end of radiotherapy>19.5ppbs was found to have a closely relation with radiation pneumonitis.

Background:
Detection of EGFR mutations using cell-free DNA in plasma has recently emerged as a novel diagnostic approach to lung carcinoma. This “liquid biopsy” (LB) may also be useful for monitoring disease activity in EGFR-mutated tumors as well as in the management of EGFR-tyrosine kinase inhibitor (TKI) therapy. We present data collected in one year of use and report on applicability and diagnostic value in daily clinical practice.

Methods:
EGFR Mutations were analyzed using the semi-quantitative Roche cobas® EGFR Mutation Test v2, comprising 42 mutations. Cell free DNA was extracted from EDTA-Blood with the Qiagen QIAsymphony circulating DNA Kit. LB was initially used for follow-up of known EGFR-mutated tumors and/or in patients under TKI-therapy. Subsequently, we introduced routine LB testing in the primary diagnostic workup of lung cancer patients.

Results:
From July 2015 to June 2016 we performed a total of 92 liquid biopsies in 77 patients (60% male, mean age 65y) in whom EGFR mutations could be detected in 10 cases (13%). EGFR status from histological samples was available in 40 patients, in 14 (18%) of them mutations were reported. Compared to histological EGFR status, LB reached a sensitivity and specificity of 0.57 and 0.96, respectively. A total of 9 patients had multiple LB testing during follow-up. Three of them initially had detectable mutations by LB, which turned undetectable upon tumor-specific treatment. Two patients remained EGFR-positive during follow-up despite of therapy, whereas four patients remained negative throughout follow-up and therapy. Resistance mutations under TKI-therapy were not observed. Primary LB (before initiation of any tumor-specific therapy) was obtained from 47 patients (72% male, mean age 66y). EGFR mutations by LB were detected in 2 patients (4%; 1 Ins. Exon-20, 1 L858R), while histology revealed EGFR mutations in 2 out of 22 patients (9%; both L858R). Comparison yielded a sensitivity of 0.5 and a specificity of 0.95 for LB.

Conclusion:
Testing for EGFR mutations using cell-free DNA has been established as a new powerful tool in the field of pulmonary oncology. Apart from sole detection of EGFR mutations, especially the application of LB in following patients over time will provide valuable new opportunities in clinical routine and decision making

Background:
Photodynanic therapy (PDT), is a treatment modality for many cancers, and uses a tumor-specific photosensitizer and laser irradiation. PDT is recommended as a treatment option for centrally located early lung cancer. The detection of peripheral lung cancers is increasing, and stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation are emerging as alternatives to surgical resection, but PDT has not been a modality. Recently, we have developed a new minimally invasive laser device using a 1.0 mm in diameter composite-type optical fiberscope (COF), which could transmit laser energy and images for observation in parallel. In this study, we aimed to develop a new endobronchial treatment for peripheral cancer using PDT and a 1.0 mm in diameter composite-type optical fiberscope (COF), and we evaluated the feasibility of PDT using COF for peripheral lung cancer.

Methods:
This phase I study enrolled patients with peripheral lung cancers (primary tumor< 20 mm, stage IA), which were definitively diagnosed by bronchoscopic modalities using radial-probe endobronchial ultrasound (EBUS) and guide sheaths. We conducted irradiation using a diode laser (664 nm) and optical fiberscope (COF), four hours after the administration of NPe6 40 mg/m2. Before performing PDT, we evaluated the tumor lesions using EBUS through the guide sheaths for peripheral small lesions. Then, we introduced the COF into the peripheral lung cancer, observed the lesions and irradiated of red light 664 nm (120 mW, 50 J/cm2).

Results:
Three patients met our criteria, and 2cases were adenocarcinoma and 1 case squamous cell carcinoma. We were able to observe the cancer lesions at the peripheral lung by the COF, and feasibly irradiated. Two weeks and 3 months after NPe6-PDT, there was no morbidity including pneumothorax, pneumonia, skin photosensitivity.

Conclusion:
The 1.0 mm COF was a very useful device of NPe6-PDT for peripheral lung cancers, and PDT using the COF was a feasible and non-invasive treatment. Now, we have started phase II study of PDT using the COF for peripheral lung cancers. In the future, for non-invasive adenocarcinoma such as AIS, NPe6-PDT using COF will play an important role.

Abstract not provided

Abstract not provided

Abstract:
LYMPH NODE MAPPING IN LUNG CANCER Kenji Suzuki (Japan), David Waller (UK) The How and Why ? The Aim will be to outline the various methods to map the extent of lymph node metastasis from a primary NSCLC and to assess the clinical application and implications of each intervention. The Aim will also be to highlight the following areas of clinical debate and controversial issues 1.Preoperative Non-invasive – Lymph node mapping may start with simple Ultrasound guided cervical node aspiration cytology [1] . Can this be all that is needed in some advanced cases? c Can computed tomography/ positron emission tomography (CTPET) be relied upon to obviate the need for invasive nodal mapping ? Can newer techniques including CT lymphography [2] improve the accuracy of mapping ? Does magnetic resonance imaging (MRI) have a role in preoperative lymph node mapping. Invasive – We will consider in detail the debate between endobronchial and endoluminal ultrasound (EBUS/EUS) and surgical lymph node mapping. What role, if any, does cervical mediastinoscopy have in addition to EBUS/EUS [3] ? Does the increased sensitivity of more invasive surgical mediastinal procedures like VAMLA [4] and TEMLA contribute significantly to preoperative mapping ? We will discuss why these investigations should influence primary therapy and which patients should undergo induction therapy and which should have primary resection. Evidence from the latest TNM revision suggest that mediastinal nodal disease needs more accurate mapping than previously appreciated. We will consider how many of these stages of mapping are required before making a decision to operate and will propose a controversial algorithm for surgical treatment of N2 disease [5]. 2.Intraoperative We will discuss the arguments surrounding the necessary extent of intraoperative lymph node dissection. We will consider the relative merits of the methods for intraoperative sentinel node identification including Near Infrared thoracoscopy and radiolabelling [6,7]. We will ask whether the investment in technology and time is beneficial for the patient. Is the added information about metastases of clinical value ? We will evaluate the argument between nodal sampling vs systematic nodal dissection [8] and attempt to formulate an intraoperative mapping algorithm. Intraoperative nodal mapping has been proposed as a prerequisite to direct the extent of lung resection. We will examine how the findings of nodal disease have been used to discriminate between lobectomy vs pneumonectomy or between lobectomy vs segmentectomy. We will consider the argument that nodal metastatic disease is not a justification for more extensive sacrifice of functioning lung tissue. Is there any role for intraoperative nodal analysis in determining the extent of resection? How reliable is this method of nodal mapping. 3.Postoperative Once the pathologist has the resected lymph nodes we will attempt to rationalize how they should be analysed, asking the question : “ What are the minimum sampling requirements ?”. We will also analyse whether the more detailed nodal mapping of micrometastatic disease by immunohistochemistry significantly influences patient management or outcome [10] ? Finally we will discuss how these pathological results could influence the use of adjuvant chemotherapy/ radiotherapy or more interestingly targeted therapies. We intend the session to be interactive between presenters and delegates with a free exchange of ideas and experience. We hope to stimulate delegates to re-evaluate their own approach to lung cancer staging. References 1. Chang DB, Yang PC, Yu CJ, Kuo SH, Lee YC, Luh KT.Ultrasonography and ultrasonographically guided fine-needle aspiration biopsy of impalpable cervical lymph nodes in patients with non-small cell lung cancer.Cancer. 1992 Sep 1;70(5):1111-4 2. Suga K, Yuan Y, Ueda K, Kaneda Y, Kawakami Y, Zaki M, Matsunaga N Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization. Invest Radiol. 2004 Jun;39(6):313-24. 3. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial .JAMA. 2010 Nov 24;304(20):2245-52 4. Witte B, Hürtgen M.Video-assisted mediastinoscopic lymphadenectomy (VAMLA).J Thorac Oncol. 2007 Apr;2(4):367-9 5. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 6. Hachey KJ, Colson YL. Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer. Semin Thorac Cardiovasc Surg. 2014 Autumn;26(3):201-9 7. Tomoshige K, Tsuchiya T, Otsubo R, Oikawa M, Yamasaki N, Matsumoto K, Miyazaki T, Hayashi T, Kinoshita N, Nanashima A, Nagayasu T.Intraoperative diagnosis of lymph node metastasis in non-small-cell lung cancer by a semi-dry dot-blot method.Eur J Cardiothorac Surg. 2016 Feb;49(2):617-22 8. Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, Jones DR, McKenna RJ, Landreneau RJ, Rusch VW, Putnam JB Jr. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial . J Thorac Cardiovasc Surg. 2011 Mar;141(3):662-70 9. Nomori H, Cong Y, Sugimura H. Utility and pitfalls of sentinel node identification using indocyanine green during segmentectomy for cT1N0M0 non-small cell lung cancer. Surg Today. 2016 Aug;46(8):908-13 10. Deng XF, Jiang L, Liu QX, Zhou D, Hou B, Cui K, Min JX, Dai JG Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis. J Cardiothorac Surg. 2016 Feb 16;11:28.

Background:
Detection of actionable genomic alterations is now required for NCCN guideline-compliant work-up of NSCLC adenocarcinoma. Next-generation sequencing (NGS) of ctDNA, if sufficiently sensitive and specific, could provide a non-invasive, comprehensive genotyping platform relevant to clinical decision-making when tissue is insufficient or at time of progression on targeted therapies.

Methods:
A highly accurate, deep-coverage (15,000x) ctDNA plasma NGS test targeting 54-70 genes (Guardant360) was used to genotype 5,206 advanced-stage NSCLC patients accrued between 6/2014 – 4/2016. The frequency and distribution of somatic alterations in key genes were compared to those described in TCGA (Pearson and Spearman correlations). The clinical impact of ctDNA testing was evaluated by identification of resistance mechanisms emergent at progression on targeted therapies, and through analysis of additional driver mutations detected by ctDNA at baseline in 362 consecutive NSCLC patients with tissue mutation data available. The positive predictive value (PPV) of ctDNA sequencing was assessed in 229 patients with known tumor driver alterations.

