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Weijie Ma



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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-06 - Real World Diagnosis and Treatment Outcomes in Patients with EGFR-Mutant Metastatic Lung Cancer (Now Available) (ID 2979)

      08:00 - 18:00  |  Author(s): Weijie Ma

      • Abstract
      • Slides

      Background

      We recently showed that lung cancer incidence and mortality rates have steadily decreased in California between 1990 and 2014. Improvements in overall and yearly survivals were most pronounced for Asian and female patients, and for patients with adenocarcinoma after 2004, when molecularly targeted therapy was introduced (Pan et al., ASCO 2018). The objective of this study was to determine the impact of molecular diagnosis and targeted therapy on survival by time interval, gender, race/ethnicity, and smoking status in patients with EGFR-mutant metastatic lung cancer.

      Method

      This retrospective study included consecutive cases from patients with locally advanced or metastatic EGFR-mutant NSCLC seen at an academic clinic between 2009 and January 2018 with follow up through February 2019. Allele-specific PCR was used before 2014 (Cohort 1, N=94)) and FoundationOne® was used after 2014 (Cohort 2, N=101). Kaplan-Meier curves were estimated for overall survival and stratified by smoking status, gender, and race/ethnicity. Relative survival rates were calculated for 1 year, 2 years and 5 years.

      Result

      A total of 83 and 88 patients with metastatic lung cancer who received ≥1 EGFR TKI were identified in Cohort 1 and 2, respectively. Table below summarizes demographic characteristics, median overall, 1-year, 2-year and 5-year survivals for each cohort. Relative to cohort 1, all cohort 2 subgroups saw improvements in survival. Improvement was most pronounced for never smoker, female, asian and white patients. Survival rates among both cohorts were significantly higher than that of all patients in California during the same periods.

      EGFR TKI-Treated Patients

      Cohort 1

      (N=83)

      Cohort 2

      (N=88)

      HR (95% CI)

      Age (mean ± SD) (years)

      58.7 ± 11.7

      67.2 ± 14.3

      Median Overall Survival (months)

      33.5

      45.3

      0.6 (0.39-0.80)

      1-year survival rate (%)

      91.5%

      93.9%

      2-year survival rate (%)

      64.3%

      79.5%

      5-year survival rate (%)

      16.1%

      43.2%

      Never smoker: No. Patient (%)

      52 (62.7%)

      54 (61.4%)

      Median survival (months)

      32.5

      60.2

      0.4 (0.27-0.71)

      Female: No. Patient (%)

      51 (61%)

      54 (61%)

      Median survival (months)

      31.6

      78.8

      0.4 (0.27-0.71)

      Male: No. Patient (%)

      32 (39%)

      34 (39%)

      Median survival (months)

      31.6

      78.8

      0.8 (0.27-1.39)

      White: No. Patient (%)

      59 (71.1%)

      52 (59.1%)

      Median survival (months)

      37.9

      45.3

      0.55 (0.35-0.87)

      Asian: No. Patient (%)

      21 (25.3%)

      26 (29.5%)

      Median survival (months)

      34.4

      80.0

      0.50 (0.22-1.06)

      Conclusion

      Advances in the diagnosis and treatment for patients with EGFR-mutant lung cancer have increased patient survival times. Further study is needed to determine the causes of gender and ethnicity differences.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-60 - Statins Overcome Resistance to Tyrosine Kinase Inhibitors in Patient-Derived, Oncogene-Driven NSCLC Models (ID 2969)

      09:45 - 18:00  |  Presenting Author(s): Weijie Ma

      • Abstract

      Background

      Despite the improved efficacy of newer generation targeted TKIs, nearly all patients with EGFR- and ALK-driven NSCLC eventually acquire resistance and succumb to the refractory metastatic disease. Previous studies have shown that simvastatin has more potent antitumor effects compared to other statins. The objective of this study was to determine whether simvastatin could overcome TKI resistance using in vitro and in vivo NSCLC models.

