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Valliappan Muthu



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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: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.09-15 - Preliminary Experience with Liquid Biopsies in a Resource Constrained Setting and its Impact on Treatment Decision Making (ID 13411)

      16:45 - 18:00  |  Presenting Author(s): Valliappan Muthu

      • Abstract
      • Slides

      Background

      Liquid biopsies are potentially useful for molecular testing in the presence of inadequate tissue and for detection of resistance mechanisms in EGFR mutated NSCLC patients. Initial experience with liquid biopsies for advanced/metastatic NSCLC patients in a resource constrained setting is described herein.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective audit of liquid biopsies performed over a 21-month period for NSCLC patients at a tertiary referral centre in North India. Testing methods included digital-droplet-PCR (ddPCR), Next-Generation-Sequencing (NGS) and Real-Time-PCR (RT-PCR). ddPCR was used to detect specific EGFR mutations (L858R exon21, E746_A750 exon19 deletions and T790M exon20) in ctDNA (detection limit based upon amplifiable DNA ranging from 0.5%-<0.01% of mutant allele). For NGS, cfDNA extracted from plasma was subjected to target enrichment by high multiplex PCR amplification and analyzed for mutations using gene panel (BRAF, EGFR, ERBB2/HER2, KRAS, MET) on the Ion Proton semiconductor sequencer (Life Technology, USA). RT-PCR assay using EGFR-RT52 kit (EntroGen USA) detects known somatic mutations in exons 18-21 of EGFR by amplifying mutant-specific sequences and relies on fluorescent probes for detection (detection limit of 1%).

      4c3880bb027f159e801041b1021e88e8 Result

      42 patients [61.9% (n=26) males] underwent liquid biopsies. ddPCR, NGS and RT-PCR were performed in 31(73.8%), 7(16.7%) and 4(9.5%) patients respectively. Timing was prior to/during first-line treatment in 23(54.8%) and at progression on first-line treatment in 19(45.2%) patients. In the former, indication was inadequate tissue for molecular analysis (n=15), detection of other targetable mutation (after EGFR wild type status on tissue; n=3) and checking ctDNA status of T790M exon 20 detected in tissue (n=5). Among 19 patients with progression on first-line treatment, 17 were those with a sensitizing EGFR mutation at baseline who had progressed on EGFR-TKI of which 47.1% (n=8) were found to have T790M exon 20 mutation. The primary EGFR sensitizing mutation detected in tissue at baseline was also detected in ctDNA in 9 of 20 patients with a sensitivity of 45.0%. Agreement between results of tissue testing and liquid biopsy testing for EGFR mutations was 48.0% (12/25). Potential change in management with use of liquid biopsies was observed in 12 patients (28.6% overall and 52.6% if done at progression).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary experience in our resource constrained setting indicates that greatest utility of liquid biopsies is for EGFR mutated patients with progression on EGFR-TKI wherein T790M detection rates are comparable to those reported in literature. However, the overall sensitivity and agreement is lower than that reported in literature and perhaps may be related to small number of patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.09-31 - Preliminary Experience with Liquid Biopsies in a Resource Constrained Setting and Its Impact on Treatment Decision Making (ID 11718)