Results:
ctDNA alterations were detected in 86% of cases; EGFR mutations in 25%, KRAS mutations in 17%, MET amplification in 4%, BRAF mutations in 3% and other rare but potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were highly consistent with those from TCGA (Pearson r=0.92, 0.99, 0.99 for EGFR, KRAS, and fusion breakpoint location). PPV of ctDNA-detected variants was 100% for EGFR[L858R], 98% for EGFR[E19del], 96% for ALK, RET, or ROS1 fusions, and 100% for KRAS[G12/G13/Q61] mutations. In 362 cases with tissue information available, 63% (229/362) were tissue quantity-insufficient or undergenotyped (QNS/UG). ctDNA analysis identified driver mutations in 51 of the 229 QNS/UG cases, a 38% increase in detection rate over tissue alone. Among 1,111 EGFR-mutant cases, resistance mutations were identified at progression at frequencies consistent with published literature: EGFR[T790M] 47%, MET amp 5%, ERBB2 amp 5%, FGFR3 fusions 0.4%, ALK/other fusions 1%, BRAF mutations 1.8%, PTEN inactivation 2.5%, NF1 inactivation 3%, RB1 inactivation 3%, KRAS mutations 1.9%. In 143 consecutive NSCLC patients with detailed follow-up and serial analysis seen at the UC Davis Cancer Center, informative driver mutations were observed in 48 (34%).

Conclusion:
This series represents the largest NSCLC ctDNA study to date. Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. At baseline, ctDNA augmented tissue analysis by identifying additional, actionable mutations when tissue was QNS/UG. ctDNA NGS conducted at progression identified emergent resistance mutations that could inform subsequent courses of therapy.

Background:
The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials for lung cancer has to be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. We previously identified a 24 plasma miRNA signature endowed with good performance in terms of sensitivity and specificity in subjects enrolled in independent LDCT screening trials. However, the relationship between circulating miRNAs in plasma and the molecular heterogeneity of the patients’ tumors needs to be considered. Linking tumor genomics to circulating miRNA profiles represent an attractive approach. In fact a plasma miRNA assay able to classify molecular subclasses of tumors could constitute a sort of “liquid biopsy” endowed with not only diagnostic but also prognostic and, potentially, therapeutic value.

Methods:
We evaluated the mutation profile by targeted Next-Generation Sequencing (NGS) analysis (Cancer Hotspot Panel v.2) in 94 Low Dose Computed Tomography (LDCT) screening-detected lung tumors resected from subjects participating in 3 screening trials for lung cancer. Mutation profile was associated with clinicopathologic, survival features and with a plasma MSC risk level of patients. The mutational profile obtained was compared with the mutations of a selected dataset of clinically detected lung tumors through The Cancer Genome Atlas (TCGA).

Results:
We showed alterations in the main genetic drivers in 79% of screening lung tumors whereas 21% of tumor samples had no alteration within these amplicons. Significant associations between TP53, squamous histology and smoking intensity as well as KRAS mutations with worse OS were detected. EGFR alterations were present in 4 tumors from heavy smokers. The 5-year overall survival (OS) of screening patients with and without mutations in the tumors was 64% and 100%, respectively (p=0.019). By combining the mutational status with the MSC risk profile, patients were stratified into 3 groups with 5-year OS ranging from 41% to 96% (p<0.0001) and the prognostic value was significant even when controlling for stage (p=0.017). A similar mutational profile and mutation frequency was observed in screening- and in clinical (TCGA) tumors, whereas difference in 5-year OS between subjects with and without mutations was exclusively detected in screening patients.

Conclusion:
The mutation profile of screening-detected tumors, while similar to that of clinically-detected tumors, was a strong predictor of OS. The combination of tumor mutational status with a circulating miRNA-based risk classifier predicts tumor aggressiveness and clinical outcome and may find rapid application in LDCT screening programs by reducing the number of unnecessary interventions and helping plan targeted treatment

Background:
Current targeted therapy options in lung cancer, such as EGFR and ALK inhibitors, are effective, though limited in use by the low percentage of patients that carry targetable mutations for these biomarkers. Targeting a broader biological process like DNA damage response (DDR), as with recent synthetic lethality exploits in BRCA-deficient tumours, may offer a form of precision therapy for a larger number of patients. We have shown that NSCLC cells deficient in the DDR protein ATM, exhibit similar synthetic lethality when treated with a PARP1 inhibitor, and that NSCLC patients lacking detectable ATM have poorer overall survival. In vitro, ATM deficient, or “ATMic” cells show increased sensitivity to chemotherapeutics at much lower levels when given in combination with PARP inhibitor. This data suggests that ATM status may be an important determinant for treatment modalities including low dose radiation or platin therapy, or novel synthetic lethality therapies. Here, we seek to determine the cause of ATM loss in NSCLC patients through targeted sequencing, and thorough transcriptomic and epigenetic analysis.

Methods:
We perform whole-transcriptome analysis on NSCLC patient samples previously characterized as normal or ATMic, to detect differences in intracellular pathway activation in these tumours. Additional analysis using OncoFinder software identifies possible effective therapies based on which signalling pathways are most active in the normal or ATMic patients. We also perform targeted NGS on these samples. To our knowledge, no sequencing of ATM has been performed on samples that have also been characterized through other methods (i.e. quantitative IHC) to be ATM deficient.

Results:
We have generated a substantial body of evidence showing that ATM loss has significant impact on the cell sensitivity to several therapeutic modalites. As such ATMic tumours may be treated more effectively using specific treatment strategies than their ATM competent counterparts. Initial analysis of NSCLC cell lines using the outlined methodologies distinguishes ATM status and identifies different therapeutic agents based on inherent molecular differences. A complete analysis of the transcriptome profiles of ATMic NSCLC patients will be presented and discussed.

Conclusion:
This research helps complete the overall picture of what the therapeutic implications of ATM loss in NSCLC actually are and how ATMic tumours can best be identified in the clinic. Together, these analyses will give us a stronger understanding of the mechanism for ATM loss in NSCLC, as well as allow us to develop an ATMic “signature” for reliably determining ATM status in patients for directing their treatment options.

Abstract not provided

Background:
It is hypothesized that low or absent expression of the excision repair cross-complementation group 1 (ERCC1) protein predicts improved survival in NSCLC patients treated with platinum-based therapy. However, the International Adjuvant Lung Cancer Trial Collaborative Group concluded that current ERCC1 assessment methods are inadequate for clinical decision-making. Due to the unreliability of ERCC1 immunohistochemistry (IHC), the IFCT-0801 TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial of adjuvant therapy for NSCLC was discontinued. We reevaluated a subset of samples from the TASTE trial using mass spectrometry-based proteomics to quantitate ERCC1 protein. We correlated ERCC1 proteomic status with survival after chemotherapy with cisplatin/pemetrexed and compared it to ERCC1 IHC ranking.

Methods:
Formalin-fixed, paraffin-embedded NSCLC tumor tissues were laser microdissected, solubilized, digested, and proteomically analyzed. A multiplexed, selected reaction monitoring mass spectrometric assay was used to quantitate levels of multiple proteins including ERCC1. The Kaplan-Meier method and univariate Cox analysis assessed overall survival (OS) and relapse-free survival (RFS). A chi-squared test compared binary proteomic levels of ERCC1 (detectable vs. undetectable) with the IHC status assessed using an anti-ERCC1 antibody (8F1) during the TASTE trial.

Results:
Of 146 evaluable patients, 33 (22.6%) had undetectable ERCC1 by quantitative proteomics. Proteomics found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients nor in 8/22 (19.3%) IHC-indeterminate patients. ERCC1 was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein). Undetectable ERCC1 by proteomics was prognostic of OS (hazard ratio [HR]: 5.45; p=0.031). In survival analyses of cisplatin-treated patients (n=122), only one of the 15 deaths occurred among the patients with undetectable ERCC1 protein. These patients had better OS than cisplatin-treated patients with detectable ERCC1, although the difference statistically nonsignificant (HR: 3.98; p=0.102). RFS was similar between patients with and without detectable ERCC1. GARFT protein (predictive of response to pemetrexed) was quantified in 100% of patients (range: 492-4006 amol/µg). The 10 cisplatin/pemetrexed-treated patients with GARFT levels >900 amol/µg had nonsignificantly worse OS than their counterparts with lower GARFT levels (p=0.08).

Conclusion:
Although underpowered to detect statistically significant survival differences, this study clearly demonstrates that quantitative proteomics can increase accuracy in identifying NSCLC patients who will respond to platinum-based therapy because they do not express ERCC1. Approximately 28% of such patients were misclassified by ERCC1 IHC in the TASTE trial. Clinicians should be aware that multiplexed quantitative proteomics can quantitate ERCC1 simultaneously with multiple clinically relevant proteins in lung tumors and small biopsies.

Background:
We previously built and validated a risk classification model for resected SqCLC by combining clinicopathological predictors to discriminate patients’ (pts) prognosis (Pilotto JTO 2015). Here we (AIRCMFAG project no. 14282) investigate the molecular portrait of prognostic outliers to identify differentially expressed, potentially druggable alterations.

Methods:
Based on the published 3-class model, 176 and 46 pts with good and bad prognosis, respectively, were identified. Somatic Mutations (SM) and Copy Number Alterations (CNA) were evaluated with Next Generation Sequencing (NGS) for 59 genes (Ion Proton system, Ion Ampliseq custom panel). Moreover, RNA expression assays, immunohistochemistry (IHC) and immunofluorescence (FISH) were performed. Descriptive statistic was adopted and continuous variables were dichotomized according to AUC or medians.

Results:
Herein, the analysis of 60 pts (good/poor 27/33) is reported. In the overall population, the median rate of SM (3.3%) is lower compared to the median rate of CNA (28.3%), without significant differences between the two prognostic groups. The most frequent SM resulted to be missense (66.7%) and nonsense (20.3%) mutations, whereas the copy number gain is the most common CNA (76.7%), The distribution of relevant alterations in the main carcinogenesis pathways in term of SM, CNA and expression (by RNA, IHC and FISH), according to the prognostic subgroups, are reported in the table.