      Method

      Human NSCLC cell lines A549 (KRAS G12S), H3255 (EGFR L858R), and H1975 (EGFR L858R and T790M) were treated with simvastatin either alone or in combination with an TKI. Antitumor effect was measured by growth inhibition by MTS assay and expression of molecular targets by immunoblots. Malignant pleural effusion and biopsied tumors were collected under an IRB-approved protocol and used for primary cell culture and generation of patient-derived xenograft models in NSG mice. Mice implanted with H1975 xenografts were treated with vehicle, simvastatin, osimertinib, or both. Mice engrafted with an ALK-TKI resistant PDX were treated with vehicle simvastatin, brigatinib, or both. Tumor growth was measured every other day for 28 days or the tumor volume reached ~2 cm3. Tumors were subjected to histomorphological assessment and immune blot analyses. All data are shown as mean ± standard deviation (SD). The two-sample t-test was used for continuous variables. All statistical tests were two-sided and a p-value less than 0.05 was considered statistically significant.

      Result

      We found that simvastatin alone had a strong antitumor effect in tested NSCLC cell lines, regardless of tumor genotypes. Simvastatin and osimertinib combination showed synergistic cytotoxic effect in these NSCLC cell lines and several primary culture of patient’s pleural effusion. Simvastatin alone reduced the tumor volume by 41% and 57% compared to controls in both the EGFR- and ALK-TKI resistant PDX models. In the H1975 xenograft model, simvastatin and osimertinib combination produced a greater reduction in tumor volume than osimertinib alone (P < 0.01). In an ALK TKI-resistant lung PDX model, simvastatin and brigatinib combination resulted in a greater reduction in tumor volume than brigatinib alone (P < 0.01) and showed a synergistic effect based on a simple multiplicative model of a fixed dose, two-drug combination.

      Conclusion

      Simvastatin displays anti-tumor activity in multiple EGFR and ALK TKI resistant models, and preliminary analysis suggests potential synergism with the two tested TKIs (osimertinib and brigatinib). Further study is needed to characterize the molecular mechanisms responsible for the statin-mediated anti-tumor effect and its interactions with TKIs.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-04 - Real World Experience of Using Comprehensive Genomic Profiling of Plasma Circulating Tumor DNA (ID 3089)

      09:45 - 18:00  |  Author(s): Weijie Ma

      • Abstract

      Background

      The clinical application of molecular biomarker assays has revolutionized cancer diagnosis and treatment, enabling the current era of precision lung cancer care. Increasingly, comprehensive genomic profiling (CGP) by next generation sequencing has been used in the clinic. We here summarize our initial experience in using tissue- and blood-based tumor genomic profiling assays.

      Method

      This retrospective chart review included consecutive cases from patients with locally advanced or metastatic lung cancer seen at an academic institution between January 2014 and March 2019. A total of 596 archival tumor specimens and 128 blood samples were subjected to tissue- and plasma-based, hybrid capture-based next generation sequencing assays, respectively. Maximum somatic allele frequency (MSAF) was used to quantify the fraction of circulating tumor DNA in the plasma cell free DNA. Survival was calculated by the Kaplan-Meier method.

      Result

      We found that plasma cell free DNA (cfDNA) assay significantly reduced the sample acquisition time and test failure rate (Table below). All patients who failed tissue assay due to insufficient tissue or DNA and were willing to undergo liquid biopsy had a successful test result. Reasons for 38 patients who had liquid biopsy only are summarized below. In 117 (19.6%) identified patients with either EGFR-mutant or ALK-rearranged NSCLC tumors, median survival has improved compared to those patients diagnosed before 2014 (N=103) (48.9 vs 30.0 months, hazard ratio 0.43, 95% CI 0.31-0.60; p<0.0001). Furthermore, plasma ctDNA CGP identified suspicious germline mutations in ~16% cases.

