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    ES09 - How I Do It - Real World Issues in the Diagnosis and Treatment of Metastatic NSCLC (ID 12)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 5
    • Now Available
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      ES09.01 - How I Optimize Tissue Specimen Processing for Histopathological and Molecular Profiling (Now Available) (ID 3199)

      13:30 - 15:00  |  Presenting Author(s): Amanjit Bal

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the most common cancer in males worldwide, and the most common cause of cancer related mortality in both sexes. There have been significant advances in the treatment of non-small cell lung cancer (NSCLC) in the last several years, which require careful biopsy sample acquisition and processing. Approximately 70% lung cancer patients present in advanced stage, thus most diagnosis of lung cancer are offered on cytology specimens and small biopsies.

      Specimens for diagnosing lung cancer

      For diagnosis of lung cancer, the specimens received in pathology laboratory includes; Effusions and FNAC samples from which cell blocks can be prepared, endobronchial biopsies, transbronchial lung biopsies, CT/PET guided core biopsies and biopsies from metastatic sites like lymph nodes, bone etc. Since tissue is an issue in diagnosis and management of lung cancer, thus strategies to manage limited tissues have been developed:

      The pre-analytical steps involved in handling, fixing and processing these precious tissue samples are critically controlled to obtain accurate and meaningful biomarker tests.

      For molecular testing two block setting is used: One block for diagnostic immunostains and second block is reserved for molecular workup.

      Pathological analysis of NSCLC on small biopsies:

      Histological Sub-typing of NSCLC:The subtyping of NSCLC on small biopsies has poor inter-observer agreement. WHO 2015 classification recommends use of ancillary techniques like mucin histochemsitry and immunohistochemistry for cases that cannot be classified based on light microscopy and minimize the use of term NSCLC-NOS.1To refine separation of squamous from adenocarcinoma; use of one adenocarcinoma marker and one squamous marker is suggested to preserve tissue for further molecular testing.For adenocarcinoma, TTF-1, Keratin 7 and napsin and for squamous, P40, p63 and keratin5/6 are used. Cocktails of nuclear and cytoplasmic antibodies like, TTF1/CK5/6 and napsin/p63 are also available. For neuroendocrine tumours, the specific markers include; neuron-specific enolase, chromogranin, synaptophysin, and CD56. With the use of immunohistochemistry the NSCLC-NOS category has been reduced from 10% to 5% in our setup.2

      Morphological Patterns of Adenocarcinoma:The histologic patterns of adenocarcinoma described in WHO 2015 classification include; lepidic predominant, acinar predominant, papillary predominant, solid predominant and micropapillary predominant pattern. These histological patterns though described for resection specimens, should be reported on small biopsies as they provide prognostic information; Lepidic pattern is associated with favorable prognosis, acinar and papillary with intermediate prognosis whereas the solid and micropapillary patterns have poor prognosis.3

      Genetics for personalized medicine in lung cancer

      Epidermal Growth Factor Receptor gene (EGFR) mutation:Most common mutations in young Asian females and/or never smokers and involves exons 18-21 of EGFR gene, the encoding a portion of the tyrosine kinase domain. Ninety percent of EGFR mutations are exon 19 deletions or missense point mutation in L858P in exon 21. Additional mutations in EGFR (T790M in exon 20) as well as mutations in other genes such as MET have been responsible for resistance to EGFR inhibitors.

      Anaplastic Lymphoma Kinase (ALK) rearrangement:EML4-ALK translocation of the transcription activation domain of ALK and the dimerization domain of EML4, leads to interstitial inversion in the short arm of chromosome 2. EML4-ALK translocation is seen in 5-8% of adenocarcinomas and is detected by break apart FISH or by IHC (D5F3 clone on Ventana system).

      Overall incidence of EGFR mutations in our set up is 22.3% and for ALK re-arrangement is 9.5%.3,4

      ROS1 re-arrangement: Similar to ALK mutations, ROS1 re-arranged tumours respond to tyrosine kinase inhibitor therapyandaccounts for 1-2% of pulmonary adenocarcinomas. ROS1 expression is screened by immunohistochemistry (D4D6 clone from Cell signaling) and break-apart FISH confirms the positive cases.