Pathway	Gene [method]	Good [%]	Poor [%]	p-value
Squamous differentiation	SOX [CNA]	74.1	51.5	0.11
	TP63 [CNA]	37.0	21.2	0.25
Epithelial to mesenchymal transition	SNAI1 [RNA]	59.2	90.9	0.006
	Vimentin [RNA]	44.4	69.7	0.07
mTOR	PI3KCA [SM]	0	9.0	0.24
	RICTOR [CNA]	3.7	27.3	0.017
	p-mTOR [IHC]	11.1	18.1	0.5
Tyrosine kinase receptors	DDR2 [SM]	11.1	0	0.085
	FSR2 [CNA]	3.7	18.1	0.12
	MET [FISH]	11.1	24.2	0.32
	FGFR3 [FISH]	25.9	42.4	0.28
Cell cycle regulators	CDKN2A [CNA]	22.2	3.0	0.38
	SMAD4 [CNA]	33.3	57.6	0.074
Immune checkpoints	PD-L1 [IHC]	18.5	6.1	0.23
	PD-1 [RNA]	51.8	93.9	<0.0001

Conclusion:
Although performed on a limited number of pts, such comprehensive analysis of DNA, RNA and proteins, using different methodologies, is feasible and allow identifying potentially druggable prognostic modulators, such as RICTOR/PI3K/mTOR signaling pathway. The possibility to inhibit this pathway with selective agents is currently under investigation in in vitro preclinical models.

Background:
Veliparib is a potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor that has synthetic lethality interaction with cancers harboring homologous recombination deficiency. In preclinical models, it has also been shown to delay the repair of DNA damage induced by chemotherapeutics (platinum, alkylators, topoisomerase inhibitors). Clinically meaningful improvements in progression-free survival and overall survival were observed in a phase 2 trial of veliparib with carboplatin/paclitaxel in previously untreated metastatic or advanced NSCLC (M10-898 study). Intriguingly, smoking history had a major impact on veliparib effect—smokers benefited most from veliparib addition. The underlying mechanism for this observation remains unclear. The efficacy benefit of veliparib in smokers is not dependent on tobacco exposure during study treatment, but correlates with the duration of smoking history, suggesting a genetic basis.

Methods:
Genomic signatures in NSCLC associated with smoking status have been identified by The Cancer Genome Atlas (TCGA) Lung Cancer Project. Relevant observations were leveraged in the reported analysis. To comprehensively identify genes or genomic features that are associated with smoking status and veliparib response, patient tumor samples from the M10-898 trial were subjected to whole-exome (N = 38) and RNA sequencing (N = 75) analysis. Alexandrov somatic mutational signature was calculated from exome sequencing data.

Results:
Data from TCGA show that cancer genomes in smokers harbor significantly more genetic alterations than those in non-smokers. These alterations include high mutational burden, high C>A transversion, high mutation frequency of key cancer genes (particularly TP53), and high homologous recombination defect signature. Similar observations were confirmed in the M10-898 study. Of the 38 patients with exome data, 26 were determined to be positive for a smoking-related signature—signature 4. Elevated mutational burden was observed among current and former smokers, with a mean of 199 somatic mutations in current or former smokers vs 60 in never-smokers (p = 0.004). The small sample size of our genomic cohort nevertheless precludes conclusive association of genomic signatures and veliparib benefits.

Conclusion:
Cancer genomes in smokers are enriched with genetic alterations associated with poor outcome using standard chemotherapy, as well as with vulnerability factors that can prime tumors to respond to veliparib. For further validation, a targeted sequencing assay to detect key DNA damage and repair genes as well as key genomic signatures has been established and will be used in all phase 3 veliparib trials.

Abstract not provided

Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.

Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.

Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).

Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.

Background:
Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention.

Methods:
We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma　and 15,158 controls.

Results:
Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press).

Conclusion:
This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.

Background:
Preclinical studies provide insights to therapy mechanisms of resistance that are not feasible with clinical studies. We investigated the signaling pathways that could be involved in adaptive resistance to gefitinib and/or osimertinib in EGFR mutant cells.

Methods:
We performed several laboratory methods to examine the signaling pathways involved in EGFR mutations. Signal transduction pathway analysis was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/) Figure 1



Results:
Pathways mediating EGFR mutations are: i) ERK1/2 via Ras and MEK1/2 ii) AKT via PI3K and iii) STAT3 via JAK (Figure). By Western blot analysis, phosphorylation of Tyr705 on STAT3 was noted after 2 hours of gefitinib or osimertinib treatment in PC9 and H1975 EGFR mutant cells. Unexpectedly, YAP1 phosphorylation on Tyr357 and Notch activation was detected. Co-targeting STAT3 and Src with gefitinib or osimertinib ablates activation of STAT3 and YAP1-NOTCH3 signaling pathways (Figure). In vitro and in vivo, the combinatory therapy of gefitinib or osimertinib plus TPCA-1 (a dual inhibitor of IKKs and STAT3) plus saracatinib (a SFK inhibitor) leads to significant tumor shrinkage in PC9 and H1975 cells. In tumor samples of 64 EGFR mutant NSCLC patients treated with gefitinib, the median progression free survival (PFS) was significantly shorter in those with high levels of HES1, ALDH1A1, ALDH1A3, Bmi1, AXL, CDCP1, SHP2 and ILK (Figure). However, the mRNA levels of STAT3 and YAP1 stand out in the prediction of shorter PFS with a hazard ratio of 3.02 and 2.57, respectively (P<0.001)

Conclusion:
For the first time ever, we reported gefitinib induced activation of theYAP1-NOTCH signaling pathway, in addition to activation of STAT3, in EGFR mutant cells. Secondly, co-targeting STAT3 and Src, together with EGFR, causes significant tumor growth inhibition, in comparison with gefitinib or osimertinib single therapy.

Abstract not provided

Background:
Tumors are complex structures consisting of cancer cells surrounded by a tumor stroma that is now recognized to be critical for cancer progression. Although epidermal growth factor receptor (EGFR) mutations are frequently observed in non-small cell lung carcinoma, it remains poorly understood whether EGFR mutations in cancer cells affect the tumor stroma. In this study, we studied the status of EGFR mutations in early-stage lung adenocarcinoma and analyzed the relations of EGFR mutations to tumor-infiltrating stromal cell components.

Methods:
A total of 152 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete tumor resection in Keio University Hospital between 2010 and 2014 were studied. Genomic DNA was isolated from formalin-fixed, paraffin-embedded tumor sections and mutational analyses of EGFR gene exons 19, 20 and 21 were performed by a polymerase chain reaction-based method. Paraffin sections were also subjected to immunohistochemistry for CD3, FOXP3, CD163 or CD204. Numbers of CD3-, FOXP3-, CD163- or CD204-immunostained cells were counted by observing 5 different fields at x200 magnification.

Results:
EGFR mutations were detected in 71 (47%) of the 152 patients with clinical stage IA lung adenocarcinoma and were found more frequently in women and non-smokers. These contained 38 patients with missense mutations in exon 21 (L858R) and 30 patients with deletions in exon 19. By immunohistochemistry, the number of stromal macrophages positive for CD163 or CD204, markers for tumor-associated macrophages (TAMs), was significantly decreased within tumors with EGFR mutations compared to within those with wild-type EGFR, whereas the number of CD3[+] T cells or FOXP3[+] regulatory T cells was comparable between these groups. Both tumors with missense mutations in exon 21 and deletions in exon 19 had a similar trend toward decreased TAMs in the tumor stroma.

Conclusion:
Our data suggest that EGFR mutations in early-stage lung adenocarcinoma are associated with decreased TAMs in the tumor stroma. EGFR mutation status might act on not only cancer cell behavior but tumor microenvironment.

Background:
Carcinogenesis of non-small cell lung cancer (NSCLC) can be driven by oncogenic addiction that can be targeted by specific inhibitors. It is commonly accepted that these molecular alterations are mutually exclusive. Nevertheless, limited series suggest that concomitant molecular alteration can occur in lung cancer and little is known about their sensitivity to treatment. Based on a nationwide screening program conducted during one year, we aimed to analyze the largest molecular database to date for concomitant mutations in order to determine the prevalence of multiple genomic alterations in NSCLC and their impact on both prognosis and response to treatment.

Methods:
The database of Biomarker France IFCT study collecting the molecular profile of 17 664 NSCLC has been used. The prevalence of multiple alterations and of each association was calculated. Impact on prognosis (overall survival, OS), response to targeted or conventional treatments (progression free survival, PFS and objective response rate, ORR) were established and compared with the population of patients harboring single mutations and full wild-type.

Results:
We identified 162 (0.9%) patients with double genetic alterations and 3 with triple alterations. Multiple mutations involved preferentially KRAS (67.3%), PI3K (53.3%) and EGFR (42.4%). Patients with multiple alterations were male (56.4%) with a median age of 66.7 and essentially adenocarcinoma (83.6%). More never-smokers were observed in comparison with patient with singles alterations (34.7 vs. 25.8 %, p<0.001). OS was not significantly different between single and multiple alterations whatever the type of mutations. Patients with EGFR/KRAS and EGFR/PI3K mutated tumors had worse PFS after biomarker analysis than patients with EGFR single mutation (7.1 and 7.1 months vs. 14.9 months, p=0.02 and 0.002, respectively). Concomitant mutations in patients harboring ALK rearrangement had little impact on OS (17.7 months vs. 20.3 months, p=0.57) or PFS (10.3 months vs. 12.1 months, p=0.93). Patients harboring KRAS mutations with another alteration had similar OS (13.4 vs. 11.2 months, p=0.28), PFS (6.4 months vs. 7.2 months, p=0.78) and ORR to first-line chemotherapy (41.7% vs. 37.2%) to those only harboring KRAS mutations.

Conclusion:
With almost 1% of patients harboring multiple genomic alterations, the dogma of mutually exclusive mutations should be reconsidered. Double mutations do not significantly decrease OS but alter PFS under first line treatment for EGFR mutated patients. Therapies targeting the dominant oncogene remain generally active in this setting.

Background:
Liquid biopsy (LBx) has emerged as an alternative tool for the management of advanced lung cancer patients (pts) identifying driver mutations, and hence, improving personalized medicine. There are still controversial issues such as standardization, validation of different technologies, concordance with tissue molecular profile results (TMPR), and others. LBx offers many advantages including non-invasive, bypass tumor heterogeneity, an opportunity for serial measurements to evaluate response or early recurrence, and others.

