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Noelia Vilariño



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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.03 - Retrospective Study of Intrathecal Therapy for Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Carcinomatosis (Now Available) (ID 2086)

      14:00 - 15:30  |  Presenting Author(s): Noelia Vilariño

      • Abstract
      • Presentation
      • Slides

      Background

      Leptomeningeal carcinomatosis (LMC) is a devastating cancer-related neurological complication with poor prognosis. In EGFR-mutant (mut) NSCLC patients (pts), osimertinib achieves high penetration into cerebral-spinal fluid (CSF) and promising efficacy. However, for EGFR-mut T790M-negative pts treated with prior 1st- and 2nd-generation tyrosine kinase inhibitors (TKI) and for driver negative NSCLC pts, a combination of intrathecal therapy (IT) and systemic therapy (ST) seems to be an appropriate approach. Our purpose is to explore the clinical outcome of IT combined with ST among NSCLC with LMC depending on EGFR status.

      Method

      NSCLC pts with LMC treated with IT in our institution between 2010 and 2018 were retrospectively studied. After LMC diagnosis, intrathecal methotrexate (scheduled: 12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. A Kaplan-Meier survival analysis was performed for overall survival (OS) and progression free survival (PFS).

      Result

      A total of 39 pts were included. Patient’s clinical characteristics are summarized in table 1. EGFR status was 17 mut (del19: 11pts); 11 wild-type (wt) and 11 unknown (unk). LMC and NSCLC diagnosis were more likely to be synchronous in EGFR wt compared with EGFR mut. The median follow-up from LCM diagnosis was 10.2 months. At the time of this analysis, only 6 pts were alive. Thirty-two pts received ST in combination with IT, 18 (46%) pts chemotherapy (6wt/ 3mut/ 9unk), while 14 (36%) pts an EGFR TKI (1wt/ 13mut). Clinical response (improvement of neurological symptoms and/or KPS) was seen in 11 (65%) EGFR mut pts vs 2 (18%) wt pts (p=0.033). Median OS and PFS for the whole cohort were 23 weeks (95%CI, 8.1 to 37.9) and 10 weeks (95%CI, 7.1 to 12.8) respectively. Median OS was higher for EGFR mut pts compared to wt pts, 38 weeks (95%IC 13.6-62.4) and 19 weeks (95%IC, 4.06-33.9) respectively, however this difference was not statistically significant (p=0.36) probably due to lack of statistical power.

      table1_lmc.jpg

      Conclusion

      Methotrexate-based IT given concurrently with systemic TKI may confer a higher clinical benefit and a trend toward OS benefit in NSCLC patients with LCM and EGFR activating mutations.

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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)

      14:30 - 16:00  |  Author(s): Noelia Vilariño

      • Abstract
      • Presentation
      • Slides

      Background

      Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.

      Method

      MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.

      Result

      Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).

      Conclusion

      CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-54 - Somatic Genome Alterations in Lung Cancer Patients Diagnosed with Li Fraumeni Syndrome (Now Available) (ID 1014)

      09:45 - 18:00  |  Author(s): Noelia Vilariño

      • Abstract
      • Slides

      Background

      Li-Fraumeni syndrome (LFS) is a rare hereditary condition that consists of TP53 mutations inherited in autosomal dominant manner that confer high risk of developing cancer, including lung adenocarcinoma (LUAD). EGFR-mutated LUAD were reported in the context of LFS but there is no systematic description of somatic mutations and characteristics of lung cancer (LC) patients with LFS.

      Method

      We present a retrospective analysis of clinical and molecular characteristics of patients with LFS diagnosed with LC at the Catalan Institute of Oncology from 1999 to 2019. We collected demographical and clinicopathological features, germline and somatic mutational alterations, treatment and progression-free survival (PFS) and overall survival (OS).

      Result

      A total of 7 patients with LC and LFS were identified in the Genetic Counseling Unit database. They were carriers of germline mutations in TP53. Five of them were classified as pathogenic: c.638G>A; p.(Arg213Gln), c.725G>A; p.(Cys242Tyr), c.742C>T; p.(Arg248Trp), c.844C>T; p.(Arg282Trp) and c.1010G>A; p.(Arg337His) and two of them as likely pathogenic: c.374C>T; p.(Thr125Met) and c.473G>A; p.(Arg158His). Six out of 7 patients were female and 5 out of 7 never smoker. Median age at diagnosis was 38 year-old (range: 29-74). Five patients had stage IV at diagnosis and the most common histologic subtype was LUAD (5). Six patients had first grade family history of cancer with a median of 2 family members (range: 1-4) and 2 patients had prior history of cancer. Tumor somatic profile in LC was obtained in 6 patients, consisting on a ROS-1 rearrangement in one patient and EGFR mutations in 5 patients (exon 19 deletion in 3 patients and missense mutations in 2 patients, p.(Gly719Ala) at exon 18 and p.(Leu858Arg) at exon 21) and in 1 patient was unknown. All patients with mutant EGFR received EGFR tyrosine kinase inhibitors (TKI) with a median PFS of 29 months (95% CI 0-67). Four had partial response and one a complete response to TKI treatment. At disease progression, one patient had small cell transformation and another acquired EGFR T790M mutation. Median lines of treatment were 4 (range 1-6). Two patients are alive at data cut off. Median OS is 47 months (95% CI 32-62).

      Conclusion

      Patients diagnosed with LC and LFS are enriched with actionable genomic alterations and have an earlier onset of the disease. Clinical outcome of patients with EGFR mutations and LFS did not differ from EGFR mutated LC patients who do not carry TP53 germline mutations.

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      P1.01-93 - Metastases Sites as a Prognostic Factor in a Real-World Multicenter Cohort Study of Spanish ALK-Positive NSCLC Patients (p) (ID 1377)

      09:45 - 18:00  |  Author(s): Noelia Vilariño

      • Abstract

      Background

      ALK gene rearrangements are detected in 3-7% of Non-Small-Cell-Lung-Cancer (NSCLC) p. EML4-ALK translocation was first identified as an oncogene in NSCLC p in 2007. To date, published real-world data on the prognostic factors of patients with ALK-positive advanced NSCLC in Spain are limited. We aim to evaluate the effect of number of metastases (M1) organs on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC p diagnosed between 2008 and 2017.

      Method

      We included p with stage IV at diagnosis since 2011 to April 2018. OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of p using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model, adjusted by site of metastases, gender, age and first line type of treatment.

      Result

      Out of the 163 p in the cohort a total of 98 p were included, with a median follow-up of 28.6 m and 45 deaths reported. Characteristics at diagnosis were median age 58 years, female 46.9%, never-smokers 59.2%, 50% with comorbidities, PS by ECOG 0-1 93%, 58.2% lung M1, 45.9% central nervous system M1, 42.9% bone M1, 22.4% liver M1 and 29.6% pleural M1.

      54.3% p and 89.4% p were treated with ALK inhibitors as first line and second line respectively. The median OS was 34.4 months, being 46.9 months in p treated with ALK inhibitors and 38.8 months in p treated with chemotherapy as first line (p= 0.9).

      There were 72 p who presented M1 in more than one organ and 26 p in a single organ. The risk of death increased with greater number of organs involved at diagnosis (HR= 3.0, p=.016), and presenting liver M1 at diagnosis (HR=2.2, p=.046, with OS of 19.1 m), compared to p single site involvement (OS: 45.4 m).

      Conclusion

      OS was worse with increased metastatic sites involved at diagnosis in p with ALK positive NSCLC, being liver M1 associated with the highest risk of mortality. Brain metastases at diagnosis were not a prognostic factor for OS in our series.