      Rare genetic changes:Other rare mutations reported in lung cancer includes; HER2 mutations (1%); BRAF mutations (2%); RET and NTRK rearrangements reported in 1.9% and 0.9%, respectively

      Immunotherapy

      In addition to targetable mutations, immune checkpoint inhibitors have revolutionized the treatment of lung cancer. The programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have monoclonal antibodies directed towards them, which have shown promise with regards to overall survival in advanced NSCLC. PD-L1 expression status as assessed by immunohistochemistry is important in predicting response to PD-1/PD-L1 inhibitors. However, there are challenges in PD-L1 testing that includes; four different IHC clones on different staining platforms, due to limited tissue all assays cannot be performed, heterogeneity of staining and the need for standardization of interpretation and scoring criteria.

      Recent advances

      Since tissue is an issue in molecular testing of lung cancer, targeted next generation sequencing panels are available for testing all relevant molecular changes in one go. Oncomine Dx is one such panel for lung cancer that has got FDA approval. In absence of available tissue especially in setting of relapse, cell free DNA is an alternative for detecting molecular alterations.

      Conclusions

      The exact histological subtyping of NSCLC, thus reducing the ‘NOS’ rate, analysis of genetic alterations for targeted therapy and evaluation of targets for immune checkpoint inhibitors has significantly impacted the treatment and prognosis of lung cancer patients. Thus procurement of adequate tissue and its judicious use is of utmost importance. As the number of clinically significant targetable mutations and chromosomal rearrangements continues to grow, the next generation sequencing becomes the need of the day.

      References

      Travis WD, Brambilla E, Nicholson AG et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification.J Thorac Oncol 2015;10(9):1243 60.

      Kaur H, Sehgal IS, Bal A et al. Evolving epidemiology of lung cancer in India: Reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key. Indian J Cancer 2017;54:285-90.

      Maturu VN, Singh N, Bal A, et al. 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.

      Bal A, Singh N, Agarwal P et al. ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India.APMIS. 2016;124(10):832-8.

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      ES09.02 - How I Report Imaging for Assessment of Responses to Targeted Therapies vs. Immune Checkpoint Inhibitors vs. Chemotherapy (Now Available) (ID 3200)

      13:30 - 15:00  |  Presenting Author(s): Ritu R Gill

      • Abstract
      • Presentation
      • Slides

      Abstract

      How I Report Imaging for Assessment of Responses to Targeted Therapies vs. Immune Checkpoint Inhibitors vs. Chemotherapy

      Response assessment is an integral part of radiological reporting in tumor imaging. Our daily workflow includes diagnostic evalaution, determining resectability and response assessment. The radiology template and format is determined by the indication of the exam, and the clinical report may not include detail of all the lesions, but is a synopsis of the findings and an overview of the disease state and longitudinal change on the current therapy. In general our clinical reports do not have details related to detailed response categories and criteria. Response assessment is reported through a separate portal, which is generally overseen by the clinical trials office.

      Response to therapy is the primary endpoint in most Phase I and II clinical trials. The response criteria to be used and primary and secondary endpoints are detailed in the study protocols based on the type of drug being used. In the era of precision medicine, the traditional response criteria have been evaluated and modified to assess response in targeted and immune therapies. The immune response criteria were developed to follow delayed healing and pseudoprogression. This presentation will discuss details on how I assess response in the context of chemotherapy, targeted therapy and immunotherapy.

      Assessment of response to chemotherapy was performed using RECIST initially published in 2000 and revised in 2009(1,2). In the current practice RECIST 1.1 is used unless specified by the study protocol. The study protocol will detail the modality technique, duration and reporting criteria. In general the detailed protocol will prove information on the modality of choice. In traditional chemotherapy, the effect of cytotoxic drugs results in gross rumor reduction in most cases. Most trials require more than I independent reviewers, and may have an onsite review and a central review for confirmation of response.

      Targeted therapies require matching the right gene mutation to the right pharmaceutical agent, which improves the efficacy and the effectiveness of therapy. Response assessment is on similar lines as chemotherapy. However, response beyond RECIST progression may be allowed on investigator discretion, if the tumor is progressing very slowly and the subject is asymptomatic. In patients with EGFR-mutant NSCLC treated with EGFRTKI, continued EGFR-TKI therapy may be indicated in those patients with progressive disease as these tumors grow slowly over many months and some tumor cells may remain sensitive to EGFR-TKI (3). Erlotinib and crizotinib are commonly continued beyond RECIST progression, because of an initial dramatic response followed by slow progression over many months in relatively asymptomatic patients.