Methods:
Guardant 360 was analyzed in 100 consecutive stage IV or recurrent lung adenocarcinoma (adeno) pts. Guardant 360 is a panel of 70 genes including single nucleotide variations, amplifications, translocations, and short insertions/duplications/deletions in exons 19 and 20 of the EGFR, and others. Cell-free DNA (cfDNA) is extracted from plasma and genomic alterations are analyzed by massively parallel sequencing of amplified target genes. TMPRs from each subject was obtained or recovered for comparison with their LBx counterparts. TMPRs from this cohort was developed in different CLIA laboratories

Results:
69 pts were females; median age 72 (range, 27-99). 84/100 pts had at least 1 genomic alteration by LBx (range, 1-10). Most common abnormalities found in LBx were: TP53 (37 pts), EGFR (35 pts), NF1 (20 pts), KRAS (12 pts), MET (14 pts). From this 84 pts with + LBx results, 67 pts (80%) had TMPRs for comparison. Main reason for lack of TMPRs: insufficient tumor (19/100; 19%). For comparison between the 2 modalities, we considered all pts with available results in both tests; hence, 81 pts were used to compare tumor biopsy (TBx) vs. LBx. 37 pts out of 81 (46%) had at least 1 similar genomic abnormality found in both TBx and LBx, respectively. Most of the concordance was in EGFR alterations (19/28; 68%). LBx caught 16 additional EGFR genomic aberrations not being identified by TBx. A total of 35 EGFR genomics aberrations were identified in LBx; 16/35 EGFR mutations found in LBx were actionable and 5 of these 16 actionable EGFR mutant cases were only found in LBx not in TBx.

Conclusion:
LBx offers an alternative to identify genomic alterations. Still, insufficient tumor is the major reason for lacking of TMPRs. EGFR mutations are the most common actionable mutations found in LBx; also, it has a high correlation with TBx (68%). LBx identified more gene abnormalities than TBx, and in some cases, the actionable EGFR mutations were found only in LBx sample.

Abstract not provided

Abstract:
Introduction The pathological differential diagnosis of in a patient with synchronous multiple tumors has a similar thought process for classic morphology as for DNA analysis. Metachronous multiple lung cancers are not discussed here, as the provided title implies a clinical situation at moment in time. In the end of the text the usefulness of clinical context is mentioned.[1–5] Morphology In the setting of obvious metastatic dissemination, histologic appearance is generally conserved. This implies that most metastases look alike and in most instances also have a similar morphologic appearance as the primary tumor. However, dedifferentiation occasionally occurs in metastases. Thus it is reasonable to conclude that lesions of different histological types, e.g. squamous cell and adenocarcinoma, are two separate primary cancers. Recently, it was suggested that differences in a comprehensive histologic assessment may provide an argument for separate primary cancers. However, resection specimen analysis is required for this assessment, making this approach only useful in about 15-20% of the cases. Moreover, an evidence based data set supporting comprehensive histologic assessment is currently lacking. Reproducibility has to be taken into account.[6] In contrast to different morphological types, in case of two tumors with similar morphology a conclusion for same lineage (primary tumor- metastases relation) or different lineage (two primary tumors) is not easy to reach. The reason for this is that within an individual the genetic predisposition and etiologic factors are the same and may lead to separate tumors with the same morphology, which may still represent two lineages (thus two primary tumors) or alternatively, the same morphology in metastatic setting is one lineage. In case of multiple adenocarcinoma in-situ lesions, they are assumed to be separate primaries. In summary , in comparing two tumors differences in morphologic types is conclusive for second primary tumors, but demonstration of the same morphology is not sufficient for lineage analysis. DNA changes Demonstration of specific driver mutations by widely available PCR sequencing techniques may have use in establishing lineage.[7]In case of different driver mutations between two tumors, this obviously provides a strong argument for two primary (lung) cancers. However the frequency of discordant driver mutations is not so high. Noteworthy is that the demonstration of different passenger mutations does not have any use for lineage determination. In case of equal driver mutations a conclusion about lineage is not easy to reach.[8,9]Not only because the genetic predisposition and etiologic factors are the same, but also because in certain genes hotspot mutations occur. Thus simple demonstration of the same mutation does not provide definite evidence for lineage analysis. On this matter more research is needed with posterior probability analysis involving a relevant number of similar mutations. A detailed genetic assessment such as in comparative genomic hybridisation (CGH) may have greater discriminative power but has been used in only a few small studies.[10]In array CGH the number of data points is orders of magnitude greater than in mutation analysis. Array CGH encompasses the predisposition and etiologic factor related copy number variations (CNV) as well as lineage specific CNV. In this sense comparison of exact breakpoints in gene rearrangements is useful. Although the data are limited as the assessment was in the past complex, nowadays arrayCGH in the form of shallow sequencing can reliable be performed on small biopsies as well. To which extend NGS with a large mutation panel may be useful remains to be seen. In summary , different driver mutations is conclusive for second primary tumors, but demonstration of the same driver mutation is not sufficient for lineage analysis. Clinical context Adding clinical context provides interesting arguments. 1) Imaging may show multiple ground glass opacities (mGGO) and lack of enlarged lymph nodes. Although the morphology may be similar (lepidic pattern with AIS, MIA, Invasive adenocarcinoma) the mGGO lesions are considered to be separate primaries. In case of part solid component the morphological equivalent is usually infarction (=benign) or invasive cancer. 2) Imaging may show multiple consolidations (pneumonic type) with mostly the morphological correlate of invasive mucinous adenocarcinoma. 3) Abundance of nodular lesions, provides an argument for metastases (although rare exceptions exist, e.g. DIPNECH, Carney’s triad), while lack of nodal or systemic metastases provides an argument of two primary lung cancers. 4) Clinical follow-up is in hindsight only partly useful: lack of nodal or systemic metastases provides an argument of two primary lung cancers, while presence of local and/or distant metastases may be due to one of the two or both lung cancers. Conclusion If morphological and/or DNA analysis provides differences between two tumors it is relatively easy to establish that these pulmonary foci of cancer are separate primary tumors. Many commonly used characteristics are associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended. References 1. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J. Thorac. Oncol. 11, 639–50 (2016). 2. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 681–92 (2016). 3. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth. J. Thorac. Oncol. 11, 666–680 (2016). 4. Kozower, B. D., Larner, J. M., Detterbeck, F. C. & Jones, D. R. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, e369S–99S (2013). 5. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 651–65 (2016). 6. Thunnissen, E. et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod. Pathol. 25, 1574–83 (2012). 7. Vignot, S. et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J. Clin. Oncol. 31, 2167–72 (2013). 8. Arai, J. et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer 77, 281–7 (2012). 9. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science (80-. ). 346, 251–256 (2014). 10. Macintyre, G., Ylstra, B. & Brenton, J. D. Sequencing Structural Variants in Cancer for Precision Therapeutics. Trends Genet. 32, 530–42 (2016).

Abstract:
The Surgical Choices for Patients with Multifocal Lung Cancers Surgery for patients with multiple lung lesions is a growing domain. CT scans are obtained frequently and have high resolution such that any lesion in the lung that is 2 millimeters or larger can be identified. Also, it appears that multifocal lung lesions are more common now. At the same time, surgical technique and technology (minimally invasive) have evolved so identifying and resecting small lesions is straightforward and associated with very little morbidity and pain. In most cases there is one lesion (primary lesion) that is more concerning and others that are smaller, less solid or relatively unchanged over time. Often a diagnosis of all of the lesions is not known at the time of surgical intervention and in many cases no diagnosis is known ahead of time. Thus, the surgeon must integrate many factors when operating on multifocal lung findings. What are risk factors that the patient will have lung cancer, what are the patient’s co-morbidities and underlying lung function? When is it important to establish a pre-operative diagnosis? How important is it to resect all of the pulmonary lesions seen on CT scan? Will other therapy be needed? In general, our approach is to obtain a pre-operative diagnosis when possible if the surgery will be particularly challenging based on the location and number of the lesions and/or if the patient has very compromised lung function. The most important point is to anatomically resect the primary lesion; that nodule which is largest, most solid and/or growing the fastest. If the lesion is 2 centimeters or smaller and located within a segment that is straightforward to resect (superior segment lower lobe, lingula or upper division of the left upper lobe, posterior segment of the right upper lobe, medial basilar segment of the lower lobe or composite basilar segments of lower lobe) then a segmentectomy is the procedure of choice. This will provide an excellent oncologic outcome and more readily permit other pulmonary resection than if a lobectomy or greater had been carried out. In all cases a lymph node dissection should be performed and in the case of a sublobar resection it is important to assess, by frozen section, the intersegmental node or nodes between the area being removed and the part of the lobe being left (sump), to be sure no disease remains related to this primary lesion. If the sump node is positive then a lobectomy should be strongly considered. If the lesion is greater than 2 centimeters and for those deep seated more central lesions, a lobectomy is the best operation. If the lesion is about one centimeter and subpleural then a wide wedge resection can be considered though this is an unusual situation for the primary lesion. For the other lesions (non-primary), if they are ipsilateral and easy to identify and resect then they should be removed at the time of the surgery for the primary lesion. If it is possible to resect these lesions with a segment (preferable) or wide wedge this is best. If the non-primary lesions are pure ground glass, relatively small (i.e. less than 2-3 centimeters) and stable then it is reasonable to leave them in place for close follow-up. Once the permanent pathology including molecular analysis is done and the patient has recovered then surgery for the contralateral lesions is considered. Factors that are important in this are residual pulmonary function (repeat pft’s after the first operation), size (both baseline and recent growth) and density of the contralateral lesions. Also, pathology of the resected tumors and whether they represented separate primary tumors or possibly were metastatic tumors, although even with molecular analysis this can be difficult to ascertain, is important in planning. Surgery on the contralateral lesions should be as lung-sparing as possible with segmentectomy being the procedure of choice when possible followed by wide-wedge resections or lobectomy if dictated by size and location. The outcome of patients who had surgery for multiple lung cancers is generally quite good and not statistically different than the outcome for a solitary lung cancer. The patients in these series were highly selected. In most cases the pathology of these lesions is a mix between invasive adenocarcinoma (various subtypes), minimally invasive adenocarcinoma and adenocarcinoma in-situ. Whether mutations are identified is variable and does not seem to influence prognosis. Use of adjuvant therapy depends on the completeness of resection, the nodal status and the molecular analysis of the resected tumors. In general, assuming no nodal involvement and complete resection of the lesions removed, no adjuvant therapy is recommended. In all cases close follow-up is mandatory with visits and frequent ct scans (2-3/yr for 2 years then 1-2/year for 3 years then 1/yr for life). Graph of Survival for patients treated by surgical resection for synchronous primary lung cancers. Figure taken from: Finley et al. Journal of Thoracic Oncology. 2010. (ref 2) Figure 1 References: Shimada et al. Survival of a surgical series of lung cancer patients with synchronousmultiple ground-glass opacities, and the management of the residual lesions. Lung Cancer 2015 Finley et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. Journal of Thoracic Oncology. 2010. Bonanno et al. Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman. Lung Cancer 2016. Fonseca A and Detterbeck FC. How many names for a rose: Inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer 2014. Yasuda M et al. How should synchronous multiple primary adenocarcinomas of the lung be resected? Annals of Thoracic Surgery 2014. Wolf AS et al. Lobectomy versus sublobar resection for small (2 cm or less) non-small cell lung cancers. Annals of Thoracic Surgery 2011. Mohiuddin K et al. Relationship between margin distance and local recurrence among patients undergoing wedge resection for small (<2 cm) non-small cell lung cancer. Journal of Thoracic and Cardiovascular Surgery. 2014. Nakata M et al. Surgical treatments for multiple primary adenocarcinoma of the lung. Annals of Thoracic Surgery. 2004. Battafarano RJ et al. Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival. Annals of Thoracic Surgery. 2002. Gu B et al. A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. Annals of Thoracic Surgery. 2013.