      16:45 - 18:00  |  Presenting Author(s): Valliappan Muthu

      • Abstract

      Background

      Liquid biopsies are potentially useful for molecular testing in the presence of inadequate tissue and for detection of resistance mechanisms in EGFR mutated NSCLC patients. Initial experience with liquid biopsies for advanced/metastatic NSCLC patients in a resource constrained setting is described herein.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective audit of liquid biopsies performed over a 21-month period for NSCLC patients at a tertiary referral centre in North India. Testing methods included digital-droplet-PCR (ddPCR), Next-Generation-Sequencing (NGS) and Real-Time-PCR (RT-PCR). ddPCR was used to detect specific EGFR mutations (L858R exon21, E746_A750 exon19 deletions and T790M exon20) in ctDNA (detection limit based upon amplifiable DNA ranging from 0.5%-<0.01% of mutant allele). For NGS, cfDNA extracted from plasma was subjected to target enrichment by high multiplex PCR amplification and analyzed for mutations using gene panel (BRAF, EGFR, ERBB2/HER2, KRAS, MET) on the Ion Proton semiconductor sequencer (Life Technology, USA). RT-PCR assay using EGFR-RT52 kit (EntroGen USA) detects known somatic mutations in exons 18-21 of EGFR by amplifying mutant-specific sequences and relies on fluorescent probes for detection (detection limit of 1%).

      4c3880bb027f159e801041b1021e88e8 Result

      42 patients [61.9% (n=26) males] underwent liquid biopsies. ddPCR, NGS and RT-PCR were performed in 31(73.8%), 7(16.7%) and 4(9.5%) patients respectively. Timing was prior to/during first-line treatment in 23(54.8%) and at progression on first-line treatment in 19(45.2%) patients. In the former, indication was inadequate tissue for molecular analysis (n=15), detection of other targetable mutation (after EGFR wild type status on tissue; n=3) and checking ctDNA status of T790M exon 20 detected in tissue (n=5). Among 19 patients with progression on first-line treatment, 17 were those with a sensitizing EGFR mutation at baseline who had progressed on EGFR-TKI of which 47.1% (n=8) were found to have T790M exon 20 mutation. The primary EGFR sensitizing mutation detected in tissue at baseline was also detected in ctDNA in 9 of 20 patients with a sensitivity of 45.0%. Agreement between results of tissue testing and liquid biopsy testing for EGFR mutations was 48.0% (12/25). Potential change in management with use of liquid biopsies was observed in 12 patients (28.6% overall and 52.6% if done at progression).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary experience in our resource constrained setting indicates that greatest utility of liquid biopsies is for EGFR mutated patients with progression on EGFR-TKI wherein T790M detection rates are comparable to those reported in literature. However, the overall sensitivity and agreement is lower than that reported in literature and perhaps may be related to small number of patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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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      P2.01-77 - Interconversion of Two Commonly Used Performance Tools: An Analysis of 5844 Paired Assessments in 1501 Lung Cancer Patients (ID 12723)

      16:45 - 18:00  |  Author(s): Valliappan Muthu

      • Abstract
      • Slides

      Background

      Karnofsky Performance Status (KPS) scale and Eastern Cooperative Oncology Group (ECOG) scale are the most commonly used performance status (PS) tools worldwide. The current study aimed to assess correlation between KPS and ECOG PS in a large cohort from a lung cancer (LC) clinic database and to determine KPS categories which were most equivalent to ECOG PS scores.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients attending LC clinic at a tertiary care centre over a 5-year period were assessed with both KPS and ECOG PS scales at each visit. Correlation between KPS and ECOG PS was assessed using Spearman’s correlation coefficient. Different KPS categories equivalent to ECOG PS were compared using hit rate and weighted kappa (κw).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 1501 patients were assessed over study period providing 5844 paired KPS and ECOG PS assessments. The cohort had a mean (standard deviation SD) age of 58.4 (10.8) years with majority being current/ex-smokers (76.9%) and males (82.3%). NSCLC was commonest histological type (n=1196, 79.7%) with majority having advanced (stages IIIB/IV) disease (83.4%). Mean baseline KPS and ECOG PS scores were 77.6 (SD=14.4) and 1.5 (SD=1) respectively. Overall correlation between KPS and ECOG PS was good [Spearman r = (-)0.84, P<0.0001] but ranged from -0.727 to -0.972 between visits. KPS categories derived from our cohort (10-40 [ECOG 4], 50-60 [ECOG 3], 70 [ECOG 2], 80-90 [ECOG 1], 100 [ECOG 0]) performed better (hit rate 78.1%, κw = 0.749 [0.736-0.762] P<0.0001) than those suggested in the past literature.

