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Alan Spatz



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    MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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      MA09.09 - EBUS-TBNA in Assessing PD-L1 Expression in NSCLC (ID 13471)

      16:15 - 16:20  |  Author(s): Alan Spatz

      • Abstract
      • Presentation
      • Slides

      Background


      Pembrolizumab is the only immunotherapy approved as a first line agent for metastatic NSCLC in patients with high programmed death‐ligand 1 (PD‐L1) expression. The standard samples for PD-L1 testing are considered surgical or core biopsies. In this study, our primary objective is to identify the adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) tumor samples in detecting PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between July 2016 and April 2017 a total of 1352 consecutive cases of non-small cell lung cancer (NSCLC) were identified. 29 specimens were deemed inadequate (less than 100 viable tumor cells) and were excluded. 1323 specimens analyzed included surgical samples (N=238), small biopsy (N=744) and cytology cell blocks (N=341). Cytology cell blocks were from EBUS-TBNA (N=190), fine needle aspiration (FNA) (N=61) and pleural/pericardial fluid (N=90). PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1-49% and ≥ 50% tumor cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Most of the 1323 specimens (84%) were non-squamous carcinomas. Overall yield for TPS > 50% was 36%. Rate of PD-L1 positivity was no different in non-squamous (37%) compared to squamous (32%). Diagnostic yield of PD-L1 for different sample types varied substantially (Table 1). The EBUS-TBNA samples had the highest yield for TPS ≥ 50% (p=0.025).

      TPS Surgical resection Small biopsy EBUS-TBNA FNA Fluid cytology Total
      Adequacy 100% 99% 98% 96% 92% 98%
      ≥ 50% 69 (29) 269 (36) 84 (44) 21 (34) 38 (42) 481
      1-49% 87 (37) 274 (37) 57 (30) 22 (36) 22 (24) 462
      <1% 82 (35) 201 (27) 49 (26) 18 (30) 30 (33) 380
      Total 238 744 190 61 90 1323
      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that cytology cell blocks could be considered as a valuable resource for PD-L1 testing in advanced NSCLC. Future studies are warranted to explore clinical correlation of PD-L1 on EBUS-TBNA samples and immunotherapy outcome.

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.09 - Differential Gene Expression in Tumor and Normal Tissue Reveals New Insights in the Biology of Non-Small Cell Lung Carcinoma. (ID 13341)

      16:15 - 16:20  |  Presenting Author(s): Alan Spatz

      • Abstract
      • Presentation
      • Slides

      Background

      Effective use of targeted cancer therapies typically depends upon the identification of actionable genomics somatic alterations, benefiting only a minority of Non-Small Cell Lung Carcinoma (NSCLC) patients. To integrate transcriptomic assessment in cancer precision medicine, we have evaluated the mRNA expression levels in tumors and their matched normal lung tissues with the hypothesis that mRNA quantification in tumors relative to their matched normal tissue may better reveal small transcriptional differences that are associated with major biological effects.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The discovery set used 123 frozen macrodissected treament-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Mutualiste Montsouris Institute (Paris, France), and the validation set used 143 FFPE macrodissected treatment-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Jewish General Hospital (Montreal, QC, Canada). A pathology review was performed in all cases. In the discovery set, expression levels of 17,318 genes were analysed using an Agilent Technologies platform; in the validation set, the NanoString nCoutner technology was used with a customized 148 probeset that was designed according to the results of the discovery phase. The primary objective of the study was post-surgery progression-free survival (PFS). The secondary objectives were post-surgery overall survival (OS) and the identification of pathway-driven expression signatures.

