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C.O. Lara-Torres

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    ED 11 - Extending Personalized Treatment Beyond EGFR (ID 11)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Community Practice
    • Presentations: 1
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      ED11.02 - Communicating with Pathologists About Molecular Testing (ID 1815)

      14:15 - 15:45  |  Author(s): C.O. Lara-Torres

      • Abstract
      • Presentation

      Technologic and scientific development in medicine and the biomedical sciences has led to almost immediate transfer of knowledge and methodology applied initially in the research lab to the clinic, producing a profound impact in screening, diagnosis and treatment. These enormous amount of information and specialized skills in the medical practice have made it necessary to integrate multidisciplinary teams to improve quality of cancer care.Lung cancer is the most common neoplasia worldwide as well as the leading cause of cancer-related death, with more than 50% of patients presenting with stage IV disease at diagnosis (1). Therefore, lung cancer management usually requires the collaboration of surgeons, medical oncologists, radiation oncologists, pathologists, nurses, and other health care professionals (2). Given the fact that many patients will present with locally advanced or metastatic disease, only small amounts of tissue or cell preparations will be available for morphologic analysis, immunohistochemistry and molecular testing. Recommendations from academic centers and agencies are in favor of limiting the amount of immunohistochemical stains in order to save tissue for molecular assays, stressing the need to integrate pathologist to multidisciplinary teams, where clinical information is exchanged, and specific differential diagnosis and objectives established in a case-to-case basis (3). The traditional role of pathologist in lung cancer has been to establish histological diagnosis of malignancy, as well as proper taxonomic allocation according to widely accepted classification schemes. (4) This approach sets pathologist within single moment interventions early in the course of patient management, aside from opportunities to collaborate during the rest of care. However, the advent of personalized medicine, characterized by the identification of biological features in cells that predict benefit from specific targeted drugs, opened up the way for pathologist to actively participate with the team in the selection of treatment and patient follow-up. Overall, from 60-70% of NSCLC have specific mutations of well characterized oncogenic drivers, some of them with 1st line treatment drugs and many with targeted therapies under development. Current guidelines of advance stage disease recommend initial characterization of EGFR mutation status and ALK rearrangement, although there is building evidence to support testing of a number of actionable genes such as HER2, BRAF, MET, RET, ROS1, or other biomarkers with predictive capacity such as microsatellite instability (5). Multiple methods and technological platforms have been developed to identify gene mutations, and although most of them have very high specificity values, the sensitivity to detect a mutant clone from a background of wild type DNA is wide. Conventional Sanger sequencing will identify a mutation if it is present in 10-20% of the sampled cells, pyrosequencing increases the level to 1%, mutant-enriched polymerase chain reaction (PNA-LNA PCR, ARMS, etc.) can detect a mutant gene among as many as 10[3] wild-type alleles (0.1-1%) with comparative performance to next generation sequencing(6). These differences in analytical sensitivity do not only affect the number of EGFR mutated cases identified, but may also impact the clinical results obtained when using TKI therapy. For example, studies suggest that high EGFR mutation allele burden at diagnosis may be associated with increased progression-free survival and overall survival in patients treated with tyrosine kinase inhibitors, based in sensitivity differences between conventional sequencing and allele-specific PCR(7,8). In the light of these challenges, pathologist face the need to secure tissue availability and adequacy for testing in order to increase the diagnostic yield of molecular characterization. This demands the establishment of changes in sample management and processing, depending on the biological material to be tested. For example, rapid on-site evaluation may be performed in cytological specimens from fine needle aspirates. In the case of CT-guided transthoracic biopsies, one initial core may be submitted for frozen section or studied with cytological imprints to assess tumor viability. If proper cellular material is identified, this core may be entirely used for molecular testing and subsequent cores destined for histological processing. Once the tissue is paraffin-blocked, the tissue cuttings product of facing the block may be saved in a sterile, DNAase/RNAase-free tube for later use if necessary. It is established that patients will ultimately develop resistance to targeted therapies through different mechanisms, either the emergence of mutations in the target gene or the acquisition of mutations or over-expression of oncogenes that overcome this inhibition. Studies have proved that at tumor progression, a number of cases may have a morphological switch from adenocarcinoma to sarcomatoid carcinoma or small-cell carcinoma (9), requiring therapy adjustments. Re-biopsy allows molecular evaluation as well as morphologic analysis, however; it is an invasive procedure that not all patients may undergo. Alternative highly sensitive molecular methods may be used for patient follow-up without the need of invasive interventions. Blood sample-based PCR or NGS can detect circulating free DNA from the tumour (liquid biopsy), the concordance rate between tissue and plasma for EGFR mutation going from 58.3% to 93.1%, stressing the need of analytical improvement. Of especial interest is the fact that when examining the appearance of the T790M mutation in serial blood samples, this mutation could be detected in the plasma DNA before clinically evident disease progression. (10) NSCLC diagnostics is rapidly changing to combine a dual morphologic-molecular approach, where initial HE-slide examination is used to confirm malignancy and to allocate the tissue sample to a group of molecular test relevant to the cellular composition of the tumour. Continuous increase in the number of genes responsible of oncogenesis in lung carcinoma ensures the development of new targeted drugs as well as active communication from all the members of the multidisciplinary team. References 1) Aisner DL, Marshall CB. Molecular pathology of non-small cell lung cancer: a practical guide.Am J Clin Pathol. 2012 Sep;138(3):332-46. 2) Pan CC, Kung PT, et al. Effects of Multidisciplinary team care on the survival of patients with different stages of Non-Small Cell Lung Cancer: A National Cohort study. PLoS One. 2015 May 12;10(5):e0126547. 3) Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137:828-860, 2013 4) Cagle PT, Myers J.Precision medicine for lung cancer: role of the surgical pathologist. Arch Pathol Lab Med. 2012 Oct;136(10):1186-9. 5) Dacic S, Nikiforova MN.Present and future molecular testing of lung carcinoma. Adv Anat Pathol. 2014 Mar;21(2):94-9. 6) Young EC, Owens MM, Adebiyi I, et al. A comparison of methods for EGFR mutation testing in non-small cell lung cancer. Diagn Mol Pathol. 2013 Dec;22(4):190-5. 7) Kim HS, Sung JS, Yang SJ. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One. 2013 Dec 20;8(12):e81975. 8) Zhou Q, Zhang XC, Chen ZH. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 20;29(24):3316-21. 9) Sequist LV, Waltman BA, Dias-Santagata D. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. 10) Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer. 2014 Dec 15;120(24):3896-901.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-028 - Defining the Molecular Profile of Non-Small Cell Lung Carcinoma in a Comprehensive Cancer Center in Mexico City (ID 868)