      Table: Comparison of various suggested KPS categories for KPS-ECOG PS interconversion in the current cohort
      Author, Year N (Patients [assessments]) Suggested KPS Categories Hit rate κw (95% confidence interval)
      AJCC, 1977 - 10-20, 30-40, 50-60, 70-80, 90-100 43.6% 0.376 (0.363-0.389) P<0.0001
      Minna, 1985 - 20-30, 40-50, 60-70, 80-90, 100 75.2% 0.701 (0.687-0.714) P<0.0001
      Buccheri, 1996 536 [1656] 10-50, 60-70, 80-100

      83.2%

      0.695 (0.679-0.711) P<0.0001
      Ma, 2010 1385 (1385) 10-30, 40-50, 60-70, 80-90, 100 75.2% 0.701 (0.687-0.714) P<0.0001
      de Kock, 2013 955 (674) 10-20, 30-40, 50, 60-100 43.2% 0.079 (0.068-0.090) P<0.0001
      Current study 1501 (5844) 10-40, 50-60, 70, 80-90, 100 78.1% 0.749 (0.736-0.762) P<0.0001
      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study provides largest set of paired KPS-ECOG assessments till date. Although both PS tools had good correlation, the performance of the KPS categories previously suggested as being equivalent to ECOG PS categories was found to be highly variable. Cancer clinics should develop and validate their own population-specific KPS categories for interconversion of KPS to ECOG PS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 981)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.15-02 - Carboplatin Dose Calculated Using Different Formula for eGFR and Their Comparison with Actual Dose Administered in Lung Cancer Patients (ID 12712)

      12:00 - 13:30  |  Author(s): Valliappan Muthu

      • Abstract
      • Slides

      Background

      Carboplatin dosage for chemotherapy is usually estimated using AUC-based dosing. Several equations are available for estimating GFR(eGFR); including Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI), and a recent equation(1). However, while calculating dosage of carboplatin, several factors other than estimated-GFR[including performance status(PS), vial package strengths] merit consideration. Do we require high degree of precision in eGFR and how does each of these equation perform in real-life settings?

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a retrospective audit of lung cancer patients undergoing first-line chemotherapy at our centre, with the aim of determining discrepancies between actual doses of carboplatin administered versus those calculated using different equations. Calvert formula was used to calculate carboplatin dose, with the eGFR being obtained from Cockcroft-Gault, CKD-EPI and the Janowitz-equation.(J Clin Onc2017;35(24):2798-805) Dose derived from GFR estimated using latter was considered reference standard. Carboplatin dose was also calculated using manufacturer’s instructions[body surface area(BSA) in kg/m2 x 300 for GFR>60 mL/min; BSA×250 for GFR=41-60 mL/min; BSA×200 for GFR≤40mL/min]. Absolute dosage differences and percentage errors(PE) for above equations were calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      77 subjects received carboplatin-based chemotherapy(Jan-Aug 2017). Dosage calculated by Cockcroft-Gault based GFR and manufacturer’s recommendation had significant variation as compared to new equation-based dose. However, the actual administered doses were lower than both Cockcroft-Gault-based and manufacturer’s recommended doses. Significant proportion(n=48, 62.3%) had >20% absolutePE of carboplatin dose as compared to reference standard. Carboplatin dose PEs(actual administered, calculated as per Cockcroft-Gault, CKD-EPI equation and manufacturer’s recommendation) were plotted against the reference standard as waterfall chart(Figure 1A-D). All, except six(7.8%) patients(none of them were≥20% higher than the predicted), received doses≤ that calculated from the reference.figure 1 jco final.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Actual carboplatin administered is lower than the predicted in majority(irrespective of equation used for eGFR). Hence the probability of administering a potentially toxic dose, owing to incorrect eGFR might be negligible. Thus, using more accurate equations/measuring GFR may not be required.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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