      4c3880bb027f159e801041b1021e88e8 Result

      A set of highly expressed genes correlated with post-surgery PFS. Details of the prognostic signature will be presented at the meeting. Importantly, mRNA levels in normal tissues were highly variable between individuals. Organ matched reference enabled to control for the noise signals related to individual background genetic variability. The cell cycle G2/M checkpoint was the most significantly deregulated expression pathway in this cohort; nine genes in the signature are involved in this pathway and were upregulated in tumors, dependending on their histology: CHEK1, TOP2A, AURKA, CDC2, PLK1, CDC2, CDC25A, CDC25B, and CDC25C. CHEK1 is a pivotal gene in regulating the G2/M cell cycle pathway that triggers the double-strand base excision repair in which the main effector is PARP1. CHEK1 was overexpressed in 86% of adenocarcinomas, versus 42% for PARP1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conventional transcriptomic approaches using expression metrics obtained in tumor pools may miss important changes due to individual variability in non-tumoral tissue.The present work illustrates that paired matched tumor and normal tissues can identify new key genes involved in the biology and pathogenesis of NSCLC, and opens new avenues for integrating transcriptomic investigations in the precision medicine arena.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.09-08 - Integrating NGS Information for Staging Multiple Lung Adenocarcinoma: A McGill University Health Centre Retrospective Study. (ID 12635)

      16:45 - 18:00  |  Author(s): Alan Spatz

      • Abstract
      • Slides

      Background

      The incidence of patients with multiple primary lung adenocarcinoma (MPLC) is increasing and the optimal management of these patients remains unclear. Distinguishing between MPLC and intrapulmonary metastases is at the heart of the diagnostic dilemma. The Comprehensive Histologic Assessment (CHA) relies on microscopic examination including histological subtypes, cytological and stromal features. CHA has shown a good reproducibility but with a non-negligible rate of disagreement, even between expert pathologists. Moreover, predictive biomarker testing has become standard of care for lung cancer patients and the use of Next-Generation Sequencing (NGS) is now widely available. The goal of this study was to evaluate how the NGS information may be integrated in the diagnostic strategy for distinguishing between MPLC and patients with stage III/IV disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective study of all surgical patients with > 1 synchronous lung carcinoma over two years. We identified 59 cases and reviewed initial clinical, pathological and molecular reports. Patients having multifocal lung adenocarcinoma with prominent lepidic component or an adenocarcinoma associated with another histological type were considered as synchronous primaries and not tested for molecular aberrations. The NGS panel analysis using an Illumina miSeq platform included the following genes: AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3A, RET, and TP53.

      4c3880bb027f159e801041b1021e88e8 Result

      Histologically, the majority were considered as MPLC with only four suspected metastases. Twenty-five patients had adenocarcinoma with prominent lepidic component and one case had two different histological differentiations (adenocarcinoma and squamous cell carcinoma). Most of the suspected synchronous primary tumours had different mutations in the separate tumours. Relevant mutations were found in KRAS and P53 genes, with fewer mutations in EGFR, PIK3CA and BRAF genes, in accordance with known frequencies. In 12% of the cases, the NGS was not informative with no molecular mutation in either tumours. One case was reclassified from MPLC to intra-pulmonary metastases and restaged after NGS. For one patient, a TP53 mutation allowed us to reclassify two nodules as metastases from a previous adenocarcinoma originally diagnosed in 2012. In one patient having three separate nodules, different KRAS and TP53 mutations allowed the diagnosis of two nodules as intrapulmonary metastases and one contralateral nodule as synchronous primary adenocarcinoma.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although CHA is an efficient method for diagnosing MPLC from intra-pulmonary metastases there are still difficult cases with a risk of misdiagnosis. Integrating NGS analysis in the diagnostic strategy may lead to improved quality and accuracy in the staging of MPLC.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-04 - Reducing Time to Molecular Diagnosis for Advanced NSCLC in the Context of a Reference Testing Center (ID 13972)