Abstract:
History of standard surgical procedure for lung cancer In 1933, Graham reported the first successful pneumonectomy for a lung cancer patient, who survived for 18 years after surgery. In 1951, Cahan suggested that pneumonectomy with regional lymph node dissection should be a routine procedure for lung cancer in 1951. Then in 1960, Cahan reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.” Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. As for sublobar resection, segmentectomy was initially used for the resection of localized bronchiectasis as reported by Churchill and Belsey (1939). In 1973, Jensik reported their 15-year successful experience of segmentectomy for lung cancer patients. However, the use of sublobar resection as definitive management of NSCLC has been a controversial issue. Lung Cancer Study Group (LCSG) (1995) conducted the only randomized trial comparing sublobar resection with lobectomy for stage IA NSCLC patients. They observed a 75% increase in recurrence and a 50% increase in cancer death in the patients undergoing sublobar resection, compared to those in the patients undergoing lobectomy. This is the reason why lobectomy has remained a standard lung cancer surgery for a half century since Cahn’s successful report in 1960. However, recently, we encounter many patients with the subsolid nodule、and a certain percentage of those patients are multifocal lesion. The significance and role of sublobar resection for subsolid tumor have become importanat so far. Controversies in sublobar resection for patients with small-sized NSCLC Sublobar resection is a lung parenchyma-preserving surgery with limited nodal dissection. However, even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%. Although positron emission tomography (PET) is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis, the assessment of nodal status by PET is not reliable in patients with microscopic nodal metastasis. Riquet (1989) reported that lung cancer metastasizes so easily to the mediastinum that selection of the patients for limited surgery should be discussed carefully. Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20-38% in N2 patients. Therefore, lobectomy with hilar and mediastinal lymph node dissection is considered to be a basic standard procedure for lung cancer. Differences in survival between sublobar resection and lobectomy However, with the recent development of the CT scanner, the number of very early-stage lung cancer showing ground-grass opacity (GGO) on CT is rising as well, and a new therapeutic strategy for nodal dissection has been required. Proposals of sublobar resection for small-size lung cancer less than 2 cm have been undertaken in some previous reports. Many retrospective studies of sublobar resection have already been undertaken for stage IA NSCLC patients. Regarding surgery for compromised stage IA patients, Hoffmann (1980), Landreneau (1997) and Campione (2004) showed no significant survival difference between sublobar resection and lobectomy group. Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20mm or less in diameter. They showed no significant difference in survival between two groups and suggested that sublobar resection was acceptable operation for small-sized lung cancer. Nakamura (2005) reported the results of meta-analysis of 14 comparative studies showing survival difference between lobectomy and sublobar resection. He showed survival after lobectomy was slightly better at 1, 3, and 5 years, but the differences were not significant. Therefore, lobectomy with mediastinal dissection could be an excessive resection for selected patients with early lesion. Lobectomy, however, still remains to be a standard procedure for most patients with lung cancer, simply because there has been no universally accepted guidelines for conducting sublobar resection in the clinical settings. We should wait the final results of clinical trials shown in the following chapter. Clinical trials regarding sublobar resection vs. lobectomy and future perspective Japan Clinical Oncology Group (JCOG) has conducted a cohort study (JCOG0201) evaluating correlation between radiological and pathological findings in stage I adenocarcinomas. With pathologic non-invasive adenocarcinoma defined as those with no lymph node metastasis or vessel invasion, radiological non-invasive lung adenocarcinoma was defined as those with a consolidated maximum tumour diameter to tumour diameter ratio (C/T ratio) of less than 0.5. Currently, a prospective, randomized, multiinstitutional phase III trial for small-sized (<=2 cm) lung cancer patients is being conducted by Cancer and Leukemia Group B (CALGB140503) to determine the effectiveness of an intentional sublobar resection for small-sized peripheral tumors. Similar phase III study is also being conducted by JCOG (JCOG0802). JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multiinstitutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0802, wide wedge resection or segmentectomy for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 50% solid part inside and 2.1-3.0 cm in tumor diameter. Since the clear evidence regarding the survival benefit of sublobar resection for lung cancer patient is lacking so far, lobectomy should be an appropriate therapy for medically operable lung cancer patient at the moment. Abovementioned randomized trials will clearly define the role of sublobar resection in patients with stage I patients. As the number of early-stage peripheral lung cancers is increasing, and a certain number of patients are with multifocal small lesion, the surgical procedure for lung cancer should be tailored to each case by considering CT findings.

Abstract not provided

Abstract:
Background Cancer is set to become a major cause of morbidity and mortality in coming decade in every region of the world.Methods The mortality, morbidity and treatment variants in Russia were evaluated.Results The incidence of lung cancer morbidity in Russia in 2014 numbered 57 685, mortality – 49 730. Standardized index incidence rate demonstrates improvement of men since year 2009. It was 55,0 on 100 000 population in 2009; 49,15 in 2013 and 49,0 in 2014. It means a 10,9% decrease since 2009 to 2014. It takes stable first place in men. In women the same years showed different values: 7,0; 7,17; 7,3 at 2009, 2013 and 2014 years respectively, that means + 4,3%. It takes 10-12 places of all malignant diseases among women. Among men lung cancer is on the first place (26,6%) in mortality rates. A non-interventional, prospective cohort study included 838 patients, average age 58,7; male – 78,4%; female – 21,6%, smokers – 26,5%; ex-smokers – 24,1%, current smokers – 49,4%. Disease stages at diagnosis were: stage I-II – 36,8%; stage III – 37,8%; stage IV – 25,4%. It was squamous-cell carcinoma – 54,3%; adenocarcinoma – 31%; BAR – 6,4%; LCC – 2,9%, adenosquamous carcinoma – 2,3%, other – 3,1%. Proportion of EGFR positive tumors constitutes 10,1% (85/838) pts. Surgery was performed for 393 pts (46,9%). Radiotherapy was administered to 145 pts (17,8%). 370 pts (44,2%) underwent first-line CT and 96 (11,8%) – second-line. The treatment depends on the morphology type of the tumor. We consider four main types NSCLC (AdenoCa and SCC), LCLC and NETs. NETs group included typical and atypical carcinoids, LCNEC, SCLC. We participated in 53 different multicenter international trials in lung cancer, including 930 patients. Outside of these protocols we analyzed 567 pts with advanced NSCLC: 255 pts with squamous cell cancer (SCC) and 250 pts with non-SCC for 1st line chemotherapy (CT). ORR was 20-25% for platinum-duplets, 1-year survival – 27,5-37,5 month. The 1-year survival showed best results in absolute figures with paclitaxel and platinum compounds in SCC and gemcitabine and platinum compounds in non-SCC, but the value was not statistically significant neither for 1-year nor for median survival. For SCLC new combination with irinotecan and platinum compound showed ORR – 55,1% and stabilization of disease in 24,3% of pts.Conclusions Nowadays the treatment approaches to lung cancer in Russia depends from morphological type of tumors, IGC results and needs further investigations.

Abstract:
Lung cancer is still the leading cause of cancer death in China. The estimated new lung cancer cases and deaths were 733,300 and 610,200 in 2015, respectively. Non-small cell lung cancer (NSCLC) remains the predominant form of the disease in China, with majority of patients being diagnosed at advanced stages. Thus this presentation will focus on advanced stage NSCLC. Current treatment strategy The current treatment algorithm for wild-type non-squamous and squamous NSCLC were shown in Figure 1 and 2, respectively. Figure 1 Figure 1. Treatment algorithm for non-squamous NSCLC (wild-type) Figure 2 Figure 2. Treatment algorithm for advanced squamous NSCLC For patients with activating EGFR mutations, EGFR-TKIs therapy will be used as front-line therapy. Commercial available EGFR-TKIs in China include Gefitinib, Erlotinib and Icotinib. For patients harbouring an ALK rearrangement, crizotinib will also be considered as first-line treatment. When failed from EGFR-TKIs or ALK-Inhibitor therapy, patients will be treated according to clinical model of disease progression. For patients with asymptomatic progression, continuing EGFR-TKIs or ALK-Inhibitor is recommended. For patients with local progression, EGFR-TKIs or ALK-Inhibitor will also be continued with additional local therapy such as whole brain radiation. However, for patients with aggressive progression, EGFR-TKIs or ALK-Inhibitor will be substituted by chemotherapy. Unfortunately, it is difficult to overcome drug resistance according to molecular mechanism because novel agents such as Osimertinib and Alectinib haven’t been approved by Chinese FDA. Challenge and perspective 1. Genetic alterations assays Genetic alterations are frequent in Chinese NSCLC patients. According to PIONEER study (NCT01185314), which is a prospective molecular epidemiology study in newly diagnosed advanced lung adenocarcinoma, the EGFR active mutation rate is 50.2% in Chinese patient population. The incidence of EGFR mutations in patients who never smoked can be as high as 59.6%. ALK rearrangement is also common in this patient population. In a large cross-sectional study enrolled 1160 NSCLC patients, the incidence of ALK rearrangements is 8.1%. Noteworthy, 44% of patients younger than 30 years old harbor ALK rearrangements. However, genetic alterations test rate used to be low in China. According to a large national survey, the EGFR mutation test rate was only 9.6% in 2011. However, as the turnover time shortens, the testing fee decreases, and ctDNA testing becomes available, the EGFR/ALK assays have turned into routine practice in China. Moreover, NGS platforms detecting panels of mutations are commonly used in some leading centers now. 2. Novel agent availability There is severe delay in the approval for novel agents by Chinese FDA. For instance, Bevacizumab was approved by FDA for treatment of NSCLC in 2006, while it was approved by Chinese FDA 9 years later. To improve availability of novel agents, Chinese oncologists are active in participation in international multi-center clinical trials. In addition, more and more innovative drugs have been developed by domestic pharma industry and entered clinical trials (Table 1). Moreover, Chinese FDA makes new policies to encourage innovative drugs and accelerating new drug application.

