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Deepali Jain



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-22 - Liquid Biopsy in the Detection of EGFR Activating and Resistance Mutations in Advanced Pulmonary Adenocarcinoma (Now Available) (ID 1761)

      08:00 - 18:00  |  Author(s): Deepali Jain

      • Abstract
      • Slides

      Background

      Approximately 30% of the advanced pulmonary adenocarcinoma (PADC) patients are found to be mutated with epidermal growth factor receptor (EGFR). Nearly 60% of EGFR mutated patients develop T790M resistance mutation against which third generation TKIs are available. Detection of T790M mutation is a challenge due to non availability of enough tumour tissues in patients receiving first-generation EGFR-TKI treatment. Liquid biopsies (cell- free DNA) are promising for detection of EGFR activating and resistance mutations. The current study focuses on detection of EGFR mutations in cell-free DNA from patients with histologically confirmed EGFR mutation status.

      Method

      50 PADC patients (22 males; 28 females with mean age 63 years) were studied for EGFR mutations. Out of them 40 were TKI naïve and 10 patients were treated with EGFR-TKIs. Follow up biopsy from TKI treated patients was not available for resistant mutation studies. Real-time PCR and Digital droplet PCR techniques were adopted for studying EGFR exon 19 (deletions), 20 (T790M) and 21 (L858R) mutations in tissue and plasma samples respectively.

      Result

      Clinically all patients were in stage III-IV and 52% were never smokers. Out of 40 TKI naive cases, 20 cases were positive for EGFR activating mutations in tissue and 17 in plasma. Twenty cases were negative for EGFR mutations in both tissue and plasma. In 10 EGFR-TKI treated patients, founder activating mutation was still present in plasma of 7 cases and 3 of them also showed T790M resistance mutation. Two patients carrying this resistant mutation died subsequently. Remaining three TKI treated patients did not harbour even founder activating mutation in the plasma.

      Conclusion

      We observed a concordance of 88% (44/50) between liquid biopsy and tumour tissue. Our study highlights role of liquid biopsy as an alternative for detecting EGFR activating and resistance mutations in advanced PADC. EGFR mutation analysis in liquid biopsy can be helpful in those patients where the tissue biopsy is not possible.

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    EP1.17 - Treatment of Early Stage/Localized Disease (ID 207)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.17-13 - Operated Stages I-IIIB NSCLC Among Young Indian Cohorts - Clinical Profile and Outcomes (Now Available) (ID 2233)

      08:00 - 18:00  |  Author(s): Deepali Jain

      • Abstract
      • Slides

      Background

      Lung cancer is the third highest cause of mortality in India. Young lung cancers are on a rise and the characteristics of operable NSCLC among these group needs evaluation. We aim to compare the differential risk factors of Indian young NSCLC patients compared to the older group who underwent resection.

      Method

      A retrospective analysis of NSCLC patients operated from May 2012 to December 2018 at DR.BRAIRCH, All India Institute of Medical Sciences, New Delhi,India. Patients were divided into two groups, group (Gp)-YON includes young patients (defined as age 50 years or less) and Gp-OLD includes those older than 50 years. Factors analysed were demographics, histology, stage, disease free survival(DFS) and overall survival(OS) rates.

      Result

      A total of 143 patients of NSCLC underwent resection (including those post neoadjuvant chemotherapy). Gp-YON includes 37 (26%) and Gp-OLD 106 (74%) patients. Significant differences were observed between Gp-YON vs GP-OLD among non-smokers 40% vs 26% (p=0.025). Young females were higher in number 27% vs 18% but was insignificant (p=0.229). Other factors between the two groups like performance status(ECOG-2) 5% vs 4% (p=0.297), histologic subtypes(p>0.05)-squamous cell carcinoma(49% vs 55%), adenocarcinoma(38% vs 43%) and NSCLC(not otherwise specified) (2% vs 4%) did not reach statistical significance. The distribution of cases in various stages were stage IA(13% vs 18%), IIA (24% vs 17%), IIB (18% vs 16%) , IIIA 35% vs 36%) and IIIB (10% vs 13%). Stage for stage evaluation was insignificant(p>0.05). Family history, FEV1, intraoperative blood loss, postoperative complications, chest tube drainage and postoperative hospital stay were also insignificant (p>0.05). Distant metastases was lesser in Gp-YON (27% vs 16%, p=0.046). Median follow up was 40.7 months (95%CI 29.7-47.2).The median DFS in Gp-YON (23.3 months, 95% CI: 17.1-28.5) was higher than Gp-OLD (13.6 months, 95% CI: 10.1-15.3). Median OS in Gp-YON (38months, 95% CI: 32-45) was also higher than Gp-OLD (24months, 95% CI: 19-27). Only independent adverse prognostic factor was NACT(neoadjuvant chemotherapy) (HR,2.254, CI:0.98-5.15,p=0.050).