      Immunotherapy trials are assessed using immune response criteria (iRECIST), the main difference between iRECIST and RECIST, is that the patients are allowed to continue on therapy once disease progresses (PD) for another cycle is continued PD, to ensure it is not pseudoprogression(4). Response assessment in immune therapy trials, allows an extra cycle at 4 to 5 weeks after progression is documented before a decision is made to change therapy. Progression is confirmed at the following cycle or with pathology confirmation.

      Additional criteria from PETCT and MRI and CT using volumetric assessment is used in the research arena, but not yet used universally for clinical trials. Modified RECIST(5) is more appropriate for pleural tumors as it improves reproducibility of measurements across reviewers and time points. Volumetric assessment is thought to more representative of the morphological changes but definite cut offs as surrogate of the response need validation(6). MRI can assess both size and cellularity and function and hence MR based response assessment derived from apparent diffusion coefficient and pharmacokinetic parameters such as area under the curve, permeability coefficient and elimination coefficient can provide anatomical and functional response to therapy(7,8).

      It is vital to make a note of any atypical findings and also to recognize adverse events related to the drug and help with timely management. The presentation will detail how I assess response in the real world with case specific examples and illustration of some atypical responses and lesions that can mimic progression.

      slide1.jpg

      References:

      1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New Guidelines to Evaluate the Response to Treatment. J Natl Cancer Inst. 2000;92(3):205–16.

      2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

      3. Mok TSK. Living with imperfection. Journal of Clinical Oncology. 2010;28(2):191–2.

      4. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Vol. 18, The Lancet Oncology. 2017. p. e143–52.

      5. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004;15(2):257–60.

      6. Frauenfelder T, Tutic M, Weder W, Götti RP, Stahel RA, Seifert B, et al. Volumetry: An alternative to assess therapy response for malignant pleural mesothelioma? Eur Respir J. 2011;38(1):162–8.

      7. Ohno Y, Koyama H, Onishi Y, Takenaka D, Nogami M, Yoshikawa T, et al. Non–Small Cell Lung Cancer: Whole-Body MR Examination for M-Stage Assessment—Utility for Whole-Body Diffusion-weighted Imaging Compared with Integrated FDG PET/CT. Radiology. 2008;248(2):643–54.

      8. Giesel FL, Choyke PL, Mehndiratta A, Zechmann CM, von Tengg-Kobligk H, Kayser K, et al. Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34). Acad Radiol [Internet]. 2008 May [cited 2014 Oct 2];15(5):563–70.

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      ES09.03 - How I Decide 1st Line Treatment Options for Metastatic NSCLC Without Driver Mutations - Balancing Efficacy, Toxicity and Cost (Now Available) (ID 3201)

      13:30 - 15:00  |  Presenting Author(s): Martin NA Frueh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chemotherapy alone has been the accepted standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) for more than two decades based on trials demonstrating a survival benefit and improved quality of life. In the first line setting, the addition of the anti-VEGF antibody (AB) bevacizumab and anti-EGFR ABs cetuximab and necitumumab resulted in modest improvement of survival. Recently, immune-checkpoint inhibitors (ICI) have revolutionized systemic treatment approaches of patients with EGFR/ALK wild type NSCLC in the first and further line setting, mainly due to their ability to achieve long-term tumor control in a subset of patients. Although a considerable proportion of patients doesn`t respond to ICI, immunotherapy is now widely used in combination with chemotherapy as first line treatment in an increasing number of patients as a result of the absence of a reliable predictive biomarker. This situation leaves physicians in the dilemma of balancing the benefit of potential long term disease control in a limited number of patients with the harms which include not only toxicities but also costs. The implementation of novel ICI treatment options in the first line treatment of metastatic NSCLC into current clinical practise will be discussed.