      Specimen Type Tumor Plasma cfDNA P value
      Genomic Assay FoundationOne or CDx F-ACT or FoundationOne Liquid
      All cases 596 128

      Sample acquisition time (mean with 95% CI; days)

      9.9 (8.79-10.95)

      1.3 (0.17-2.49)

      <0.0001
      Test time (mean with 95% CI; days) 13.0 (12.55-13.53) 14.7 (13.24-16.15) <0.01
      Total test time (mean with 95% CI; days) 22.9 (21.66-24.07) 16.0 (14.19-17.85) <0.0001
      No. (%) Failure cases 114 (19.1%) 4 (3.1%)
      Reasons for liquid biopsy only: N=38
      Tissue insufficient 11 (29%)
      Resistance evaluation 10 (26%)
      No record 6 (18%)
      Limited panel 7 (16%)
      Refused biopsy or too ill 4 (11%)

      Conclusion

      In our experience, the adoption of CGP with subsequent, effective targeted therapy has shown improved median survival in patients with NSCLC. CGP of plasma ctDNA is particularly useful when patients have insufficient tumor specimens and can unveil germline mutations which need further confirmation. A prospective concordance study is planned to compare the FoundationOne CDx and FoundationOne Liquid in patients with advanced NSCLC.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-55 - High Integrin α3 Expression Is Associated with Poor Prognosis in Patients with NSCLC (ID 2543)

      10:15 - 18:15  |  Presenting Author(s): Weijie Ma

      • Abstract

      Background

      Integrin α3β1 belongs to a family of heterodimeric transmembrane glycoprotein receptors that mediates cell adhesion and cytoskeleton function. We recently showed that integrin α3β1 is a promising novel cancer biomarker and drug target in NSCLC. While the integrin α3 unit (INTA3) mediates the binding to various ligands and substrates, the integrin β1 unit (INTB1) mainly is primarily responsible for the complex biological functions. INTA3 only binds to INTB1 as the binding partner. This study was undertaken to evaluate if INTA3 expression was correlated with clinicopathological parameters and survival in patients with non-small cell lung cancer (NSCLC).

      Method

      Tissue microarrays (TMAs) were made from archival formalin-fixed and paraffin-embedded tissue blocks of 161 NSCLC patients, which included 91 adenocarcinoma (LUAD), 46 squamous carcinomas (LUSC), and 24 other histology types. TMA sections were stained for INTA3 expression using anti-integrin α3 antibody (ab131055, dilution 1:100; Abcam) by immunohistochemistry (IHC) stain. Staining intensity was graded as 0 (0-5%, negative), 1+ (6-20%, weak), 2+ (21-50%, moderate), and 3+ (51-100%, strong). Kaplan-Meier curves and log-rank test were used to compare overall survival of IHC score groups. To adjust for covariate imbalance between IHC score groups, propensity-score-weighted Kaplan-Meier curves and weighted Cox models were used. Logistic regression was used to study association between INTA3 expression and patient clinicopathological parameters.

      Result

      INTA3 IHC expression was detected in 107/161 (66.5%) of the NSCLC samples. Weak (1+), moderate (2+) and strong (3+) INTA3 expression was detected in 66 (41.0%), 33 (20.5%), and 8 (5.0%) cases, respectively. Kaplan-Meier curves indicated that weak (1+) and strong (3+) INTA3 expression was significantly associated with poor overall survival in NSCLC patients (p < 0.05 and p < 0.001, respectively). Propensity-score-weighted survival analysis demonstrated that INTA3 IHC expression (1+-3+) was associated with poor prognosis (HR = 1.39, 95% CI: 1.06-1.83, p =0.02) for all NSCLC patients, as well as in subgroups of female patients (HR =1.99, 95% CI: 1.32-3.01, p < 0.01), smokers (HR =2.46, 95% CI: 1.66-3.65 p < 0.01) and differentiation grade I&II (HR =3.0, 95% CI: 1.91-4.59 p < 0.01), but not in LUSC patients (p=0.11), LUAD patients (p=0.07), male patients (p=0.06), non-smokers (p=0.34), differentiation grade III (p=0.98). Logistic regression indicated that high INTA3 expression is associated with no smoke history (OR=2.7, 95% CI:1.3-5.7, p=0.01).

      Conclusion

      INTA3 was expressed in the majority of NSCLC by IHC and was associated with poor prognosis. Further study is warranted for targeting integrin α3(β1) in NSCLC.