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Michael Cabanero



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    MA18 - Advances in Diagnosis of Common Types of NSCLC (ID 145)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      MA18.07 - Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors (Now Available) (ID 1137)

      11:30 - 13:00  |  Author(s): Michael Cabanero

      • Abstract
      • Presentation
      • Slides

      Background

      Acquired resistance after ALK tyrosine kinase inhibitors treatment has multiple known mechanisms: new mutations or gene amplifications, bypass signaling and rarely neuroendocrine histological transformation. Here we describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.

      Method

      Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment.

      Result

      All 9/9 patients consented for research sampling during clinical biopsy procedures (median 2 extra cores/passes); 2 patients were biopsied more than once; 3 PDX models from 2 patients have engrafted; 3 additional models are too early to assess engraftment. Engraftment occurred in patients with clinically aggressive tumors and poor survival outcomes. In this process, we identified 2 patients with neuroendocrine transformation post-second generation ALK TKI: (a) a 59 yo Asian female, never smoker, diagnosed six years prior with metastatic disease, heavily pretreated with crizotinib (12 months), pemetrexed (16 months), ceritinib (25 months), alectinib (6 months) and brigatinib (3 months); post-alectinib biopsy showed no transformation, while post-brigatinib liver biopsy demonstrated transformation to large cell neuroendocrine carcinoma; (b) a 75 yo Caucasian female, never smoker, diagnosed eight months prior and started on alectinib with a partial response, progressed in a single site; endobronchial biopsy demonstrated high grade neuroendocrine transformation. Both biopsies were positive for neuroendocrine markers (chromogranin and synaptophysin), TTF-1 and diffusely co-expressed ALK on immunohistochemistry. Assessment of PDX engraftment of these models is ongoing.

      Conclusion

      Routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally).

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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      OA08.01 - Organoid Cultures as Novel Preclinical Models of Non-Small Cell Lung Cancer (Now Available) (ID 2115)

      11:00 - 12:30  |  Author(s): Michael Cabanero

      • Abstract
      • Presentation
      • Slides

      Background

      There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. Organoids, which are cells grown in three-dimensional environments in Matrigel, have emerged as novel preclinical models of cancer. Recently protocols for generating NSCLC organoids have been reported, but the growth, and molecular features of organoids as compared to their matching primary patient tumor or patient-derived xenografts (PDX) remain vague.

      Method

      Thirty surgically resected NSCLC patient tumor and 35 PDX tissue of lung adenocarcinoma and squamous cell carcinoma subtypes were processed for organoid establishment. Organoids and matching tumor tissues were characterized by histology and immunohistochemistry, and molecularly profiled by whole exome and RNA-sequencing. Subcutaneous injection of organoids in vivo was performed to confirm tumorgenicity. Organoids were subjected to drug testing and drug response was verified in the matched PDX.

      Result

      Using a novel culture condition that our laboratory developed, we have collected tumor samples from 16 primary and 13 PDX samples of adenocarcinoma (n=29) and 14 primary and 22 PDX samples of squamous cell carcinoma (n=36). Over 85% (57/65) of our patient and PDX tumor tissues formed organoids that exhibited a wide range of short-term (<3 months) and long-term (>3 months) growth. Specifically, the success rate of establishing short-term and long-term models are 74% (48/65) and 14% (9/65), respectively. The long-term propagable organoids recapitulated the histology of the patient and PDX tumor. They also retained the ability to form xenograft in NOD-SCID mice. The organoids preserved mutation, copy number aberrations and global gene expression profile of the parental tumors. We additionally showed the utility of short-term and long-term organoids for identifying biomarkers of sensitivity to drugs and combinational targeted therapies.

      Conclusion

      NSCLC organoids are novel patient-derived ex-vivo tumor models for anti-cancer drug screening and biomarker discovery, thus could be incorporated into novel drug discovery pipelines. Further efforts are ongoing to increase the success rate of establishing long-term organoid lines.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-30 - Non-Small Cell Lung Cancer (NSCLC) Next Generation Sequencing (NGS): Integrating Genomic Sequencing into a Publicly Funded Health Care Model (Now Available) (ID 2588)

      09:45 - 18:00  |  Author(s): Michael Cabanero

      • Abstract
      • Slides

      Background

      Standard of care (SOC) molecular diagnostics for stage IV NSCLC patients in Ontario, Canada includes publicly reimbursed EGFR/ALK, and BRAF/ ROS-1 testing in selected cases. Other genomic alterations are not tested routinely at all institutions; however, enhanced molecular testing may broaden treatment options for patients by identifying actionable targets. This study evaluated costs, identified actionable targets, and determined clinical trial eligibility as a result of using the Oncomine Comprehensive Assay v3 (OCA v3, ThermoFisher) NGS in stage IV NSCLC patients at a single institution.