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      ES09.04 - How I Decide 2nd Line Treatment Options for Relapsed/Refractory Metastatic NSCLC (Now Available) (ID 3202)

      13:30 - 15:00  |  Presenting Author(s): Navneet Singh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Management of advanced and metastatic non-small cell lung cancer (NSCLC) has been revolutionized in the past decade with the advent of testing for ‘druggable’ molecular driver alterations and availability of therapies for the same. More recently, immunotherapy (in particular PD-1/PD-L1 immune check point inhibitors) have opened up a fifth frontier for the treatment of this disease. However, barring exceptions, patients with advanced/metastatic NSCLC relapse irrespective of whether they received a targeted therapy or chemotherapy (with/without immunotherapy) or immuno(mono)therapy in the front line setting. This is understandable as cures are uncommon in metastatic disease although sustained and durable responses to immunotherapy and targeted therapies are well known. Treatment of relapsed disease presents a greater challenge as performance status, ability to bear cost of treatment and finally wishes of patients and caregivers often change as opposed to the treatment naïve state. Additional factors also come into play in low and middle income group countries (LMICs) and resource constrained settings.

      Practicing precision medicine remains the goal even for the relapsed setting. However, finding additional targets or drugs for identified secondary targets mandates rebiopsy which may be limited by ease of access to the desired site for rebiopsy as well as patients’ willingness to undergo the same. Liquid biopsy (typically blood and less commonly other body fluids) appears to be an increasingly promising alternative to conventional tissue biopsy with the availability of highly sensitive testing platforms (especially NGS) and the ability of the former to provide ‘global’ assessment of biomarker status as opposed to the latter. Tissue heterogeneity is more pronounced in the setting of relapsed disease as compared to treatment naïve settings.

      In case of EGFR mutated NSCLC, the advent of T790M inhibitors (osimertinib) was the preferred treatment approach for patients progressing on 1st/2nd generation EGFR TKIs and with a demonstrable exon 20 T790M mutation on either tissue or liquid biopsy (AURA trial). However, the FLAURA trial led to osimertinib moving to the frontline setting and therefore relapses on osimertinib is typically followed by chemotherapy unless specific mechanisms of resistance can be demonstrated which can be further targeted by available drugs. It is likely that 4th generation TKIs will be available for patients in the coming few years thus providing an opportunity to use another TKI following progression on osimertinib.

      For ALK rearranged NSCLC, there is a similar story. 2nd generation ALK inhibitors (alectinib, ceritinib and brigatinib) were developed and initially approved for patients intolerant to or having progressed on the 1st generation ALK inhibitor crizotinib. The ALEX/J-ALEX trials (for alectinib) and ASCEND-4 trial (for ceritinib) meant that these drugs moved to the front-line setting. In particular data from ASCEND-8 trial showed that 450 mg of ceritinib with a low-fat meal was as effective and better tolerated than the conventional 750 mg taken empty stomach. For resource constrained settings, this has an additional implication of lower cost of treatment. Lorlatinib, a 3rd generation ALK inhibitor, approved for use following progression on the 1st/2nd generation ALK inhibitors described above is also attempting to move to the frontline setting pending results of ongoing trials for this purpose.

      For both EGFR and ALK, the debate on using the best and most effective drug first vs. sequencing lower followed by higher generation drugs continues to be hotly debated as treatment options for progressors on 3rd generation TKIs given upfront are mostly limited to chemotherapy or experimental therapies as part of ongoing clinical trials.

      Platinum based doublet chemotherapy (pemetrexed based for non-squamous histology and gemcitabine/paclitaxel/nab-paclitaxel for squamous histology) was the cornerstone of treatment for patients without a targetable genetic alteration. Docetaxel single agent was the standard 2nd line treatment option and attempts were made to enhance its efficacy by combining it with VEGF inhibitors like ramucirumab (REVEL trial) or nintedanib (non-squamous only; LUME LUNG-1). Simultaneous time period saw the results of PD-1 inhibitors (nivolumab; CheckMate 017 and 057 and pembrolizumab; KEYNOTE 001 & 010) as well as PD-L1 inhibitor (atezolizumab; OAK) and thus these drugs become the preferred and standard 2nd line treatment. However, a similar story as for EGFR and ALK happened herein as well with the KEYNOTE 024 trial (pembrolizumab monotherapy for PD-L1 expression of 50% or higher) and KEYNOTE 189 and 407 trials (pembrolizumab combined with chemotherapy irrespective of PD-L1 expression) leading this drug to be part of front line treatment. Atezolizumab as part of a 4 drug regiment (paclitaxel-carboplatin-bevacizumab-atezolizumab) also appeared to provide similar efficacy in the front line setting (IMPOWER 150) for non-squamous NSCLC although concerns about toxicity remain. The effect of immunotherapy coming to the front line treatment setting (alone or in combination with chemotherapy) also implies that these drugs have no proven role in relapse as there is no data currently that patients treated initially with immune check point inhibitors benefit from the same class of drugs on relapse.