      Conclusion

      The number of young operable lung cancer is increasing in India (26%). Non-smokers contribution is significant. Incidence among young females is slightly higher. Patients receiving NACT has an adverse prognosis. Histologic type has no predilection to young age. No survival difference among young compared to old with respect to TNM substages. Distant metastases is lesser in young. Short-term follow up shows that overall young patients have a better DFS and OS as observed from our study.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-48 - Whole Exome Sequencing (WES) in Non-Small Cell Lung Carcinoma (NSCLC): Identification of Novel Biomarkers (Now Available) (ID 1712)

      09:45 - 18:00  |  Author(s): Deepali Jain

      • Abstract
      • Slides

      Background

      Significant advancement has been made in the treatment of patients with pulmonary adenocarcinoma (ADC) on the basis of the molecular profile. However, no such molecular target exists for squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). WES has been in wide use for the discovery of new genetic markers, which may offer more information for the development of personalized medicine for all subtypes of lung cancer. The aim of the current study is to find out novel genetic markers for NSCLC which can be used as a universal biomarker for the treatment.

      Method

      WES of 20 advanced NSCLC patients (10 ADC and 10 SCC) was done on the Illumina HiSeqX10 with paired end 151bp chemistry. The Male: female ratio was 5.6:1 and a median age 56 years. Only 3 patients were non-smoker and in one case smoking history was unknown. 75% of patients were present with co-morbidities, all patients were either in stage III or IV and performance status was either 1 or 2.

      Result
      Table 1: WES data statistics and the total number of variants identified:
      S.No WES data Numbers
      1 Average raw data 13.6 GB
      2 Average processed data 12.1 GB
      3 Average reads aligned 80.2%
      4 Average total variations 34173
      5 Average SNPs 26030
      6 Average INDEL 81423
      7 Average frameshift deletions 2185
      8 Average frameshift insertions 3571
      9 Average non-frameshift deletions 368
      10 Average non-frameshift insertions 1292
      11 Average non-synonymous 13418
      12 Average stop gain 10337
      13 Average stop loss 38
      14 Average synonymous SNPs 11607
      15 Average variations reported in databases 20269
      16 Unknown mutations 659

      WES data statistics has been depicted in table 1 including number of variants identified. After excluding common variants (MAF > 0.05), a total of 23 rare variants (0 < MAF < 0.01), possibly linked to lung carcinoma was identified in the exome. Further stringent filtering showed allele frequencies of mutations in GPRIN2 (G protein-regulated inducer of neurite outgrowth 2), KCNJ18 (potassium voltage-gated channel subfamily J member 18) and TEKT4 (Tektin 4) genes which were present in all the cases. The variations of amino acid substitutions were i) TEKT4: p.A223T and p.A405T (rs75603622); ii) GPRIN2: p.V241M (rs9422022), p.V47M (rs3127819); iii) KCNJ18: p.L211F (rs1435776313), p.I262S (rs1450551937)

      Conclusion

      Although the mechanism of GPRIN2, KCNJ12 and TEKT4 in tumorigenesis is unclear; our results suggest that these may play a major role in NSCLC and it is worth to be investigated in future. Validation of these genes is under process.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-11 - Dose Dense Paclitaxel and Carboplatin as Neoadjuvant Therapy for Resectable/Borderline Resectable NSCLC - A Phase II Trial  (Now Available) (ID 1604)

      09:45 - 18:00  |  Author(s): Deepali Jain

      • Abstract
      • Slides

      Background

      Neoadjuvant chemotherapy in locally advanced NSCLC is controversial. Available data suggest modest benefit and ideal regimen is unknown. Dose dense approach has not yet been tested in neoadjuvant setting.

      Method

      This phase II trial tested a novel approach of dose dense paclitaxel at 80mg/m2on d1, d8, d15 with three weekly carboplatin at AUC-6 for 4 cycles. Only patients with ECOG PS 0-2 with non-bulky N2 (defined as single lymph node < 2cm or multiple LNs or conglomerate, all < 2cm) were included in the study. Response assessment was done after two and four cycles. Primary end point was objective response rate. Relative dose intensity was calculated to define safety and tolerability. Secondary end points included progression free survival (PFS) and recurrence free survival (RFS) for patients who underwent surgery. IEC approved the study and the trial was registered with CTRI (ref no-CTRI/2016/05/006916).