      Method

      This prospective study of stage IV NSCLC out-patients at Princess Margaret Cancer Centre (Toronto) began in February 2018 and recruitment is ongoing (NCT03558165). NSCLC patients without EGFR/ALK/KRAS/BRAF alteration (unless failure of prior targeted therapy and tissue rebiopsy), had diagnostic samples tested by OCAv3 (ThermoFisher; 161 genes: hotspots, fusions, and copy number variations). Primary endpoints were identification of incremental actionable targets and clinical trial opportunities as a result of broader OCAv3 testing. Secondary endpoints include feasibility and cost from the Canadian public healthcare perspective.

      Result

      From Feb 2018- Jan 2019 65 patients were enrolled [62% (N=40) completed/ 21% (N=14) screen fail/ 17% (N=11) pending], median age of completed cohort was 65, 60% (N=24) female, never/light smokers 68% (N=27), Asian 38% (N=15), previously treated 33% (N=13). Actionable targets beyond SOC were identified in 33% (N=13): ERBB2 (N=8), BRAFV600 (N=3), NRG fusion (N=1), MET exon 14 (N=1). Failure of NGS was secondary to insufficient tissue. 91% (N=10) of screen failures was secondary to tissue exhaustion from prior sequential SOC molecular testing. New clinical trial options were identified in 70% as a result of OCA v3 testing. Incremental costs per case beyond EGFR/ALK are estimated at $540 CAD. If ROS-1 and BRAF testing were publicly reimbursed at current rates, the incremental profiling cost with OCAv3 would be $90 CAD per case.

      Conclusion

      The OCAv3 consolidates genomic testing, identifies additional actionable targets, and substantially increases clinical trial eligibility for patients at a small incremental cost. Sample failures are reflective of exhausted diagnostic tissue as a result of prior sequential genomic testing. The key barrier to implementation of NGS remains funding in the Canadian health care system.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-62 - Early, Subclinical SCLC Transformation in Patients with EGFR Mutant Lung Cancer Receiving Osimertinib, Detected Through Cell-Free DNA (ID 812)

      10:15 - 18:15  |  Author(s): Michael Cabanero

      • Abstract

      Background

      Liquid biopsies provide a convenient approachfor serial sampling and real-time disease monitoring, leading to the early detection of treatment response, disease progression and drug-resistance. Here,we present genomic profiling of serial liquid biopsies from seven lung cancer patients with activatingEGFRmutations receiving osimertinib in clinical practice.

      Method

      At Princess Margaret Cancer Centre, in the Lung Cancer Outpatient Clinics, plasma samples were obtained from each patient at defined clinical visits (between ~1–5 months in-between visits). Cell-free DNA (cfDNA; with a median of 57 ng; range: 3.5 to 3806 ng) was extracted from plasma samples and profiled using targeted capture next-generation sequencing with the Geneseeq Prime 425-gene panel, at a mean coverage depth of 4892X (with a deduplicated mean coverage depth of 2108X).

      Result

      Systemic tumour burden correlated with the detection of genomic alterations in cfDNA: Four of four of the patients with low tumour burden, despite minor disease progression, exhibited minimal EGFR and co-mutation allele frequencies (AFs). Conversely, significant increases in systemic (but not central nervous system) tumour burden led to increases in driver and co-mutation AFs (two our of three patients). EGFR C797S mutation and inactivating mutations in RB1 and TP53 were detected in the cfDNA of one patient nearly four months prior to the development of small cell lung cancer (SCLC) transformation confirmed on tissue biopsy with distinct transformed and untransformed areas. Both of the specific RB1 and TP53 mutations found in cfDNA have been previously associated with SCLC. Subsequent combination cisplatin-etoposide chemoradiation resulted in temporary complete remission of the transformed SCLC, corresponding to loss of RB1 mutation detection by cfDNA testing.

      Conclusion

      Profiling of plasma cfDNA using hybrid capture deep sequencing of a large gene panel can detect early subclinical transformation of EGFR-mutated lung cancer into small cell lung cancer (i.e., neuroendocrine transformation), leading to earlier diagnosis and management of the transformed disease. Serial liquid biopsy profiling can also be used to monitor disease progression. However, detection sensitivity of tumour cfDNA largely depends on systemic tumour burden.