Agent ID	Classification	Indication	Phase
Avitinib	Mutation selected EGFR-TKI	EGFR T790M Mutation	Phase I
Apatinib	VEGFR-TKI	Nonsquamous NSCLC in 3L	Phase III
Famitinib	VEGFR-TKI	Nonsquamous NSCLC in 3L	Phase III
Theliatinib	EGFR inhibitor	EGFR amplification	Phase I
Volitinib	c-MET inhibitor	c-MET amplification	Phase I
SHR-1210	PD-1 antibody	NSCLC in 2/3L	Phase I

Table 1. Innovative drugs from China in clinical trials 3. Lung cancer prevention The incidence rate of lung cancer remains high in China between 2000 and 2011. Factors that have contributed to this issue include tobacco smoking and air pollution. 50% adult Chinese men were current smokers in 2010. In addition, smoking rates in adolescents and young adults are still rising in China. To reduce tobacco use in China, the government enact a strict smoking control law in Beijing in June 2015. However, the air pollution is still a severe problem and needs to be improved urgently. 4. Economic burden There are several factors which have contributed to the heavy economic burden of lung cancer patients in China. First, the residents’ income is still low in China. In 2015, per capita disposable income (one year) was only $3300. Second, the cost of anti-cancer drugs is very high (Crizotinib/cycle $8500, Gefitinib/cycle $2200, Pemetrexed/cycle $3000, and Bevacizumab/cycle $4500). Moreover, only 20% of whole medical expense can be covered by insurance, and majority of targeted drugs can’t be covered.

Abstract:
Lung cancer is the commonest type of cancer in males and the leading cause of cancer death in both sexes world-wide. It is also the commonest in men in India accounting for 11.3% of all new cancers and also is the most common cause of cancer death (13.7%). In contrast to a decline trend in men in developed countries with a plateau for females, in India, the incidence continues to rise for both males and females. Data from the population based cancer registries developed under the National Cancer Registry Program of the Indian Council for Medical Research(ICMR) indicates that there is wide geographical variability in the incidence of this disease in different parts of the country. The highest age adjusted incidence rates of 45 per 100000 population are seen in the North-East region of India and are similar to areas reporting the highest incidence rates in some parts of the US and Europe. In other areas of India, especially the Western region, the age adjusted incidence rates are as low as 2 per 100000 population. The demographic profile including age, gender, stage, histology and even the molecular epidemiology (prevalence of EGFR mutations and ALK rearrangements) varies considerably in different parts of India. However, the overall incidence is much lower than that compared to many western countries. The demographic profile of lung cancer seen in India needs special mention. In the past, a single-centre large series of 1009 patients presenting to our institute from 1977-86 had shown squamous histology to the commonest (34.3%) followed by adenocarcinoma (25.9%) and small cell lung cancer (SCLC; 20.3%). Subsequent analysis of 250 patients presenting to us three decades later (2007-09), we found that the histological pattern was largely unchanged with squamous still being the commonest (34.8%) followed by adenocarcinoma (26.0%) and SCLC (18.4%). The male-female ratio as well as the current/ex-smoker to never-smoker ratio was also similar between the two cohorts. A possible reason for the lack of change in demographic profile of lung cancer was thought to be related to the fact that ‘bidi’ and NOT cigarette is the most common form of tobacco smoking in India. The ratio of bidi to cigarette smoking in India ranges from 2.5:1 to 7.0:1 in different parts of India and unlike cigarette making, there has been no change in the process of bidi manufacturing which is primarily a cottage industry. The other important aspect related to its association of quantified tobacco smoke exposure. The smoking index (SI; number of combined bidis and cigarettes smoked per day multiplied by number of years smoked) has been developed for this purpose. Patients can be categorized as either never-smokers (SI=0), light to moderate smokers (SI=1-300) and heavy smokers (SI≥301). In a cohort of 520 non-small cell lung cancer (NSCLC) patients, we observed that age, gender, histological type and stage differed significantly between the three groups. Never-smokers had significantly more females (52%), were younger (mean age 54.5 years), lesser squamous histology (28%), more advanced stage (IIIB/IV; 92%), more metastatic disease (67.4%) and more extra-thoracic metastases (42%) while group of heavy smokers had more males (98%), were older (mean age 61.2 years), more squamous histology (58%), lesser advanced stage (81%), lesser metastatic disease (39%) and lesser extra-thoracic metastases (17%). We have identified another risk factor in women to be the exposure to Biomass fuel. Majority of patients (approximately 83% of NSCLC histology at our centre) present with advanced stage(IIIB/IV) at the time of diagnosis and are managed non-surgically. Misdiagnosis as tuberculosis and empirical treatment with anti-tubercular drugs prior to referral to higher centre is one of the important causes for delayed diagnosis of this disease in India. Developing and under-developing countries are often constrained with regards to availability of health care and other resources necessary for appropriate management of the health related requirements of their population and this holds true for lung cancer as well. Some of the challenges in resource constrained settings include: · Large population with high population density · Illiteracy and poor health awareness · Sub-optimal economic and infrastructure inputs for health care · Suboptimal ratios of doctor and nurses for population · Overburdened hospitals and health care facilities · Huge burden of TB that hinders differentiation by the primary physician with lung cancer Important issues in resource constrained settings include choosing the platinum agent as well as the non-platinum agent. Decision on dose intensity may also be influenced by similar factors (efficacy, tolerance, toxicity profile and packaging strengths of marketed drugs). A list of some of the important factors influencing decision are shown below.

Characteristic	Relative importance
Disease related
Age	++
Gender	+
Histology	+++
Molecular profile of tumor	++
Stage	+
Performance Status	+++
Unrelated to disease
Co-morbid illnesses	+
Socio-economic background/financial constraints	+++
Medical reimbursement/insurance issues	+++
Wishes of patient/family members	++
Frequency of hospital visits	++

Dr. D. Behera Senior Professor & Head, Dept. of Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh - 160012 (INDIA) Email: [email protected] Select References and suggested reading 1. Behera D, Balamugesh T. Lung cancer in India. Indian J Chest Dis Allied Sci 2004; 46 : 269-81 2. Behera D. Managing lung cancer in developing countries: difficulties and solutions. Indian J Chest Dis Allied Sci 2006; 48: 243-4 3. Jindal SK, Behera D. Clinical spectrum of primary lung cancer: review of Chandigarh experience of 10 years. Lung India 1990; 8: 94-98 4. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Unchanging clinico-epidemiological profile of lung cancer in North India over three decades. Cancer Epidemiol 2010; 34: 101-4. 5. Behera D, Balamugesh T. Indoor air pollution as a risk factor for lung cancer in women. J Assoc Physicians India 2005; 53: 190-2. 6. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012; 4: 474-84. 7. Singh N, Behera D. Lung cancer epidemiology and clinical profile in North India: Similarities and differences with other geographical regions of India. Indian J Cancer 2013; 50: 291 8. Singh N, Aggarwal AN, Behera D. Management of advanced lung cancer in resource constrained settings : a perspective from India. Expert Rev Anticancer Ther 2012: 12: 1479–95. 9. Maturu VN, Singh N, Bal A, Gupta N, Das A, Behera D. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival. Lung India 2016; 33: 257-66. 10. Bal A, Singh N, Agarwal P, Das A, Behera D. ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India. APMIS 2016 Aug 8; DOI: 10.1111/apm.12581 [Epub ahead of print]

Abstract not provided

Abstract:
Lung cancer has been the most common cancer in the world for several decades. The number of new cases estimated in 2012 is 1.8 million cases (12.9% of the total), 58% of which occurred in the less developed regions. The disease remains as the most common cancer in men worldwide (1.2 million, 16.7% of the total) with the highest estimated rates in Nothern America (33.8%) and Northern Europe (23.7%), a relatively high rate in Eastern Asia (19.2) and the lowest rates in Western and middle Africa (1.1 and 0.8 respectively). In developing countries, lung cancer is the most common cancer among males and the third most common cancer among females. Lung cancer is the most common cause of death from cancer worldwide estimated to be responsible for nearly one in 5 (1.59 million deaths, 19.4% of the total) (1). Temporal analyses reveal that significant reductions in lung cancer mortality have been observed in developed countries due to increased awareness of the harmful effects of smoking , asbestos and other factors The role of early detection is also evident. (2). In contrast, lung cancer incidence and mortality rates have increased in some low and medium resourced countries (3). The regional differences are mainly due to increased tobacco smoking in the developing countries , smoking waterpipe, cannabis or even passive and secondary smoke and in the mean time there is lack of proper tobacco control. There are also occupational risk factors such as asbestos exposure, dust, fumes, nickel ,silica and insecticides and up till now there are areas that have not banned asbestos or succeeded to control occupational and environmental exposure and incidence of mesothelioma is increasing. (4) Many studies have shown that cases have genetic susceptibility to develop lung cancer specially in North Africa. Another important factor specially the Middle East North Africa is the increase in the elderly population that may be attributed to better infection control and improvement of general health care . As life expectancy continues to increase throughout the African continent, the burden of cancer is likely to increase. Given that an estimated 32,640 new lung cancer cases will be seen in Africa in 2015 ( 5) .We have to remember also that cancer diagnosis rate in Africa is relatively low and patients present usually in an advanced stage so underreporting may be another factor . Accordingly, it is essential to know the magnitude of lung cancer in different regions in Africa by having cancer registry for the countries . So, obstacles to the global fight against lung cancer include lack of registry in some parts of Africa, low public awareness of lung cancer and absence of screening for the high risk cases , overburdened treatment centers and insufficient financial support. The ways to combat all these obstacles start by setting strategies for prevention and earlier detection in the low income countries. Public health awareness of the risk factors that cause lung cancer and the importance of avoiding / stopping smoking and banning asbestos should be clear and this is the role of public health authorities, medical journals and public media. The war against tobacco companies should start and everyone should understand the danger of smoking. This is done also by cooperation of scientific organizations of governmental and non governmental organizations. Also, we should reduce air pollution and regulate the occupational exposure of the employees to avoid the appearance of lung cancer and mesothelioma. As for early detection , screening can help in high risk patients and many authorities and NGOs can help to catch the early cases. In the mean time there should be ways to access modern imaging techniques to detect the cancer and use the minimal requirements for diagnosis and care . Accordingly it is essential to set the treatment guidance protocols to facilitate the management of the patients and to educate and train the doctors that should acquire degree granting programs and get certificates in the oncological field. It is mandatory to to lower the cost of health care to encourage the patients to go for treatment and to get the proper care. There should be special dealing for the economic pressure and avoidance of financial toxicities for the patient. The last point that have to be ameliorated in Africa developing countries is research through International collaboration as studying genetic polymorphism and relation to smoking and changing patient concept about drugs received in clinical trials that use new drugs, proper investigations and lower the cost of treatment and may get better outcome. References 1- Globocan 2012 (IARC): Estimated cancer incidence, mortality and prevalence worldwide, section of cancer surveillance 2- Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19: 1893-1907. 3- Sankaranarayanan R, Jayant K, Brenner H 2011: An overview of cancer survival in Africa, Asia, the Caribean and central America: the case for investment in cancer health services. IARC Sci Publ: 257-291. 4- Gaafar RM, Eldin NH (2005) Epidemic of mesothelioma in Egypt. Lung Cancer 49: S17-S20. 5- Tao Z, Shi A, Lu C, Song T, Zhang Z, etal. 2014: Breast cancer : Epidemiology and Etiology. Cell Biochem Biophysi

