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S. Otsuka



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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-021 - Implications of CXCR4 and Estrogen/Progesterone Receptor (ER/PR) pathway activity in Non Small Cell Lung Cancer (NSCLC) (ID 3431)

      15:10 - 15:27  |  Author(s): S. Otsuka

      • Abstract

      Background
      CXCR4 is a chemokine receptor that activates signaling pathways responsible for trafficking of cells to sites of inflammation, retention of stem cells in the bone marrow and plays a role in migration and metastatic processes in tumour cells. Previous work by the Bebb lab demonstrated that female stage IV NSCLC patients with high CXCR4 expression have significantly worse survival compared to their low CXCR4 expressing counterparts. Recently, a positive regulatory loop was discovered linking CXCR4 and ER signaling pathways leading to increased gene expression of SDF-1 and other ER dependent genes. We explored the relationship between CXCR4 and ER/PR signaling in NSCLC cell lines, and assessed the expression of ER/PR in stage IV tissue samples to determine if ER/PR could be contributing to the observed gender dependent difference in clinical outcome seen in CXCR4 high expressers.

      Methods
      Two male and two female NSCLC cell lines were characterized for ER and CXCR4 by western blot. Activity of the CXCR4 and ER pathways in each cell line after stimulation with SDF-1 and estradiol (E2), respectively, were assessed by western blot of downstream signaling targets ERK, AKT, phospho-ER and PR. Cross activity of the CXCR4 and ER pathways was examined by stimulating cells with E2 and quantifying SDF-1 and PR mRNA by rtPCR. Tumor specimens from stage IV NSCLC patients (Glans-Look Lung Cancer Database) previously assessed for CXCR4 were analyzed for ERα and PR expression by quantitative immunohistochemistry (IHC) using the HistoRx AQUA® platform. Correlation between CXCR4 and ER/PR expression was assessed using Pearson’s rank correlation, and associations between marker expression and clinical factors/overall survival were assessed using a Cox proportional hazards model.

      Results
      All cell lines expressed varying levels of CXCR4, ERα and ERβ, and were responsive to both SDF-1 and E2 stimulation. Preliminary data suggests that activation of AKT and ERK after stimulation with SDF-1 occurs more rapidly in the male cell lines than in the female cell lines, and that there were differences in SDF-1 gene expression after E2 stimulation between the male and female lines. Other experiments are ongoing and full data will be presented. ER and PR AQUA scores were obtained for 131 patients (63 females and 68 males). There were weak positive correlations between both ER/CXCR4 (r = 0.153) and PR/CXCR4 (r = 0.278), however, only the correlation between CXCR4 and PR was significant (p = 0.002). Similarly, only PR expression was significantly associated with overall survival in the model (p = 0.03)(HR = 1.46). More detailed sub-group analyses further exploring the association with gender is ongoing, and will be presented.

      Conclusion
      The CXCR4 and ER pathways are active in NSCLC cell lines. There appears to be differences in the responsiveness of male and female NSCLC cell lines to CXCR4 and ER pathway activation. ERs and PRs are present in stage IV NSCLC tissue samples, and are associated with both CXCR4 expression and overall survival in our patient cohort. The full implication of these observations is still being investigated and further analyses will be presented.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-054 - Metastatic NSCLC Outcomes at a Single Canadian Institution Over a Decade (ID 3415)

      09:30 - 09:30  |  Author(s): S. Otsuka

      • Abstract

      Background
      In the past 10 years, the standard of care in non small cell lung cancer has seen the adoption of several less toxic and better tolerated therapies, allowing a greater proportion of metastatic patients the opportunity to receive 2[nd] and even 3[rd] line treatment. We investigated whether this improvement in the number of available therapies for metastatic NSCLC had any bearing on overall patient survival, by retrospectively analyzing patients diagnosed in 1999/2000, 2004/2005 and 2009/2010 at our centre.

      Methods
      After ethical approval was obtained demographic details, clinical variables and outcome data were gathered retrospectively via chart review, on NSCLC patients diagnosed at the Tom Baker Cancer Centre (TBCC) in 1999/2000, 2004/2005 and 2009/2010 (Glans-Look Lung Cancer Database). All patients were restaged according to the new 7th Edition of the American Joint Committee on Cancer TNM system for NSCLC staging. Stage IV patients and early stage patients with subsequent metastatic recurrence were included in the analysis. Survival was analyzed using the Kaplan-Meier method and differences measured by a log rank test.

      Results
      1290 patients were included in the preliminary analysis (data only from 1999, 2004/2005 and 2009/2010), 1018 of which were stage IV at diagnosis, 272 who recurred with metastatic disease. The median overall survival (MOS) of patients increased slightly from 1999 to 2009/2010, from 4.5 months in 1999, to 5.7 months in 2004/2005 to 4.6 months in 2009/2010, as did the proportion of patients who received systemic treatment (21.3% in 1999, 28.9% in 2004/2005 and 28.1% in 2009/2010). However, the proportion of patients who received 2 or more lines of chemo doubled from 1999 to 2009/2010 (7.3% in 1999, 12.1% in 2004/2005 and 14.6% in 2009/2010)(p = 0.04). In addition, there was a trend towards increasing median overall survival (MOS) of systemically treated patients over 1999-2009, from 9.6 months (95% CI: 7.6-11.6) in 1999 to 12.7 months (95%CI: 11.0-14.4) in 2009/2010 (p=0.25).

      Conclusion
      Our analysis suggests that there are an increasing proportion of metastatic NSCLC patients being treated systemically at our centre, specifically, the proportion being treated with two or more lines of systemic therapy has significantly increased over the decade from 1999-2009/2010. This study also suggests a trend toward an increased MOS for systemically treated patients diagnosed in 2009/2010 compared to those diagnosed in 1999. However, the vast majority of patients (>3/4) are still not being treated with systemic therapy, despite the increase in available therapies now compared to a decade ago. The reasons for this are not clear but may include poor ECOG performance status, rapid decline, sub-optimal referral pathways and rural residence. Further analyses will be presented.