Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

L. Wang



Author of

  • +

    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • +

      MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)

      11:00 - 11:05  |  Author(s): L. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.

      Methods
      A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.

      Results
      Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.

      Conclusion
      Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)

      11:25 - 11:30  |  Author(s): L. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.

      Methods
      Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.

      Results
      For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).

      Conclusion
      As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      MO16.09 - Patterns of metastasis and survival in patients with PI3K-aberrant and FGFR1 amplified stage IV squamous cell lung cancers (SQCLCs) (ID 1666)

      17:05 - 17:10  |  Author(s): L. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%) pathways. The biologic behaviors and natural histories of these subtypes are not well characterized. Characterization of these data may help to elucidate the biologic relevance of these putative oncogenic events.

      Methods
      As of October 2011, all patients with SQCLCs at MSK have undergone prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH, FGFR1:CEP8 ≥ 2.2), PIK3CA mutations (Sequenom and exon sequencing), PTEN loss (IHC, Cell Signaling), and PTEN mutations (exon sequencing), among others. The PI3K abberant group was defined as PIK3CA mutant, PTEN complete loss, or PTEN mutant. Patient characteristics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional hazards methods.

      Results
      77 stage IV SQCLC patients were analyzed. Genotypes were: FGFR1 amplified (23%); PTEN loss (22%), PIK3CA mutant (8%), PTEN mutant (7%). Events were non-overlapping save for 2 cases with PTEN nonsense mutations and PTEN loss. The sole significant clinical difference (KPS, age, sex, lines of tx, smoking status) was sex (women in PI3K group 52% vs. in others 23%, p=0.02). Metastatic patterns for PI3K and FGFR1 vs. all others were:

      Site PI3K p FGFR1 p Other Total
      Brain 6 (22%) 0.002 0 (0%) 0.6 0 (0%) 6 (7%)
      Pleura 5 (19%) 0.4 5 (28%) 0.7 9 (28%) 19 (25%)
      Liver 5 (19%) 0.4 1 (6%) 1 1 (3%) 7 (9%)
      Bone 8 (30%) 0.8 3 (17%) 0.7 10 (31%) 21 (27%)
      Lung 12 (44%) 0.8 10 (56%) 0.2 12 (38%) 34 (44%)
      Adrenal 3 (11%) 1 3 (17%) 1 4 (13%) 10 (13%)
      Pericardium 1 (4%) 1 1 (6%) 0.3 0 2 (3%)
      Median OS for PI3K vs. all others: 9mo (95%CI:8-NR) vs. 16mo (95%CI:11-NR), p=0.004. Median OS for FGFR1 vs. all others: 20mo (95%CI:11-NR) vs. 10mo (95%CI:9-16), p=0.06. Multivariate analysis for risk of death: PI3K HR=3.3 (95%CI:1.5-7, p=0.003); FGFR1 HR=0.5 (95%CI:0.2-1.1, p=0.06); Age ≥65, HR=1.3 (95%CI:0.6-2.8, p=0.5); KPS≤70, HR=3.2 (95%CI:1.6-.6.4, p<0.001); Lines of therapy ≥ 2, HR=2.3 (95%CI=0.8-5.7, p=0.08), male gender, HR=0.7 (95%CI:0.3-1.4, p=0.3).

      Conclusion
      Patients with stage IV PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs while patients with FGFR1 amplified SQCLCs have a trend towards better survival. Brain metastases in SQCLC are rare, and occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may be an effective therapeutic strategy. Whole exome and RNA-sequencing data from 8 resected SQCLC brain metastases (4 paired with lung primaries) will be presented.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P2.11-026 - RET Fusion-Positive Advanced Lung Cancers: Response to First-Line Chemotherapy and Survival in Comparison to ROS1 and ALK Fusion-Positive and EGFR- and KRAS-Mutant Lung Cancers (ID 1964)

      09:30 - 09:30  |  Author(s): L. Wang

      • Abstract

      Background
      RET fusions are novel targetable drivers in non-small cell lung cancers. While the clinicopathologic profile of patients with RET fusion-positive tumors has been described in early-stage disease, little is known regarding clinical behavior in advanced unresectable disease.

      Methods
      Patients with advanced unresectable (stage IIIB/IV) pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, and AKT, and fusions of ALK or ROS1) were screened for RET fusions via dual-probe break apart FISH testing. Upstream partners were identified via RT-PCR and next-generation sequencing whenever possible. A retrospective review of patient records was conducted to determine response to systemic therapy and overall survival (OS). OS was calculated from diagnosis of metastatic disease and compared to patients with ALK and ROS1 fusion-positive, and EGFR- and KRAS-mutant lung cancers. Survival curves were estimated using the Kaplan-Meier method. Differences in survival between groups were assessed by the log-rank test.

