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Steven G. Gray
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MA06 - Molecular Developments and Novel Treatments in Mesothelioma and Thymoma (ID 134)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA06.03 - Phosphorylated Ribosomal Protein S6, Correlation With Characteristics and Clinical Outcome in Patients With MPM: Results from ETOP Mesoscape (ID 2260)
14:15 - 15:15 | Author(s): Steven G. Gray
- Abstract
- Presentation
Introduction
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. The European Thoracic Oncology Platform (ETOP) Mesoscape project was designed to address clinical, pathological, and molecular characteristics of MPM patients and their impact on outcome, along with having formalin-fixed paraffin embedded tumour tissue available for central analysis. In previous studies the phosphorylated ribosomal protein S6 (pS6), which is a downstream target of PI3K /mTORC1 signaling, was associated with clinical outcome, and low pS6 immunoreactivity was significantly correlated with longer progression free survival in other MPM patients. Correlating pS6 with the clinical as well as pathological information in Mesoscape allows researchers to improve the knowledge and facilitate decision-making in patients with MPM.
Methods
A biobank with fully annotated tissue samples was established for ETOP Mesoscape, and Tissue Micro Arrays (TMAs) were constructed. Expression of phospho-S6 (p-S6, Ser240/244, Cell Signaling Technology, 1:50 dilution) was explored in the ETOP Mesoscape cohort. Immunohistochemical evaluation of the TMAs was conducted by two independent observers in a blinded manner. The staining intensity was semi-quantitatively scored 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). Furthermore, the percentage of cells with any positivity was proportionally scored 0 (0%), 0.1 (1%–9%), 0.5 (10%–49%), or 1.0 (50% and more). An aggregate H-score was obtained by multiplication of intensity with percentage staining (final range: 0-3 per core). The final H-score was determined by averaging the H-scores of all the cores from the same patient. Patients’ classification as pS6-high/low, was based on median H-score.
Results
Up to 14 July 2020, the ETOP Mesoscape included pS6 IHC results on 269 of the 499 patients from 10 centers, diagnosed between 1999-2018. The remaining cases are currently undergoing pS6 scoring.
Overall, patients in the Mesoscape database are primarily men (84%), of 0/1 ECOG Performance status (46/46%), with known previous exposure to asbestos (75%) and a median age of 64 years. The primary histology of included tumours is epithelioid (72%), followed by biphasic (22%) and sarcomatoid (6%). Clinical staging is available for 77%. The stage distribution (I/II/III/IV) is 14/29/42/15%.
Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97%; WT1: 89%). Also, 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive. Palliative treatment has been administered in 41%.
PS6-high patients (128 patients with H-score>1.375) are significantly associated with higher age, more T-stage of 3/4, and higher percentage of right localization compared to pS6-low patients (141 patients with H-score≤1.375). Overall survival (OS) is non-significantly different between pS6-low and pS6-high patients (medians: 21.4 months; 95%CI:[15.3-23.4] and 17.8 months; 95%CI:[15.1-20.7], respectively; log-rank p=0.61]. In the multivariate Cox model, pS6 is also non-significant (p=0.31), while gender, histology, and treatment strategy are the only significant survival predictors.
Conclusion
Based on preliminary data, high pS6 expression is associated with higher age and T-stage; effect in survival is non-significant. Updated and additional results on the expression and clinical significance of pS6 from the full ETOP Mesoscape cohort will be presented at the conference.
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P34 - Pathology - Liquid Biopsy (ID 104)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P34.01 - Utility of Assessment of the EGFR Resistance Genotype using Cell-Free DNA and CTCs from Liquid Biopsies (ID 2321)
00:00 - 00:00 | Author(s): Steven G. Gray
- Abstract
Introduction
In advanced disease, the presence of an EGFR mutation confers a more favourable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Clinical studies have demonstrated that ~20% of biopsies are inadequate for molecular testing due to insufficient tumour tissue. Tissue genotyping is further limited by often inaccessible tissue, heterogeneity and risks associated with serial tumour biopsies. More than 60% of patients who initially respond to EGFR TKI therapy develop resistance due to the emergence of the T790M or other resistance mutations. In this study, we hypothesise that concurrent assessment of circulating tumour cells (CTCs) and cell-free DNA (cfDNA) enhances assessment of EGFR resistance using the liquid biopsy as a non-invasive technology.
