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Christian Rolfo



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    MS 18 - Biomarker for Anti-PD-L1 Therapy (ID 540)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MS 18.05 - Liquid Biopsy Biomarkers in IO: Is There Room? (ID 7647)

      15:45 - 17:30  |  Presenting Author(s): Christian Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE 10 - Bridging the Gap between Genomics and Clinics (Sign Up Required) (ID 559)

    • Event: WCLC 2017
    • Type: Meet the Expert
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      MTE 10.01 - Bridging the Gap between Genomics and Clinics (ID 8125)

      07:00 - 08:00  |  Presenting Author(s): Christian Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. For many years, NSCLC has been considered an easy to treat disease, with few chemotherapeutic agents producing a limited survival improvement in unselected patients. In the last decade, identification of key genetic events driving tumor growth and metastatic spread led to postulate the concept of oncogene-addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient outcome. This is the case of Epidermal Growth Factor Receptor (EGFR) and its activating mutations. Strategies against EGFR mutant (EGFR[mut]) NSCLC represent a relevant example on how genomic discoveries dramatically changed clinical practice. The most common – also named classic - EGFR mutations are inframe deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21. Nine large randomized trials conducted in more than 1900 patients harboring classical EGFR mutations clearly demonstrated the superiority of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib, when compared to conventional platinum-based chemotherapy. Additional rare EGFR mutations, such as point mutations in exon 18, have been associated with some sensitivity to first and second generation EGFR TKIs, although their ability to predict radiological and clinical response to such drugs is less striking than that of classic EGFR mutations. However, despite an initial dramatic response, virtually all EGFR[mut+ ]NSCLC progress due to the occurrence of acquired resistance. So far, several mechanisms underlying acquired resistance to EGFR-TKIs have been elucidated and they conventionally belong to two categories. The first group of mechanisms is considered as target-dependent, because they preserve the dominance of EGFR signaling and occur preferentially through secondary mutations in the kinase domain of the receptor. The first and most well characterized is the T790M mutation, also called ‘gatekeeper’ mutation for its ability to interfere with the ligand site of EGFR TKIs. The second group includes non-target dependent mechanisms, as they determine i) activation of other oncogenes, such as BRAF and PIK3CA, ii) up-regulation of other signaling pathways, such as MET, HER2, fibroblast growth factor receptor (FGFR), and AXL and iii) histologic transformation, mainly represented by small cell transformation or epithelial to mesenchymal transition. Identification of the molecular mechanisms responsible for resistance to EGFR-TKIs is of crucial relevance in clinical practice so that new effective therapeutic strategies may be developed for our patients. As the T790M accounts for approximately 60% of the EGFR TKIs failures, investigations have focused on the potential efficacy of a new class of drugs that irreversibly inhibit mutant EGFR, in particular T790M, with minimal or no activity against wild-type EGFR. This new class of agents includes several new drugs, with osimertinib (Tagrisso, AZD9291) as the most promising. Osimertinib is a mutant-specific EGFR-TKI currently approved for the treatment of pretreated EGFR[T790M+] patients. In the AURA 3 trial, 419 EGFR[T790M+] patients who had disease progression after first-line EGFR-TKI therapy, were randomized to receive either osimertinib or chemotherapy. The study demonstrated that osimertinib was superior to standard chemotherapy in terms of response rate (RR, 71% versus 31%, p<0.001) and progression-free survival (PFS, 10.1 versus 4.4 months, p<0.001). Among 144 patients with metastases to the central nervous system, the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). An ongoing study evaluating osimertinib versus first-generation TKIs as first-line treatment for patients with EGFR mutation-positive NSCLC may help to define the role of the drug as front-line therapy (FLAURA trial). Unfortunately, acquired resistance to osimertinib therapy also occurs and identification of mechanisms responsible for drug failure is of clinical relevance. A report first describing the development of a resistance mutation, C797S, in a patient enrolled in the AURA phase I trial was submitted for publication 10 months prior to the FDA approval of osimertinib. Interestingly, preclinical models harboring an EGFR activating mutation alone (exon 19 deletions or L858R point mutations) that develop resistance through C797S are still sensitive to gefitinib or afatinib. The immediate clinical consequence is that the latter EGFR-TKIs could be offered to patients developing resistance after initial therapy with osimertinib. By contrast, models harboring three EGFR mutations (Del 19 or L858R plus T790M plus C797S) were resistant to all currently available EGFR-TKIs, with cetuximab still retaining some activity. Similarly to first or second-generation EGFR-TKIs, additional mechanisms of resistance have been described, including small-cell lung cancer transformation, activation of the NRAS pathway, MET amplification or FGFR3 mutation. Therefore, identification of mechanisms of resistance to EGFR-TKIs is of crucial relevance for defining which agent should be used first and the best sequencing of treatment. In conclusion, discovery of EGFR mutations led to a dramatic change in approaching NSCLC therapy. Several additional molecular events have been more recently identified, including ALK or ROS1 rearrangements, providing evidence that investigations at the genomic level are crucial in defining new and more effective strategies against cancer.