Abstract not provided

Abstract:
Muscle sparing thoracotomy has been a standard approach in thoracic surgery for a long time. Minimal invasive approaches have gained a widespread acceptance recently and were included in the treatment guidelines for early stage NSCLC by several societies. Prospective randomized trials comparing minimal invasive approaches versus muscle sparing thoracotomy in stage I NSCLC have already been performed more than twenty years ago and demonstrated equal morbidity and mortality. Nevertheless it took until 2013 that the American College of Chest Physician guidelines recommended a VATS approach for clinical stage I NSCLC over a thoracotomy in experienced centers (1). No recommendation is made for more advanced stages. When analyzing national registry data still a high percentage of procedures in performed in an open way. This means that in current practice thoracotomy is still used as a standard approach by many surgeons. Minimal invasive approaches – both videothoracoscopic and robotic – are not different operations but different approaches towards performing an operation. It has been proven in several studies that in early stage lung cancer minimal invasive approaches in its various form lead at least to equivalent or even better oncologic outcome compared to an open approach. Nevertheless in more advanced stages this proof is lacking. Experienced centers reported individual series of minimal invasive approaches towards advanced procedures such as sleeve resection, pneumonectomy, chest wall resection and Pancoast tumor resection. While this is technically feasible no data on long-term outcome of larger patient cohorts are available and an open approach is considered standard in these cases. Thus for tumors with invasion of hilar structures or sleeve resection a muscle sparing thoracotomy currently remains a standard approach. Perceived advantages of minimal invasive approaches – VATS as well as RATS – include less pain, fewer complications, shorter length of stay, faster return to normal activity and higher rate of adjuvant chemotherapy compliance. There are a few single center studies challenging these assumptions (2,3) as well as a recent analysis of Danish national data (4), however the majority of studies are in favor of minimal invasive approaches. In summary muscle sparing thoracotomy remains a standard approach for advanced stage tumors, whereas early stage lung cancer should be treated minimally invasive in experienced centers. References 1) Detterbeck FC1, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):7S-37S. 2) Rizk NP, Ghanie A, Hsu M, Bains MS, Downey RJ, Sarkaria IS, Finley DJ, Adusumilli PS, Huang J, Sima CS, Burkhalter JE, Park BJ, Rusch VW. A prospective trial comparing pain and quality of life measures after anatomic lung resection using thoracoscopy or thoracotomy. Ann Thorac Surg. 2014 Oct;98(4):1160-6. 3) Kuritzky AM, Aswad BI, Jones RN, Ng T. Lobectomy by Video-Assisted Thoracic Surgery vs Muscle-Sparing Thoracotomy for Stage I Lung Cancer: A Critical Evaluation of Short- and Long-Term Outcomes. J Am Coll Surg. 2015 Jun;220(6):1044-53 4) Licht PB, Schytte T, Jakobsen E. Adjuvant chemotherapy compliance is not superior after thoracoscopic lobectomy. Ann Thorac Surg. 2014 Aug;98(2):411-5

Abstract:
Since the introduction of the videothoracoscopic anatomical lung resections in the early 90-ties both indications and contraidications for this type of approach have changed dramatically (1,2). There is common agreement that the oncological principles during surgery for lung cancer have to be the same regardless the type of approach: standard, minimally invasive (MIS – VATS multiportal or uniportal, intubated or non-intubated) or robotic. It regards predominantly requirements such like careful and atraumatic dissection, sufficient free-of-neoplasm margins and proper lymphadenectomy (standard or extended). Keeping it in mind we have to admit that stage I NSCLC seems „ideal” indication for MIS, particularly for less experienced surgeons. This type of surgery (MIS for stage I) is widely accepted and performed worldwide in thousands of cases. However, many experienced centers and surgeons have moved the borders forward treating more advanced cases by MIS with acceptable results regarding complications, mortlity, conversion rate or quality of lymphadenectomy. Gonzalez-Rivas presented the series of 43 advanced patients (tumors bigger > 5cm, T3 or T4, treated by neoadjuvant chemo- or radiotherapy) who were treated by uniportal VATS with good results comparable with earlier stages (3). Authors stated that „Skilled VATS surgeons can perform 90% or more of their lobctomies thoracoscopically, reserving thoracotomy only for huge tumors or complex bronchovascular reconstructions”. Large multicenter series of more than 400 advanced cases treated by VATS approach compared with propensity score matched open thoracotomy group with no differences in overall survival was published by Cao et al. (4). According to the VATS Consensus Statement (among 50 international experts to establish a standardized practice of VATS lobectomy after 20 years of clinical experience) eligibility for VATS lobectomy should include tumors <7cm and N0 or N1 status. Chest wall involvement was considered contraindication while centrality of tumour was considered a relative contraindication when invading hilar structures (5). This important statement is widely accepted however some surgeons consider it too restrictive regarding chest wall invasion. Currently there is a relatively small (but growing) group of thoracic surgeons who are performing double-sleeve (pulmonary vessels and bronchi) and carinal resections by MIS – extremely complex procedures even in open surgery (6). It requires modern instruments, sutures and definitely is not a procedure for beginners. Published series are small and overall experience is limited but this initial efforts are good example of the continuos drive of thoracic surgeons community to move indications for MIS further and further. Advanced NSCLC cases started to be treated by MIS just few years ago and there are no prospective randomised studies available in medical literature therefore we cannot definitively compare and assess the long term results but keeping in mind that the main oncological principles should be preserved and remain the same in every type of surgical approach we can expect comparable and similar results as it was reported in currently published papers. We all know that generally speaking the future is unpredictable but inevitable from the other side. Considering MIS in advanced NSCLC cases we can state with just minimal exagerration that the future is now. Selected references: 1. Roviaro G, Varoli F, Vergani C et al.: Long term survival after videothoracoscopic lobectomy for stage I lung cancer. Chest 2004;126:725-732 2. Hanna JM, Berry MF, D`Amico TA: Contraindications of videoassisted thracoscopic surgical lobectomy and determinants of conversion to open. J Thorac Dis 2013;5:182-189 3. Gonzalez-Rivas D, Fieira E, Delgado M et al.: Is uniportal thoracoscopic surgery a feasible approach for advanced stages of NSCLC? J Thorac Dis 2014;6:641-648 4. Cao C, Zhu ZH, Yan TD et al.: Videoassisted thoracic surgery versus open thoracotomy for NSCLC: a propensity score analysis based on a multi-institutional registry. Eur J Cardiothorac Surg 2013;44:849-54 5. Yan TD, Cao C, D`Amico TA et al.: Videoassisted thoracoscopic surgery lobectomy at 20 years: a consensus statement. Eur J Cardiothorac Surg 2014;45:633-639 6. Lyscov A, Obukhova T, Ryabova V et al.: Double-sleeve and carinal resections using the uniportal VATS technique: a single centre experience. J Thorac Dis 2016;8 (suppl 3):235-241

Abstract not provided

Abstract:
Introduction Uniportal video-assisted thoracic surgery (VATS) has been established as an alternative surgical approach for the treatment of most intrathoracic conditions. The potential benefits of a better view, anatomic instrumentation, better cosmesis and potential less postoperative pain and paraesthesia have led this approach to become of increasing interest worldwide. Performing surgery through a single incision approach represents an evolution of VATS to a less invasive approach. The early period of uniportal VATS development was focused on minor procedures until the second phase uniportal VATS started in 2010 with the development of the technique for major pulmonary resections. The creation of specific uniportal VATS programs in high volume centers like the Shanghai pulmonary hospital (the biggest thoracic program in the world with more than 8000 major resections per year) has contributed to spread out the technique to a large number of surgeons from all over the world in a short period of time. Surgical technique Uniportal VATS represents a radical change in the approach to lung resection compared to the conventional three-port VATS. Since the placement of all the surgical instruments and the camera is done through the same incision, Uniportal VATS can pose a challenge for both the surgeon and the assistant. The surgeon and the assistant should be positioned in front of the patient in order to have the same thoracoscopic vision during all steps of the procedure and experience more coordinated movements. Even though the field of vision is only obtained through the anterior access site, the combined movements of the thoracoscope along the incision will create different angles of vision (in this context, a 30 degree thoracoscope is recommended to achieve a panoramic view). The advantage of using the thoracoscope in coordination with the instruments is that the vision is directed to the target tissue, bringing the instruments to address the target lesion from a direct, sagittal perspective. Instruments must preferably be long and curved to allow the insertion of 3 or 4 instruments simultaneously.Optimal exposure of the lung is vital in order to facilitate the dissection of the structures and to avoid instrument interference. The rule of thumb is that for any lobectomy, the Uniport is best sited between the mid- and anterior axillary lines in the 5[th] intercostal space. This slightly anterior position takes advantage of the naturally wider intercostal spaces at the front of the human body. If the wound is sited too high – in the 4[th] space for an upper lobectomy – the dissection of the hilar vessels may be easier, but the instruments enter directly towards the hilum so that there is a smaller angle for the stapler to pass without impinging on the structures behind. If the wound is too low, there may be a good angle for the stapler to pass, but the distance to the hilum becomes too great and the arc in which instruments can be placed towards the hilum becomes too narrow – leading to more chance of ‘fencing’ between the instruments and camera. The incision itself is typically 3-4cm long, although longer incisions can be used (e.g. for an inexperienced surgeon, large tumor, thicker chest wall, etc) without any obvious disadvantage to the patient. It is helpful to rotate the surgical table away from surgeons during the hilar dissection and division of structures, and towards the surgeons for the lymph node dissection. For most of the surgical steps the thoracoscope is usually placed at the posterior part of the utility incision working with the instruments in the anterior part. For lower lobectomies the normal sequence of dissection is as follows: inferior pulmonary ligament, inferior pulmonary vein, pulmonary artery, bronchus and finally completion of the fissure. In case of upper lobectomies, the pulmonary artery is normally divided first, followed by vein, bronchus and fissure. When the lobectomy is completed, the lobe is removed in a protective bag and a systematic lymph node dissection is accomplished. The intercostal spaces are infiltrated with bupivacaine at the end of the surgery under thoracoscopic view. A single-chest tube is placed in the posterior part of the incision. We do not routinely employ epidural or paravertebral catheters. Future Recent industry improvements such as the specifically designed surgical instrumentation with double articulation, improvements in high definition video-camera systems, new energy devices and more narrower and angulated curved tip staplers have made single-port VATS, for major lung resections, easier to adopt and learn than conventional VATS. The demonstrated benefits of geometrical characteristics of the technique enables expert surgeons to perform complex cases and reconstructive techniques, such as broncho-vascular procedures or even carinal resections. The future of the thoracic surgery is based on the evolution of minimally invasive procedures and innovations directed towards reducing even more the surgical and anaesthetic trauma. We can expect more developments of subcostal or embryonic natural orifice translumenal endoscopic surgery access, evolution in anaesthesia strategies, and cross-discipline imaging-assisted lesion localization for single-port VATS procedures. Improvements in anaesthetic techniques such as non-intubated or awake uniportal VATS,may further quicken postoperative recovery allowing the tumor resection to be performed in an ambulatory setting. Furthermore, the need to reduce the risk of intercostal nerve damage associated with the transthoracic incision has led to the recent development of uniportal subxiphoid VATS technique for major pulmomary resections. We truly believe in the use of the uniportal approach, combined with yet-to-come 3D image systems (adapted on the screen, no glasses) and single port robotic technology and wireless cameras in awake patients. We understand that the future goes in the direction of digital technology which will facilitate the adoption of single-port technique worldwide in the next coming years.

