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Adam Januszewski



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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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      MA21.03 - Heterogeneity in MET Copy Number and Intratumoural Subsets in Pleomorphic Lung Carcinoma: Implications for MET Directed Therapy in NSCLC (ID 13061)

      15:25 - 15:30  |  Presenting Author(s): Adam Januszewski

      • Abstract
      • Presentation
      • Slides

      Background

      Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. Both epithelial and sarcomatoid phenotypes exist, suggesting an important role of epithelial-to-mesenchymal transition. We aimed to determine MET copy number (CN) within individual tumour components and establish its correlation with immunohistochemistry (IHC) expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathological assessment and diagnosis was confirmed for 57 cases of resected PCs from the Royal Brompton Hospital Biobank. DNA was isolated from multiple regions and MET copy number determined by digital droplet PCR (ddPCR). IHC using c-MET (EP1454Y) and H-scores were assigned independently by two histopathologists.

      4c3880bb027f159e801041b1021e88e8 Result

      Cases: median age 66 years, 36.2% T3, 41.4% T2 and 13.8% T1. In the epithelial areas, adenocarcinoma was the most common (45.6%) followed by undifferentiated NSCLC (22.8%) and squamous (17.5%): in pleomorphic areas, mixed giant/spindle cell (35%), spindle cell (31%) and giant cell (26%). MET-CN gain by ddPCR was seen in 25/58 (44%) of cases (CN>2.3). 3/58 (5%) had CN>5. There was a significantly higher MET-CN in pleomorphic compared to epithelial areas (2.7 versus 2.2 P = 0.046). While this did not correlate with c-MET IHC, an H-score of >223 had 75% sensitivity and 52.4% specificity for MET-CN >5.0 (Figure).

      met expression in pc2.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is intra-tumoral heterogeneity in MET-CN between tumoural subsets. This may account for the development of pleomorphic phenotypes in PC. Consequently MET-directed therapies such as crizotinib may be highly effective only against the MET-amplified component in PC and may not impact on overall tumoural control due to minimal efficacy in the non-amplified epithelial component. MET expression using IHC does not correlate with MET-CN determined by ddPCR, although may provide a screening tool for MET amplification. MET aberrations are potentially druggable and therefore this has implications for sampling and MET testing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-17 - Multicentre Phase II Trial of First-Line Afatinib in Patients with Suspected/Confirmed EGFR Mutant NSCLC: ctDNA & Long-Term Efficacy (ID 11908)

      16:45 - 18:00  |  Presenting Author(s): Adam Januszewski

      • Abstract
      • Slides

      Background

      Efficacy of afatinib in EGFR mutant patients with comorbidities or those with suspected EGFR mutations unfit for chemotherapy is poorly explored. We evaluated afatinib in this population, with serial plasma ctDNA to investigate the role of molecular EGFR genotyping and monitoring.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Phase-II trial enrolled NSCLC patients with comorbidities precluding chemotherapy, and either (i) EGFR-mutation, PS 0-3, or (ii) suspected EGFR-mutation (tissue unavailable/failed genotyping), never/former-light smoker, adenocarcinoma, and PS 0-2. Afatinib (40mg daily) given until progression/toxicity. Blood samples obtained at baseline and 12-weekly until discontinuation; plasma ctDNA performed using InVisionSeq™ (amplicon-based NGS).

      4c3880bb027f159e801041b1021e88e8 Result

      39 patients recruited (14 UK centres). Median age 72 years; 27 PS 0-1/12 PS 2-3. 21 patients (54%) had known tissue EGFR-mutations. Additional 8 patients with unknown tissue status (8/17;47%), were ctDNA EGFR-mutant, making 74% EGFR-mutant in total (29/39). Combined tissue and ctDNA data identified 21 patients with common mutations (exon 19/L858R), 8 with rare mutations (exon 18/20), and 10 suspected only. Corresponding median PFS of these cohorts were 10.2/3.9/5.3 months, with 6-month PFS of 71/38/50% all exceeding the 30% target; median OS were 24.8/5.7/11.4 months (p<0.001). Therefore, all patient groups benefitted; known EGFR-mutants having best outcomes. In April 2018, 5/39 patients survived >36 months, including 4/39 progression-free (median follow-up 33 months, maximum 55). Patients with ctDNA mutation clearance during afatinib treatment had substantially improved outcomes compared to those without clearance (Figure). 40% (4/10) of mutant cases who discontinued after 3 cycles because of progressive disease developed an exon 20 EGFR-mutation.

      timelyresults2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients unsuitable for chemotherapy with confirmed/suspected EGFR-mutations by tissue or ctDNA benefit from afatinib. Serial ctDNA is a potentially useful stratification and monitoring tool; amplicon-based ctDNA analysis can identify EGFR mutations when tissue is unavailable. Exon 20 mutations were observed at acquired resistance. ctDNA clearance during afatinib treatment is strongly associated with better PFS/OS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • 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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      P2.06-41 - Differentiating Sarcomatoid Mesothelioma from Pleomorphic Carcinoma and Chest Wall Sarcoma Using GATA-3/MUC4/BAP1 IHC (ID 12694)

      16:45 - 18:00  |  Author(s): Adam Januszewski

      • Abstract
      • Slides

      Background

      Current immunohistochemistry (IHC) biomarkers, or so-called “mesothelial markers”, lack sensitivity and specificity in differentiating sarcomatoid mesothelioma from pleomorphic carcinoma of the lung, and poorly differentiated chest wall sarcoma. Hence it frequently poses a diagnostic challenge for pulmonary pathologists. In this pilot study we evaluated the diagnostic performance of two recently proposed IHC biomarkers, GATA-3 and MUC4, in conjunction with BAP1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Sarcomatoid mesothelioma or sarcomatoid- predominant biphasic mesothelioma (10 cases), pleomorphic carcinoma of the lung (10 cases) and poorly differentiated primary or metastatic chest wall or pleural sarcoma (10 cases) were retrieved from our diagnostic archive. Resections or large biopsies were selected over small biopsies whenever possible. All the cases were diagnosed between 2009 and 2017 by a specialist pulmonary pathologist and discussed at the local multi-disciplinary team meeting in relation to final diagnosis. Whole slide GATA-3 (L50-823, pre-diluted), MUC4 (8G7, 1:50) and BAP1 (C-4, 1:50) immunohistochemistry was performed using Ventana Benchmark ULTRA system. Lymphocytes (GATA-3/BAP1) and bronchiolar epithelium (MUC4) were used as internal positive controls. Loss of GATA-3/BAP1 and MUC4 staining was defined as complete loss of nuclear or membrane & cytoplasmic signals, respectively. Any staining intensity above the external negative controls was accepted as positive. Extent of positive staining was grouped as <1%, 1-50% and >50%.

      4c3880bb027f159e801041b1021e88e8 Result

      GATA-3 was positive in 8/10 sarcomatoid mesothelioma, 6/10 chest wall/pleural sarcoma and 2/10 pleomorphic carcinoma of the lung. MUC4 positivity was observed exclusively in pleomorphic carcinoma of the lung (6/10), but only focally. BAP1 loss was infrequently observed in all three types of tumours.

      wclc figure 1 jpeg.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of GATA-3 and MUC4 immunohistochemistry show promise as markers that would help in distinguishing these three tumours. The role of BAP1 is uncertain. These pilot results warrant an extended study that consists of a larger cohort to evaluate the utility of these biomarkers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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