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-039 - Preventive and Therapeutic Action of Id1 Inhibition in KRAS-Mutant (KM) Lung Adenocarcinoma (LAC) Tumors in a Xenograft Murine Model (ID 9574)

      09:30 - 16:00  |  Author(s): Christian Rolfo

      • Abstract
      • Slides

      Background:
      Id1 has been shown to be involved in cell viability and migration of lung cancer cell lines and confer poor prognosis in LAC-patients. The most frequently mutation in LAC is KRAS, but no targeted therapy has been successfully developed. Here we study the role of Id1 in a KM-LAC murine model.

      Method:
      The expression of Id1 was analyzed in a panel of human LAC cell lines by qPCR and Western-Blot. Several human cell lines with known mutations (H1792-604, H2009, H358, H1568, H1437, H1703, H2126) were selected to deplete Id1 expression by inducible short hairpin RNA (shRNA) regulated by doxycycline. Proliferation, cell cycle and apoptosis assays were performed to study the cellular mechanism underlying the effect of Id1 deficiency. Mouse xenograft models were generated by subcutaneous injection of KM-LAC cells (H1792-604 and H2009), both shId1 and shGFP cells, in flanks of immunodeficient mice treated with doxycycline (drinking water) from the time of inoculation or once the tumors were established.

      Result:
      Id1 overexpression was observed in 11 out of 12 cell lines as occurs in previously reported clinical data. Id1 inhibition was achieved in all cell lines compared to controls. In absence of Id1, proliferation assays showed a significant impairment of cell growth in KM-LAC cell lines [H1792-604 31.61% ± 3.96 (P < 0.001); H2009 52.73% ±4.74 (P < 0.001); H358 70.85% ± 8.01 (P < 0.001)]. In KM cells, a significant arrest in G2/M phase of cell cycle was observed when Id1 was inhibited whereas no significant changes were observed in wild type(WT) KRAS cells [KM 1.86 ± 0.28;WT 1.02 ± 0.05 (P < 0.001)]. KM-cells showed a significant apoptosis increase compared to WT-cells [KM-cells 1.66 ± 0.41;WT-cells 0.99 ± 0.13 (P = 0.001)]. In vivo, we observed a significant decrease in tumor volume in mice injected with H1792-604-shId1 cells (60% ± 32.39) compared to shGFP group (356.29% ± 115.32)(P < 0.001). Moreover, mice injected with H2009-shId1 cells did not develop tumors compared to control mice (168.35 ± 68.71)(P < 0.001). Activation of shId1 in established tumors induced a significant reduction of tumor volume in both xenograft models. The inhibition led to regression of 4 out of 10 tumors H1792-604 and all tumors in H2009 inoculated mice.