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The value of any treatment is determined by the magnitude of its clinical benefit (MCB) balanced against its cost. Whereas costs of procurement and out-of-pocket expenditures vary from country to country, the MCB, as derived from well-designed clinical trials, is a relative constant. Consequently, meaningful discussion of value and relative value are predicated on an understanding of the MCB. MCB in this context refers to the added benefit, usually compared to a control (the best current standard care). Until recently there was no standard tool for grading the MCB of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long term survival). Recognising the importance of presenting clear and unbiased statements regarding the MCB from new therapeutic approaches derived from high quality clinical trials the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the MCB for cancer medicines, the ESMO MCB Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost effective and affordable cancer care. The ESMO-MCBS v1.0 [1]has been developed and validated for solid cancers. The tool is presented in two parts. Form 1 is used to evaluate adjuvant and other treatments with curative intent. Form 2 (a, b or c) is used to evaluate non-curative interventions, with form 2a for studies with OS as the primary outcome, form 2b for studies with PFS or TTP as primary outcomes, 2c for studies with QoL, toxicity or response rate as primary outcomes and for non-inferiority studies. Form 2a is prognostically sub-stratified for studies where the control arm produced OS greater or less than or equal to 1 year, and form 2b is stratified for studies where the control arm PFS is <6m or >6mth. Version 1.0 can be applied to comparative outcome studies evaluating the relative benefit of treatments using outcomes of survival, QoL, surrogate outcomes for survival or QoL (DFI, EFS, TTR, PFS and TTP) or treatment toxicity in solid cancers. Eligible studies can have either a randomised or comparative cohort design or a meta- analysis which report statistically significant benefit (P>0.05, upper limit of 95[th] percentile for HR <1) from any one, or more of the evaluated outcomes. For treatments with curative intent, the scale is graded A, B or C. Grades A and B represent a high level of clinical benefit . For cancers treated without curative intent, the scale is graded 5, 4, 3, 2, 1, where grades 5 and 4 represent a high level of proven clinical benefit. The scale incorporates a “dual rule” taking into account the variability of the estimated HR from a study, the lower limit of the 95% Confidence Interval (CI) for the HR is compared to specified threshold values; and second the observed absolute difference in treatment outcomes is compared to the minimum absolute gain considered as beneficial. Different candidate threshold values for HR and absolute gains for survival, DFS and PFS, adjusted to represent as accurately as possible the expert opinion of the oncology community, have been explored through extensive simulations. In all forms HR thresholds refer to the lower extreme of the 95% CI, analogous to the convention of evaluating null effect by the upper limit of the 95%CI <1. The performance of the evaluation rule based on the lower limit of the 95% CI of HR, was compared to the simpler rule of using a cut-off for the point estimate of HR, in conjunction with the additional rule on the minimum absolute gain in treatment outcome. The simulation results under different HR values and corresponding power, favoured the proposed approach to use the lower limit of the 95% CI which takes into account the variability of the estimate. The concern that small studies generate wider confidence intervals is real and justified, however in the ESMO-MCBS v1.0 all high grading scores in a non-curative setting incorporate both HR and absolute gain to mitigate against over valuing small studies with wide HR. This structured and disciplined approach to deriving estimates of clinically meaningful benefit from published data can be used in a range of settings: it can help public policy-makers advance “accountability for reasonableness” in resource allocation deliberations, contribute to formulation of clinical guidelines , in the clinic it can help clinicians to weigh the relative merits of competing relevant therapeutic options in situations in which there is no direct comparative data and grading may also be of benefit when explaining the relative merit of therapeutic options to patients and their families. Finally ESMO-MCBS may be of use to editors, peer reviewers and commentators in considering the clinical significance of research findings from randomised clinical studies, cohort studies and meta-analyses with statistically significant positive findings. Experience accrued in evaluating trials in the management of non small-cell lung cancer have been critical in the development process of v1.0, particularly with regard to the interpretation of PFS is studies with extensive crossover on progression that precludes meaningful OS survival results. In this cohort of studies, the inclusion of QoL evaluation was able to generate confirmatory secondary evidence to support the clinical significance of the PFS findings. The proliferation of new agents targeting NSCLC with specific mutations that have been approved on the basis if Phase I-II data have challenged the working group to expand the scope of the scale to include single arm studies. This new subscale will be among the amendments in the planned revision that is under development and scheduled for publication early next year. 1. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Annals of oncology 2015; 26: 1547-1573.

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With limited resources for health, Low and Middle Income Countries (LMICs) struggle to guarantee all members of their society toget cancer treatments, especially the innovative but expensive cancer medicines[1, 2]. Cancer is a leading cause of deathin Thailand, which is an upper-middle income country in South-East Asia. From 2003 to 2011, the mortality rate from cancer rose from 79 to 95 per100,000 populations. [3].Since the Thai health care reform in 2001[4, 5] several stakeholders have initiated policies andprogramsto facilitate access to medicines. The Thai NLEM is different from the one listed by WHO, due to the fact that WHO listed only the minimum required medicine, while the Thai list included an optimum list. At the present, the Thai NLEM has more than 700 items of active ingredients and 1000 dosage forms [6, 7]. When the NLEM was first introduced in 1981, only cost, safety, and efficacy were considered as criteria for inclusion whereas effectiveness was added to the list of criteria in 2004. Since 2008, economic evidence has become important for the Sub-committee of the NLEM to justify the new costly medicines such as type E2 to be included in the list of NLEM. As of 2009, the NLEM can be divided into six categories, which are A, B, C, D, E1, and E2. Type A: Basic medicines that every health facility must make available Type B: Alternative, second line medicines of those in category A Type C: Medicines prescribed only by specialists TypeD: Medicines used only for particular indications and diseases Type E1: Medicines used only for special or vertical programs Type E2: Medicines that are high costs but are important for particular groups of patients Heath Care Coverage for Thai residences are divided into 3 categories 1. Universal Coverage Scheme (UCS) Cover 75% of Thai population 2. Social Security Scheme (SSS) Cover 19%, Private sector employees, excluding dependants 3. Civil Servant Medical Benefit Scheme (CSMBS) Cover 9%, Government employees plus dependants (parents, spouse and up to two children age <20) The CSMBS has covered most of the cancer drugs including the expensive drugs, however UCS and SSS have covered only drugs listed in the NELM; thus there are unmet need for cancer patients with these two healthcare schemes. Thai government set up several policies to enable access to the cancer drugs such as Compulsory Licensing, Pooled purchasing (price negotiation), Special marketing arrangement (price negotiation), and E2 access program. Several pharmaceutical companies provide their own scheme for patients who are willing to pay for the drug by themselves (patient access program) Even with all the programs available, the problem of accessibility of costly anticancer drugs still persists. There should be more input into this problem. References 1. Kanavos P, Das P, Durairaj V, Laing R, Abegunde DO (2010) Options for financing and optimizing medicines in resource-poor countries World Health Organization. 2. American College of Physicians (2011) How can our Nation Conserve and Distribute Health Care Resources Effectively and Efficiently? Philadelphia: American College of Physicians. 3. MoharaA,YoungkongS,PérezVelascoR,WerayingyongP,PachaneeK,etal.(2012)UsinghealthtechnologyassessmentforinformingcoveragedecisionsinThailand.JComparEffectRes.1:137–146. 4. Damrongplasit K, Melnick GA (2009) Early results from Thailand's 30 Baht Health Reform: something to smile about. Health Aff (Millwood). 28: w457–466. doi: 10.1377/hlthaff.28.3.w457 PMID: 19336469 5. Towse A, Mills A, Tangcharoensathien V (2004) Learning from Thailand's health reforms. BMJ. 328: 103–105. PMID: 14715608 6. Yoongthong W, Hu S, Whitty JA, Wibulpolprasert S, Sukantho K, et al. (2012) National drug policies to local formulary decisions in Thailand, China, and Australia: drug listing changes and opportunities. Value Health. 15: s126–131. doi: 10.1016/j.jval.2011.11.003 PMID: 22265059 7. Turongkaravee S, Rattanavipapong W, Khampang R, Leelahavarong P, Teerawattananon Y, et al. (2012) Evaluation of high-cost medicine scheme (Category E2) under the 2008 National List of Essential Medicines. Nonthaburi: Health Intervention and Technology Assessment Program.

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