      09:30 - 17:00  |  Author(s): C.O. Lara-Torres

      • Abstract
      • Slides

      Molecular characterization of lung cancer is of paramount importance. Although genetic drivers such as EGFR,KRAS and ALK mutation are routine, they represent 30-40% of all mutations identified. The relative frequency vary according to the population studied and scarce data exist on Mexican population. The aim of the study is to describe the clinicopathologic characteristics and molecular profile of the population of NSCLC patients studied in a recent molecular pathology laboratory.

      Cases diagnosed with NSCLC from January 2012 to March 2015 seen at the department of surgical and molecular pathology of TheAmerican-BritishCowdrayMedical Center in Mexico City were retrieved. Medical records were reviewed for data on clinicopathologic characteristics (age, sex, biopsy site, histological parameters, and mutational status of EGFR, KRAS and ALK. DNA extraction was done using QIAampDNAFFPE Tissue Kit(Qiagen). EGFR and KRAS determination was performed using scorpion-ARMS technique(Therascreen/Qiagen) in Rotor-GeneQThermalcycler(Qiagen). ALK rearrangement was determined using ALK-LSI probes(Abbott Molecular), and evaluated with OlympusBX53 fluorescence microscope. All the procedures were carried out according to manufacturer instructions.

      90 cases were retrieved, 77(85.6%) adenocarcinoma, 6(6.7%) squamous cell carcinoma, 3(3.3%)large cell carcinoma and 4(4.4%) mixed cells types (2 adenosquamous carcinoma, 1 adenocarcinoma with neuroendocrine component, and 1 sarcomatoid carcinoma). Histologic subclassification showed predominant acinar in 56%, solid 20%, lepidic 15%, and 9% micropapillary pattern. Lung biopsies were the tissue specimen in 58 cases(64.4), metastatic site in 28(31.1)(lymph node 9, bone 8, pleura 3, skin 2, soft tissue 2, mediastinal tumor 1, ovary 1, parotid 1 and CNS 1), and non-specified 4(4.5%). Demographic variables and mutational status of EGFR/KRAS/ALK are shown in table 1. Figure 1 Figure 2

      We corroborate in our population the higher frequency of EGFR mutation in female patients, with a percentage between Caucasian and Asian populations. KRAS is the most frequent mutation and mutually exclusive with EGFR and ALK. Triple negative cases represent half of NSCLC.

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