Methods
Patients with EGFR positive disease (n=21) were consented across three Irish Oncology Centres and stratified into cohort 1 (currently receiving EGFR TKI therapy) or cohort 2 (newly diagnosed, treatment-naïve patients to receive EGFR TKI therapy). Liquid (blood) biopsies were collected every 3 months over two years. Plasma genotyping of cell-free DNA was carried out using the FDA-approved Cobas® EGFR mutation test v2 (Roche Diagnostics) for the most common EGFR mutations across exons 18-21 of the EGFR gene. Analytical performance of the Cobas® EGFR mutation test was compared with two next generation sequencing (NGS) cell-free DNA panels (Oncomine & Avenio). In addition, the potential clinical utility of CTC numbers in monitoring response to therapy and the emergence of resistance (T790M) were assessed. CTCs were isolated from blood at each time-point using ScreenCell® size exclusion technology. Neutrophil to lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) were used as a measure of systemic inflammation and prognosis in this EGFR patient subset. Univariate Cox proportional hazards analysis was used for overall survival (OS) and time to progression (TTP).
Results
Plasma genotyping using the Cobas® EGFR mutation test identified Exon 19, L858R and L861Q mutations in 62%, 24% and 5% of liquid biopsy-derived cfDNA, respectively. The emergence of the T790M resistance mutation was detected in 57% of patients during treatment with EGFR TKIs. In contrast to cohort 2, patients in cohort 1 with a T790M had a worse OS and shorter TTP relative to patients with an EGFR sensitizing mutation. Using the Wilcoxon sign rank test, there were no significant correlations in EGFR mutation profile between the Cobas® mutation test and Oncomine (p=0.054) or Avenio (p=0.94) NGS panels. While there were no significant correlations between CTC numbers and T790M status in both cohorts, significant correlations were found between CTCs and WBC count (p=0.000073) and LDH (p=0.0010) in cohort 1 only. High CTC numbers correlated with a shorter TTP in both patient cohorts. This however was not statistically significant. Patients with T790M had a significant increase in inflammatory biomarkers (NLR, LDH, WBC) when examined across all time-points (p<0.05).
Conclusion
While larger prospective studies are warranted, these data add further knowledge to the use of cfDNA plasma genotyping and CTCs for the rapid detection of EGFR genomic alterations in patients with NSCLC during EGFR TKI therapy and treatment resistance.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.49 - The Impact of Baseline Systemic Inflammatory Status Parameters in Patients Treated with EGFR-Tyrosine Kinase Inhibitors (ID 2272)
00:00 - 00:00 | Author(s): Steven G. Gray
- Abstract
Introduction
Elevated neutrophil to lymphocyte ratio (NLR),derived neutrophil to lymphocyte ratio (dNLR),lung immune prognostic index (LIPI) and circulating tumour cells (CTCs) are associated with inferior outcomes in non-small cell lung cancer (NSCLC). The use of these parameters in patients treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is uncertain. We assessed the association of pre-treatment NLR, LIPI and CTCs on time to progression (TTP) and overall survival (OS) in patients treated with EGFR-TKIs.
Methods
Patients with existing EGFR-activating mutations on EGFR TKIs (cohort 1) and newly diagnosed, treatment naive (cohort 2) were recruited across three Irish Oncology centres over a two year period (n=21). Demographic characteristics were collected. Baseline NLR, dNLR (absolute neutrophil count/white blood cell concentration-absolute neutrophil count), LIPI (dNLR greater than 3 and LDH greater than ULN) consisted of 3 groups (good: 0 factors; intermediate: 1 factor; poor: 2 factors), and CTCs count was collected at baseline. CTCs were isolated from blood using ScreenCellÒ size exclusion technology.Cox proportional hazards analysis was used for overall survival (OS) and time to progression (TTP). Correlations were performed using the Wilcoxon sign rank test.
Results
16 (76%) of patients were female (median age 64.5), 20 (95%) were adenocarcinoma, 1 (5%) squamous cell carcinoma, 10 (48%) never smokers, 10(48%) ex-smokers.There was a significant correlation between LDH (p=0.02), CTCs (p=0.00067) and WCC in cohort 1. CTC count was also significantly correlated with LDH (p=0.001) in cohort 1. There was a significant correlation between LDH (p=0.003), NLR (p=0.0005) and WCC in cohort 2. NLR was also significantly associated with LDH (p<0.05). There was no significant correlation between dNLR and CTCs in either cohort. WCC, LDH, dNLR, CTCs and LIPI were not significantly associated with TTP and OS in either cohort.
Conclusion
Although there were positive correlations between baseline systemic inflammatory parameters, these were not prognostic for survival in patients treated with EGFR-TKI therapy. Larger clinical studies and sequential follow up parameter measurements during treatment will be valuable in assessing these markers during EGFR-TKI therapy.