      Results
      A RET fusion was found in 16% (n=12/76, 95%CI 8%-24%) of pan-negative tumors and 19% (n=10/48, 95%CI 10%-33%) of pan-negative tumors from never-smokers. Patients with RET fusion-positive tumors were predominantly never-smokers (83%, n=10/12, 2 patients with 7 and 10 pack-year histories, respectively) with advanced-stage disease at diagnosis (92%, n=11/12 stage IIIB/IV). Fusion partners were identified in 6 patients (4 KIF5B-RET, 1 TRIM33-RET, 1 NCOA4-RET). Eight patients (67%) received first-line platinum-based therapy, 6 of whom (50%) received maintenance pemetrexed and/or bevacizumab. Partial responses (PRs) were seen in 3 patients (38%) and stable disease (SD) in 5 patients (62%). 1-year OS on chemotherapy and median progression-free survival were 47% and 7.3 months, respectively. 1-year and 2-year OS for patients whose tumors harbored RET, ROS1, or ALK fusions, or EGFR or KRAS mutations is summarized below (Table). OS was not significantly different between RET, ROS1, ALK, or EGFR cohorts when RET was compared to each of the latter three cohorts separately. The presence of a RET fusion was associated with improved OS compared to the presence of a KRAS mutation (HR 0.39, 95%CI 0.21-0.74, p=0.004). Of the 11 patients with RET fusion-positive lung cancers, 4 patients (36%) were treated with cabozantinib on a phase 2 protocol (NCT01639508) with disease shrinkage of -66%, -32%, -23%, and -19% via RECIST v1.1.

      Driver Detected OS 1-year [95%CI] OS 2-year [95%CI]
      RET (n=12) 100% 71% [25%-92%]
      ROS1 (n=9) 88% [39%-99%] 88% [39%-99%]
      ALK (n=44) 91% [77%-97%] 73% [55%-85%]
      EGFR (n=102) 85% [76%-91%] 58% [47%-67%]
      KRAS (n=117) 60% [50%-66%] 26% [18%-35%]

      Conclusion
      Response to platinum-based first-line therapy in patients with RET fusion-positive tumors is comparable to historical controls. Survival in patients with RET fusion-positive disease is comparable to patients with EGFR mutations and other recurrent gene fusions (ROS1 and ALK) and improved compared to patients with KRAS mutations. Cabozantinib is worthy of further study in RET fusion-positive lung cancers.

  • +

    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
    • +

      P3.02-019 - FGFR1 amplification is associated with improved survival in patients with early-stage squamous cell carcinomas of the lung (SQCLC) (ID 2987)

      09:30 - 09:30  |  Author(s): L. Wang

      • Abstract

      Background
      The spectrum and frequency of oncogenes in squamous cell lung cancers (SQCLCs) is actively being defined. Amplification of fibroblast growth factor receptor 1 (FGFR1) is the most common targetable oncogenic driver in SQCLCs, occurring in ~20%. Clinical trials of FGFR1 inhibitors for advanced SQCLCs are ongoing. The frequency, clinicopathologic features, and prognosis of FGFR1 amplification in early-stage SQCLCs have been reported but with discrepant results.

      Methods
      A cohort of histopathologically-defined and clinically-annotated resected SQCLCs was tested for FGFR1 amplification by FISH (Zytovision Dual Color Probe). Amplification was defined by FGFR1 copy number ≥2.2x CEP8 control copy number and was assessed by two evaluators (MW, LW) who were blinded to clinical results. Disease-free survival (DFS) defined as date of surgical resection until disease recurrent, relapse, or death, which ever occured first. DFS was estimated using Kaplan-Meier method. The association between FGFR1 status and clinical features (unpaired T-test, Fisher’s exact, Chi-square tests) and DFS (log-rank test for unadjusted analysis; Cox proportional hazards regression for multivariate analysis) were assessed.

      Results
      63 resected SQCLCs were evaluated. FGFR1 amplification was detected in 16 (24%). 56% were stage I, 24% were stage II, and 20% were stage IIIA. There was no association between FGFR1 amplification and age (p=0.86), sex (p=0.80), smoking status (p=0.37), or stage of disease (p=0.16). Median DFS was significantly longer in FGFR1-amplified cases compared to non-amplified cases: not reached vs 2.3 yrs (95% CI 1.1-3.4 yrs), p=0.02, with a corresponding unadjusted hazard ratio of 0.41 (95%CI: 0.19-0.88). Adjusted for sex and stage, multivariate analysis found FGFR1 amplification significantly associated with improved DFS (HR 0.31, 95%CI 0.1-0.89, p=0.03). Figure 1

      Conclusion
      FGFR1 amplification is associated with improved prognosis in this cohort of resected SQCLCs. The distinctive natural history substantiates FGFR1amplified SQCLCs as a unique, oncogene-defined subgroup. There was no association between FGFR1 status and sex, age, smoking status, or stage. FGFR1 amplification is common in SQCLCs.