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A.L. Moreira



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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.09 - Patterns of metastasis and survival in patients with PI3K-aberrant and FGFR1 amplified stage IV squamous cell lung cancers (SQCLCs) (ID 1666)

      16:15 - 17:45  |  Author(s): A.L. Moreira

      • 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.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      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 - 16:30  |  Author(s): A.L. Moreira

      • 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.