      Result

      A total of 33 patients were included in the study. Male to female ratio was 1.75:1. The median age was 54 years (40-78) and majority were smokers (78.8%). Most common histology was squamous cell carcinoma (57.6%) followed by adenocarcinoma (36.4%). Sixteen patients (48.48%) had N2 disease by PET out of which only three were TBNA positive, all were non bulky (<2cm). Around 76% of patients were able to complete the planned 4 cycles of treatment with only one patient having CTCAE ver 5 grade ¾ toxicity. Objective response rate was 61.3%. Relative dose intensity of 80.25% was maintained in patients who completed 4 cycles. Around 58% patients required dose modification, most common reasons included peripheral neuropathy (47%), myalgia (16%), diarrohea (10.5%) and neutropenia (10.5%). A total of 138 grade ½ toxicity events were reported in the study over 12 courses of chemotherapy, with nausea (48.5%), myalgia (42.4%), neutropenia (30.3%), peripheral neuropathy (27.3%) and diarrhea (27.3%) being the most common. Thirteen patients underwent surgery with majority undergoing lobectomy (77%). After a median follow-up time of 19.3 months, median PFS was 11.1 months (95%CI 7.26-18.16) and median overall survival was 26.63 (95% CI 15.03-NR). TNM stage on CT/PET and PET response to NACT significantly correlated with progression free survival on univariate analysis. In patients who underwent surgery, median RFS was 17.36 months (95%CI 6.5-31.86) and 2 year RFS rates were 25%.

      Conclusion

      Dose dense therapy with paclitaxel/ carboplatin is feasible, safe and efficacious and can be considered for N2 negative/ low node burden patients.

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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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      P2.09-06 - Epidermal Growth Factor Receptor (EGFR) Mutation Spectrum in Pulmonary Adenocarcinomas: Indian Experience (ID 2447)

      10:15 - 18:15  |  Presenting Author(s): Deepali Jain

      • Abstract

      Background

      Incidence of lung cancer is rising in India, which is the major cause of mortality worldwide. The identification of EGFR mutations and ALK fusions in lung cancer has changed the treatment paradigm. The use of tyrosine kinase inhibitor (TKI) is now well established in clinical practice as it improves treatment outcomes. Molecular testing using tumor tissue is the gold standard for targeted therapies. The aim of the present study is to analyze the exact frequency of EGFR activating, rare and coexisting mutations in pulmonary adenocarcinoma (ADC).

      Method

      A total of 783 ADC (755 biopsies and 28 cytology aspirate smears) cases were studied. The male: female ratio was 1: 0.3 with age ranging from 20 to 78 years. During grossing, two tumor blocks were made, one for immunohistochemistry studies and other for mutation testing. In high- cellularity, low- tumor fraction cases, tumor enrichment was done by manual microdissection. We used more than one aspirate smears/biopsy blocks in cases with low- cellularity, high- tumor fraction. Probe-based real-time PCR (RT-PCR) technique was used to analyze EGFR hotspots mutations (exons 18 to 21). Before proceeding for molecular testing, histo/cytomorphology, tumour content and DNA quality were determined. For checking the quality of DNA, RT-PCR was done using wild type EGFR exon 2 primers.

      Result

      About 99% cases passed through the quality check of DNA and only 1.02% (8/783) cases failed. Overall, 234 patients (29.8%) were positive for EGFR mutations. The distribution of different types of EGFR mutations is shown in the Table 1. The common EGFR mutations were Exon 19 del and Exon 21 L858R which were equally distributed between both the genders. The EGFR mutations were more in non-smokers. T790M was present at baseline in around 3% TKI naive cases and it coexisted mostly with Exon 19 del. Cytological smears also showed EGFR mutations in the same pattern as tissue biopsies and a concordance was seen in cases where matched tissue and cytology smears were available.

      Table1: EGFR mutation spectrum in pulmonary adenocarcinomas

      EGFR Exon

      Percentage

      Single Mutations = 89.7% (210/234)

      EGFR most common mutations

      Exon 19 del

      61.5%

      Exon 21 L858R

      29.1%

      EGFR TKI resistant mutation at baseline

      Exon 20 T790M

      2.8%

      Rare EGFR Single Mutations

      Exon 18 G719X

      2.4%

      Exon 20 S768I

      1.4%

      Exon 21 L861Q

      1.4%

      Exon 20 Ins

      1.4%

      EGFR double mutations = 10.2% (24/234)

      Common double mutations

      Exon 19 del: Exon 20 T790M

      11

      Exon 19 del: Exon 21 L858R

      5

      Rare double mutations

      Exon 18 G719X: exon 20 S768I

      2

      Exon 21 L858R: exon 20 S768I

      2

      Exon 20 T790M: Exon 18 G719X

      1

      Exon 20 T790M: Exon 20 Ins

      1

      Exon 19 del: Exon 21 L861Q

      1

      Exon 19 del: Exon 18 G719X

      1

      Conclusion

      With judicious use and triaging of lung cancer diagnostic specimens, it is possible to perform successful mutation testing in >98% cases. EGFR mutation was positive in about a third of ADC including rare, TKI resistant and coexisting mutations in approximately 10% cases which may have significant therapeutic implications. In patients with limited amounts of tissue, cytology samples can be used for EGFR mutation testing as a promising alternative.