      Conclusion:
      These findings support a crucial role of Id1 in tumor development in KRAS-driven adenocarcinoma of the lung. Id1 targeting was proven effective in both, tumor prevention and treatment in our humanized murine model of KM LAC.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-035 - Lymphocytes and Neutrophils Count After Two Cycles and TTF1 Expression as Early Outcome Predictors During Immunotherapy (ID 10308)

      09:30 - 16:00  |  Author(s): Christian Rolfo

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) therapeutic paradigm has dramatically changed with immune checkpoint blockers. The unconventional response patterns seen in patients treated with immunotherapy (IT) make it difficult to differentiate patients who respond from non-responders early on in treatment; and biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT.

      Method:
      We enrolled 32 consecutive patients with advanced NSCLC treated with IT at Clínica Universidad de Navarra (Spain) since 2015. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC (<1,000 vs >1,000) and ANC (<4,000 vs >4,000) after 2 cycles and response to IT. TTF1 expression was correlated with IT response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC.

      Result:
      TTF1 tumor expression in adenocarcinoma histology (n= 18) was significantly associated with response to IT (88% vs 45%, p= 0.03). Patients with ANC <4,000 after two cycles showed a longer median OS (NR vs 4.9 months; p=0.02). An ALC increase after 2 cycles was associated with DCR compared to progression (147 vs -155; p=0.05). ALC >1,000 after 2 cycles seemed to be more frequent among patients with TTF1+ tumors (82% vs 45%; p= 0.05) and among those experiencing DCR compared to progression (73% vs 58%; p=0.30).

      Conclusion:
      Our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger series.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-088c - Exosomal Amphiregulin Induce Osteoclastogenesis Through Osteoclast Differentiation Mediated by EGFR Pathway (ID 9342)

      09:30 - 16:00  |  Presenting Author(s): Christian Rolfo

      • Abstract
      • Slides

      Background:
      Bone metastasis is the most frequent complication in NSCLC resulting in osteolytic lesions. During the bone metastasis, there is an increase on the osteoclastogenesis in detriment of the bone formation processes. Epidermal growth factor receptor (EGFR) pathway is constitutively activated in NSCLC and it is known that EGFR binds Amphiregulin (AREG) that is overexpressed in several cancers such as colon, breast and lung. Moreover, its levels in plasma derived from NSCLC patients correlate with poor prognosis. AREG was recently described as a signaling molecule in exosomes derived from cancer cell lines. Exosomes have a key role in the cell-cell communication and they were indicated as important actors in metastatic niche preparation. For this reason, in the present work, we hypothesize a role of AREG carried by exosomes derived from NSCLC cells and plasma of NSCLC patients, in osteoclast differentiation.

      Method:
      Exosomes were isolated from CRL-2868 cells, by ultracentrifugation and characterized by Western Blotting (WB) and electron microscopy analysis. AREG expression and EGFR phosphorylation was evaluated by WB in, CRL-2868 cells, exosomes and exosomes isolated from plasma derived from NSCLC patients. The osteoclasts morphology was assessed by confocal microscopy and RANKL, MMP9 and TRAP mRNA expression were measured by Real time PCR and RANKL and MMP9 secretion was evaluated by ELISA. The human biological material used in this publication was provided by Biobank@UZA (Antwerp, Belgium; ID: BE71030031000) and Banco de muestras biologicas Centro de investigacion Medica Aplicada (CIMA) Universidad de Navarra.

      Result:
      Exosomes derived from NSCLC plasmacontains AREG that induces EGFR pathway activation in pre-osteoclasts increasing the expression of RANKL which is able to induce the expression of proteolytic enzymes, MMP9 and TRAP, well-known markers of osteoclastogenesis. AREG function has been confirmed by loss and gain experiments with recombinant and neutralazing AREG, furthermore, knockdown-AREG exosomes do not induce osteoclast differentiation. To conclude, exosomes released in plasma of NCSLC patients, contain AREG, and induce osteoclasts differentiation of human primary osteoclasts.

      Conclusion:
      Exosomal AREG induces EGFR pathway activation that can induce RANKL expression that in turn, increases the expression of MMP9 and TRAP initiating an osteolytic bone metastasis.

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