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C. Rolfo



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    MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI23.04 - Familial Clustering of Lung Cancer (LC) Cases in a South European Population (sEp) (ID 2540)

      17:00 - 17:05  |  Author(s): C. Rolfo

      • Abstract
      • Presentation
      • Slides

      Background:
      The National Lung Cancer Screening Trial found, after 6.5 years, a 20% reduction in LC mortality in high-risk patients (pts) screened with low-dose computed tomography compared to chest x-ray. However, LC screening programs (SP) result controversial due to potential cost-effectiveness issues. Familial LC aggregation (fLCa) has been described previously. The estimated relative risk of LC is ∼1.8 for offspring of parents with LC. Linkage analysis has mapped a dominant locus to chromosome 6 in LC pedigrees. Therefore, in this high-risk subpopulation, SP may have clear advantages. This is the first study to investigate the incidence of fLCa conducted in a sEp.

      Methods:
      Overall, 509 cancer pts of Spanish (n = 473) or Portuguese (n = 36) origin were included in the analysis. A cohort of 236 consecutive pts (cases) diagnosed with LC was studied for family history (FH) of any type of cancer including LC. Another cohort of 273 pts (controls) with similar demographic characteristics diagnosed with cancer types other than LC was also studied for FH of cancer. We investigated whether LC pts show a higher incidence of fLCa than subjects with other solid tumors.

      Results:
      Among LC pts with a positive FH for LC, 36.7% showed one of their parents as the only LC relative, 26.5% showed one or more siblings, 18.4% one or more either uncle or aunt, 6.1% their grandfather/grandmother and 12.2% other combinations. Regarding the number of relatives affected, in our LC cohort one relative was the most frequent finding with 42/49 pts (85.7%), 2 in 3 cases (6.2%) and > 3 relatives in 4 subjects (8.1%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (72.9% vs 67.4%; p = 0.18). However, in our cohort of LC cases, 49/236 pts (20.8%) had a FH of LC in first or second degree whereas among cancer controls only 29/273 pts (10.6%) showed a LC FH (p = 0.002).

      Conclusion:
      This is the first estimation of LC FH in a non-selected sEp with LC. 20.8% of LC cases showed a positive FH for LC, being significantly higher (twofold) compared to other cancer pts. Therefore, the usefulness of directed SP for subjects with positive FH of LC should be prospectively evaluated and potential genomic drivers studied.

      Table 1. Comparison of incidence of any type of familial cancer and fLCa between a cohort of LC patients and a cohort of subjects with other solid tumors
      LC patients Other solid tumor patients p value
      N= 236 N=273
      Familial cancer (any type) (n (%))
      Yes 172 (72.9) 184 (67.4) 0.18
      No 64 (27.1) 89 (32.6)
      Familial Lung Cancer (n (%))
      Yes 49 (20.8) 29 (10.6) 0.002*
      No 187 (79.2) 244 (89.4)
      *Statistically significance at p < 0.05
      fLCa: familial lung cancer; LC: lung cancer


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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.02 - Inhibitor of Differentiation 1 (Id-1) Gene Silencing Reduces Liver Metastases Formation in a NSCLC Animal Model (ID 2995)

      18:35 - 18:40  |  Author(s): C. Rolfo

      • Abstract
      • Presentation
      • Slides

      Background:
      Around 30% of non-small cell lung cancer (NSCLC) patients present LM during the disease course causing a negative clinical impact on survival and quality of life. The expression of certain genes in cancer cells might be crucial for allowing tumor cells to spread to the liver. According to this hypothesis Id1 and Id3 genes, part of the signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

      Methods:
      Three cohorts including totally 80 mice were compared; Id1 wild-type C57BL/6 (WT) female mice (n = 40) vs. Id1 knock out (IDKO) female animals (n = 28) vs Id1/Id3 knock out mice (Id1Id3KO) (n = 12). In both groups of mice 500,000 Lewis Lung Carcinoma cells (LLC) Id1 WT (Id1+/+) Id3 WT (Id3+/+), or Id1 homozygously deficient (Id1-/-) and Id3 WT (Id3+/+) or Id1-/- and Id3 heterozygously deficient (Id3+/-) were generated through gene silencing, and intrasplenically injected. Thereafter, both groups of mice were weekly monitored with FDG-micro-positron emission tomography (mPET) scans for LM formation. Animals were sacrificed (and tissues microscopically analyzed) by the time LM were developed and clinical deterioration was evident.

      Results:
      Expression of Id1 in both the host and the tumor cell line injected were independent predictive factors for the presence of LM. In fact, silencing Id1 expression in tumor cells (OR = 0.04; CI 95% 0.2 (0.04-0.9) or knocking down Id1 in the host tissues (OR: 0.2; CI 95% 0.06-0.7), impaired LM presentation. Silencing Id3 seemed not to diminish the risk of LM presentation.

      Conclusion:
      Absence of Id1 expression in the host partially impairs LM presentation. Silencing Id1 in tumor cells diminish the odds of presenting LM. Knocking down Id1 in the host or targeting Id1 in the tumor cell may represent a new approach to prevent LM presentation, and thus, improving the outcome in NSCLC patients.

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    ORAL 31 - PD1 Axis Inhibition (ID 143)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL31.01 - PD-L1 Expression as Predictive Biomarker in Patients with NSCLC: A Pooled Analysis (ID 1578)

      16:45 - 16:56  |  Author(s): C. Rolfo

      • Abstract
      • Presentation
      • Slides

      Background:
      Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and PD-L1 expression in pre-treated NSCLC patients.

      Methods:
      Data from all published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status.

      Results:
      A total of six studies, with 776 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.53; 95% CIs: 1.65-3.87). Figure 1Figure 2





      Conclusion:
      PD-L1 tumor expression seems to be associated with clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated, NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients who may benefit more from these therapies. Further analysis from ongoing phase II/III clinical trials will provide more information about this observation.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-013 - EGFR Mutations and Targeted Treatment Reverse the Bad Prognosis of Stage IV NSCLC Associated to Liver Metastasis (ID 2961)

      09:30 - 09:30  |  Author(s): C. Rolfo

      • Abstract
      • Slides

      Background:
      Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment. response to Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment.

      Methods:
      A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed.

      Results:
      At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 mo. vs. 21 mo.; p =0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 mo. vs 13 mo.; p=0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tirosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 mo; p=0.81).

      Conclusion:
      Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis in first-line treatment of EGFR mutated tumors and, more interestingly, in patients with EGFR wild-type NCSLC receiving EGFR TKIs after progression to chemotherapy. Table 1. Multivariate regression model.

      Variable HR p
      Sex 1.28 0.32
      Age 1 0.9
      N 1.28 0.06
      EGFR 0.24 0.001
      TKIs (after progression) 0.44 0.03
      Liver metastases at onset 1.5 0.28
      Liver metastases during disease 1.28 0.43
      Bone metastases at onset 1.6 0.22
      Bone metastases during disease 1.19 0.64
      Skin metastases at onset 2.2 0.31
      Adrenal metastases at onset 1.37 0.29


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