      Patients in LMICs and resource constrained settings tend to get treatment in more conventional ways than listed above as newer drugs and regimens are either not available or are not approved as fast as in the US/Europe or are very expensive. Hence it is fairly common for EGFR mutated patients to receive 1st generation EGFR TKIs, for ALK rearranged patients to receive crizotinib and for those without any driver mutations/rearrangements to receive only platinum doublet chemotherapy in the first line setting. This sort of represents a time lag compared to what is applicable in the US/Europe. The need to provide affordable yet effective treatment remains the primary aim of clinical oncologists in LMICs and precision medicine is therefore informally and practically adapted to the available resources.

      Navneet Singh MD DM

      Email: [email protected]; [email protected]

      [The author is a thoracic medical oncologist and pulmonologist currently working as an Additional Professor of Pulmonary Medicine at PGIMER, Chandigarh, India. He is a member of IASLC’s Staging & Prognostic Factors Committee; Publications and its Regent for South Asia. Additionally, he is Chair of American Society of Clinical Oncology’s(ASCO) International-Development-and-Education-Award(IDEA) Working Group and Thoracic-Cancer Guideline Advisory Group. His detailed profile is accessible at http://www.linkedin.com/in/navneet-singh-160012.]

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      ES09.05 - Limitations in the Availability of Radiotherapy (Now Available) (ID 3203)

      13:30 - 15:00  |  Presenting Author(s): Jamal Saleh Khader

      • Abstract
      • Presentation
      • Slides

      Abstract

      Limitations in the Availability of Radiotherapy

      Abstract

      The annual global incidence of cancer, according to Globocan 2018 report is 18 million new cancer cases, and the number is projected to rise in 2035 to 25 million cases (13 million deaths), with 70% occurring in low- and middle -income countries (LMICs), where there is a severe shortfall in the availability of radiotherapy (1). Radiotherapy is an essential component of overall curative and palliative cancer care. It is estimated that about half of cancer patients would benefit from radiotherapy for treatment of localized disease, local control, and palliation (2). Yet, this crucial component of the response to cancer has been largely absent from global health discourse, and has received limited domestic and international funding. As a result, there is a worldwide shortfall of radiotherapy services; with more than 90% of the population in low-income countries, lacking access to radiotherapy(2). The growing burden of cancer will place increased demand on the already-scarce radiotherapy services worldwide. A 2015 report by the Global Task Force on Radiotherapy for Cancer Control estimated that by 2035 at least 5000 additional megavolt treatment machines would be needed to meet LMIC demands, together with about 30 000 radiation oncologists, 22 000 medical physicists and 80 000 radiation therapy technologists(3).

      Many of the challenges in delivering radiotherapy in LMICs that were identified including: (a) a shortage of good-quality radiotherapy equipment capable of both simple and more complex radiotherapy treatment delivery, (b) the challenge of servicing the linacs, both for preventative maintenance and upon equipment breakdown and (c) the chronic shortage of adequately trained personnel(3). In LMICs, the costs of equipment, building and salaries are 81, 9 and 10% of the total cost of the facility, respectively, compared with 30, 6 and 64% in high-income countries. Some of the challenges facing LMICs are also related radiofrequency power systems, linac beam production and control, durable and sustainable power supplies, computer applications in radiation therapy & linac safety and operability(4). Investment in radiotherapy is crucial and an imperative in low-income and middle-income countries, if unnecessary cancer deaths and suffering are to be avoided. Investment in radiotherapy is timely for many reasons, including evidence from The Lancet Commission on Investing in Health (5) showing the benefits of investing in health to achieve convergence in health outcomes between low-income countries and upper-middle-income countries, the momentum for investing in low-income and middle-income countries to expand surgery,(6) and the UN resolution on sustainable development, which recognises that “universal health coverage is a key instrument to enhancing health, social cohesion and sustainable human and economic development”.(7)

      Conclusion

      It is a call for action to enhance population-based cancer control plans, expansion of access to radiotherapy, human resources for radiotherapy, sustainable financing to expand access to radiotherapy and align radiotherapy access with universal health coverage.

