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Alain Borczuk



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    GR03 - Problem Areas for the Next WHO Classification of Lung Cancers (ID 31)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      GR03.03 - Pleomorphic Carcinomas (Now Available) (ID 3311)

      15:45 - 17:15  |  Presenting Author(s): Alain Borczuk

      • Abstract
      • Presentation
      • Slides

      Abstract

      The category of sarcomatoid carcinoma in lung cancer classification is composed of five tumor types - pleomorphic, spindle, giant cell, carcinosarcoma and blastoma. While these are all relatively rare tumors, the pleomorphic carcinoma category is the most common of this group. Pleomorphic carcinomas are defined as combinations of adenocarcinoma, squamous carcinoma or large cell carcinoma with a spindle or giant cell element. It may be that spindle or giant cell examples, while diagnostically more challenging, represent variants of similar histogenesis but with complete mesenchymal transformation. Small cell carcinoma in a pleomorphic carcinoma is exceedingly rare. These tumors are often bulky tumors at presentation, with a propensity for central necrosis. Historically, this tumor is highly aggressive and treatment refractory.

      The histology of this tumor type includes correct identification of a malignant spindle component morphologically, or a giant cell component. While nuclear pleomorphism is an aspect of the tumor, the degree of nuclear enlargement, multinucleation and the presence of emperipolesis all distinguish giant cells of pleomorphic carcinoma from nuclear enlargement in high grade tumors. Immunohistochemistry has be helpful in identifiable a cytokeratin positive spindle or giant cell component. The use of zinc finger E-box binding homeobox1 (ZEB1), a protein involved in epithelial-mesenchymal transition to identify spindle or giant cell component of these tumors, both in small samples and resections, is emerging.

      Molecular alterations have also been linked to pleomorphic carcinomas. The tumors harbor mutations in KRAS as well as a higher rate of MET exon 14 skipping mutations. This is generally confined to cases with an adenocarcinoma component. TP53 mutations are also frequent. The molecular mechanisms of pleomorphic carcinoma with a squamous only epithelial component remain to be characterized.

      It has been proposed that MET exon 14 mutations may be targetable using agents such as crizotinib. In addition, these tumors show an elevated rate of high positive PDL1 immunoreactivity which may offer immunotherapy option in these patients.

      The relationship between large cell carcinoma and new entities such as SMARCA4 deficient carcinoma/sarcoma and the category of sarcomatoid carcinoma remains unclear. Greater elucidation of the molecular underpinning of sarcomatoid carcinoma categories may help clarify the place for these entities within the classification of lung cancer.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-92 - Neoadjuvant Durvalumab With or Without Sub-Ablative Stereotactic Radiotherapy (SBRT) in Patients with Resectable NSCLC (NCT02904954) (ID 2945)

      10:15 - 18:15  |  Author(s): Alain Borczuk

      • Abstract

      Background

      Preclinical evidence suggests that sub-ablative doses of radiation may have immunomodulating properties and may result in potent local and systemic anti-tumor immune-responses when combined with immune checkpoint-inhibitors (ICIs). Here we report the preliminary results of an ongoing phase-II trial of neoadjuvant therapy (NT) with Durvalumab alone or SBRT+Durvalumab followed by adjuvant Durvalumab for 12-months.

      Method

      Eligible patients were randomized to 2-cycles of Durvalumab (Arm-1) or 3 consecutive doses of SBRT(8GX3) plus 2-cycles of Durvalumab (Arm-2). Surgery was planned 1-2 weeks after last cycle of Durvalumab. Primary endpoint was DFS for both arms versus historical controls. Secondary endpoints were safety and efficacy determined by clinical/pathological response rates. We compared tumor immunephenotype (IP) in pre- and post-treatment samples by XCell deconvolution of RNAseq transcriptomic data.

      Result

      34 patients were randomized (1/1/17-1/11/19,). Patients in Arm-2 were more frequently ever-smokers and had more PD-L1+ve tumors (Table). All patients completed NT. Grade 3/4 adverse events (AEs) occurred in 4 patients after NT (3 in Arm-1, 1 in Arm-2). One patient (Arm-1) died preoperatively from an unrelated stroke. 32 patients were surgically explored and 30 resected (28R-0:87%). There were no perioperative deaths. Grade 3/4 perioperative AEs occurred in 10/32 patients (31%). In Arm-2, 8/17 (47%) patients had a major pathologic response (MPR: £10% residual tumor) compared to none in Arm-1. Excluding 4 patients with EGFR mutations, MPR occurred in 8/13(61.5%) patients in Arm-2. Relative to Durvalumab alone, SBRT+Durvalumab was associated higher abundance of dendritic cells, myeloid cells and fibroblasts. In Arm-2, tumors with MPR had a higher immunoscore and greater abundance of dendritic cells and higher HLA gene expression.

      Conclusion

      In this randomized-trial, neoadjuvant Durvalumab with or without SBRT was well tolerated. The rates of MPR after SBRT+Durvalumab are promising and suggest that sub-ablative doses of radiation may significantly enhance local immune response.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)

      10:15 - 18:15  |  Author(s): Alain Borczuk

      • Abstract
      • Slides

      Background

      PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.

      Method

      The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).

      Result

      344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.

      Conclusion

      There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.

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