      16:45 - 18:00  |  Author(s): Alan Spatz

      • Abstract
      • Slides

      Background

      Testing for mutation of the epidermal growth factor receptor (EGFR) gene is required for treatment of patients with advanced non-small cell lung cancer (NSCLC). First-line treatment with an EGFR tyrosine kinase inhibitor (TKI) in NSCLC patients with an activating EGFR mutation significantly impacts survival. Within the Rossy Cancer Network, the McGill University Health Centre (MUHC) has a supra-regional designation to perform all thoracic surgeries, while the Jewish General Hospital (JGH) is the reference testing center for specialized molecular pathology services. Significant differences in time to TKI therapy were noted between these centers. Our objective was to identify contributing factors to reduce network-wide delays.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We used the JGH molecular pathology database to identify all specimens tested for EGFR between 2015 and 2016 and mapped the process steps from diagnostic procedure to start of TKI therapy. We identified process differences and initiated reflex testing at the MUHC; EGFR testing was ordered reflexively by pathologists for all non-squamous NSCLC biopsies and other specimens from known or suspected advanced stage NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Implementation of reflex testing led to a 13-day reduction from pathology report to EGFR request (Figure 1, BàC). We subsequently identified that MUHC time from molecular results to start of TKI therapy was twice that of the JGH (24 vs 12 mean days). This was due to an additional step requiring integration of faxed molecular results into the patients’ electronic health record.

      process map for egfr testing.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      We applied lean strategies to reduce time to initiation of targeted therapy. Within our network and in the context of a reference testing center, we identified two critical components that significantly contributed to delays in treatment planning: (i) absence of reflex testing and (ii) unlinked information technology systems. As Quebec moves towards specialized testing centers, it is important to be cognisant of their impact on timely treatment.

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    P2.09 - Pathology (Not CME Accredited Session) (ID 958)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.09-07 - Does Metastatic Site Matter for PD-L1 Testing in Stage IV NSCLC? (ID 13385)

      16:45 - 18:00  |  Author(s): Alan Spatz

      • Abstract
      • Slides

      Background

      Stage IV non-small cell lung cancer (NSCLC) often presents with metastasis to multiple distant sites. Currently PD-L1 expression by immunohistochemistry (IHC) testing with Tumor Proportion Score (TPS) ≥ 50% and ≥1% is required for first- and second-line Pembrolizumab treatment respectively. However, it is not well known if PD-L1 expression differs in NSCLC specimens sampled from different distant metastatic sites. In this study, we evaluate PD-L1 expression in distant metastatic sites.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 400 NSCLC specimens from distant metastatic sites are included in this study. The metastatic sites include brain, bone, non-regional lymph nodes, serous membranes (pleura, pericardium and peritoneum) and organs outside the chest (liver, adrenal gland, skin, soft tissue). The samples are either cytology cell blocks, small biopsies or surgical resections. IHC was performed using Dako PD-L1 IHC 22C3 pharmDx. A total of 100 viable tumor cells is required for adequacy. TPS≥ 50% and 1-49% are defined as high and low PD-L1 expression respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, the rate of TPS >50% ranges from 36-47% in different metastatic organ sites (Table 1). The prevalence of PD-L1 high and low expression is similar for all distant metastatic sites (P=0.91). Brain metastases have a slightly lower rate of high PD-L1 expression but the difference is not statistically significant.

      Table 1. PD-L1 expression in different metastatic sites

      Metastatic sites

      Tumor Proportion Score (TPS)

      Total

       

      ≥50%

      n (%)

      1-49%

      n (%)

      0%

      n (%)

      n (%)

      Brain

      13(36%)

      9 (25%)

      14(39%)

      36 (100%)

      Bone

      21(44%)

      11(23%)

      16(33%)

      48 (100%)

      Nonregional lymph nodes

      6(40%)

      3(20%)

      6 (40%)

      15 (100%)

      Serous membranes

      91(40%)

      62(27%)

      74(33%)

      227 (100%)

      Organ outside chest

      35(47%)

      20(27%)

      19(26%)

      74 (100%)

      Total

      166(42%)

      105(26%)

      129(32%)

      400 (100%)

      P=0.91

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that the specimens for PD-L1 IHC testing can be sampled from any accessible distant metastatic site.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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