      References

      1.Freddie B et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.

      CA CANCER J CLIN 2018;68:394–424

      2.Barton MB et al. Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012. Radiother Oncol 2014; 112: 140–44.

      3.Atun R, et al. Expanding global access to radiotherapy. Lancet Oncol 2015;16(10):1153e1186

      4. Dosanjh M et al. Developing Innovative,Robust and Affordable Medical Linear

      Accelerators for Challenging Environments, Clin Oncol , 2019 Jun; 31(6):352-355

      5.Jamison DT et al. Global health 2035: A world converging within a generation.

      Lancet 2013; 382: 1898–955.

      6. Meara JG et al. Global Surgery 2030: evidence and solutions for achieving health,

      welfare, and economic development. Lancet 2015; 386: 569–624.

      7. UN. Sustainable development, the Future We Want, UN General Assembly

      Resolution, A/66/L.56, para 138–141. http://www.uncsd2012.org/content/documents/

      (accessed July 5, 2015).

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Author of

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    P2.11 - Screening and Early Detection (ID 178)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.11-10 - Discovery of Potential Biomarkers That Discriminate Early Stage NSCLC from Controls by Non-Targeted Metabolomics Profiling (ID 1857)

      10:15 - 18:15  |  Author(s): David Dawe

      • Abstract

      Background

      Detection of NSCLC at the early stage is a potential means to reduce mortality and morbidity of lung cancer. Development of an accurate, non-invasive, economical, and safe test to detect early stage NSCLC remains a challenge. We explored metabolomics profiling of plasma to discriminate early stage NSCLC cases from Cancer-Free Controls (CFC).

      Method

      Frozen plasma samples collected from 2004 to 2014 from 250 patients with clinical early stage NSCLC (drawn prior to surgical resection) and 250 CFCs were obtained from a provincial biorepository. Samples were thawed, extracted, and analyzed in duplicate by blinded laboratory personnel using non-targeted Ultra High Performance Liquid Chromatography/Quadrupole Time-Of-Flight Mass Spectrometry (UHPLC-QTOF-MS). Individual metabolic entities were identified and quantified using Mass Profiler Professional Software (Agilent Technologies, CA, USA). Analysis was restricted to known human metabolites identified by the Metlin and Human Metabolome databases. Candidate metabolites quantified in less than 20% of samples were dropped; missing values were replaced with one-half of the smallest measurement for each metabolite. Final candidate metabolites were screened for differential abundance (DA) between NSCLC cases and CFCs using: (1) False discovery rate (FDR)-adjusted p-values less than 1% after controlling for age, sex and smoking status in linear regression; (2) <1% change in DA due to covariates; (3) up-regulation in NSCLC.

      Result

      Of the 250 NSCLC Cases, 185 (74%) had adenocarcinoma, 65 (26%) had Squamous Cell Carcinoma; 204 (81.6%) had pathological Stage I/II disease (AJCC 7th ed) and 46 (18.4%) had stage III/IV disease. Median age was 70 (range 46-88) in NSCLC cases and 56 (20-89) in CFCs (p<0.001), and NSCLC cases had more males compared to CFCs (46.4% vs 31.2%, p <0.001). NSCLC patients had a higher proportion of current (27.2% vs 6%) or ex-smokers (64.8% vs 20.8%) compared to CFCs (p<0.001).

      A total of 1,209 known human metabolites were detected using UHPLC-QTOF-MS technique, of which 676 were present in a minimum of 80% of all samples and were used for modeling. Table 1 lists candidate metabolomics biomarkers strongly upregulated in NSCLC cases versus CFCs which were unaffected by covariates of age, sex, and smoking. A multiple logistic regression model using the top 3 metabolites correctly classified NSCLC case from CFC with an overall accuracy of 93.6% and an area under the curve of 0.975.

      table 1 snippet no compression.png

      Conclusion

      Metabolomics profiling of plasma represents a potential means to distinguish NSCLC cases from CFCs. Further targeted metabolomics analyses of specific classes of metabolites in larger cohorts are warranted.