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Pedro Rocha



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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): Pedro Rocha

      • 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.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-79 - CD73 Expression in Lung Adenocarcinomas and Immunological and Molecular Associations (ID 2412)

      09:45 - 18:00  |  Author(s): Pedro Rocha

      • Abstract

      Background

      Immune checkpoints inhibitors (ICI), in monotherapy or combination with chemotherapy, are the standard of care for lung adenocarcinoma (ADC) patients. Unfortunately, only a restricted number of patients will respond to ICI. Combination therapies such as CD73 inhibitors, are being studied with the goal to achieve synergic effects. CD73 is a membrane-bound protein with immunosuppressive functions. We previously reported that higher immune cell infiltration was associated mainly to CD73 basolateral (BL) expression, in this abstract, we show the correlation of CD73 expression at luminal (L) and BL membrane of ADC malignant cells (MCs), with annotated clinicopathological characteristics, immune and molecular biomarkers.

      Method

      CD73 IHC expression (clone D7F9A) was evaluated in 106 archived ADCs from patients that underwent surgical treatment without neoadjuvant therapy between February 1999 and February 2012 at MD Anderson Cancer Center (Houston, Texas, USA). We scored % and H-score of CD73 expression at the luminal (L) and basolateral (BL) membrane, we calculated the Total (T) CD73 as the average of L and BL, and classified ADCs in three groups: ‘T High’ (TH) (upper quartile for all tumors); ‘T Low’ (TL); ‘T Neg’ (TN) (<1%). We correlated T, L and BL expression and the three groups with clinicopathological characteristics, mutational status of KRAS and EGFR, TP53, STK11 and Tumor mutation burden (TMB), and cell densities of CD3, CD8, CD68, CD45RO, FOXP3, and Granzyme B, and PD-L1 expression (clone E1L3N) in MCs.

      Result

      T CD73 expression was found in 76%; BL in 60% and L in 57%; among ADCs with luminal membrane present (n=72), L CD73 was present in 83%. T+ and L+ expression was more frequent in never smokers (p=0.02 and p=0.003). Also higher frequency of L+ was found in older patients (>65) (p=0.01), tumors with non-solid histology patterns (p<0.001), EGFR mutation (p=0.048), non-mutated p53 (p=0.002), negative PD-L1 (p=0.03), and low TMB (<10 mut/MB) (p=0.001). Higher levels of L expression were found in KRAS mutated tumors (p=0.049). Higher BL expression positively correlated with p53 mutated tumors (p=0.038), PD-L1+ in MCs (p=<0.0001), and higher TMB (p=0.040).

      Our group analyses revealed that TH and TN were associated with ADCs from patients with >30 pack-year of smoking history (p=0.04), presence of any-solid histology pattern (p=0.03), p53 mutation (p= 0.005) and higher TMB (p=0.003) compared with TL. TH also had higher frequency of PD-L1+ tumors, and a higher cell density of CD3 (p=0.0001), CD8 (p=0.001), CD68 (p=0.048), CD45RO (p=0.036), FOXP3 (p=0.053), and Granzyme B (p=0.024) compared to TL and TN. TN showed higher frequency of STK11 mutation (p=0.034).

      Conclusion

      Based on the CD73 expression we defined subsets of lung adenocarcinomas that have distinct histological, molecular and immunological characteristics that may play a role in the response to ICI.

      Our characterization could help us to understand patient’s response to ICI, and identify patients that could potentially benefit from combination therapies.

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    P1.09 - Pathology (ID 173)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.09-32 - Concurrent Genomic Alterations in ALK-Rearranged Non-Small Cell Lung Cancer Patients (ID 2463)

      09:45 - 18:00  |  Author(s): Pedro Rocha

      • Abstract
      • Slides

      Background

      Recent progress in genomic analysis using next-generation sequencing (NGS) has enabled the comprehensive detection of targetable alterations in non-small cell lung cancer (NSCLC) patients. As the detection of ALK gene fusions is being established by NGS, identification of concurrent alterations will lead to better characterization of the molecular landscape of ALK-rearranged patients.

      Method

      Thirty-one NSCLC samples with known ALK status (18 positive and 13 negative) tested in our Institution using FISH, IHC, and NGS (Oncomine Focus Assay, ThermoFisher Scientific) were further evaluated by an expanded NGS gene panel (PGDx elio™ tissue complete assay (under developement), Personal Genome Diagnostics). This NGS panel comprises 500+ genes and screens for clinically relevant genomic alterations (single base substitutions/insertion and deletions, fusion genes and copy number variations), and provides TMB scores (expressed as mutations per megabase, exome equivalent). Statistical associations were assessed using Pearson’s χ2 and Mann-Whitney U test.

      Result

      ALK positive patients were 50% female with a median age of 59 years old and 54% of them never smokers. For the ALK negative cohort, young patients without any known driver alterations were selected: 69% male with a median age of 54 years old and 92% of them current smokers. Of the 18 ALK-positive cases identified, five were considered non-evaluable for expanded genomic analysis due to insufficient sequencing coverage (yield below minimum suggested DNA input). ALK fusions were detected by all techniques in the 13 ALK-positive cases available for analysis. EML4(13)-ALK(20) was the most prevalent gene fusion detected in seven out of 13 cases (54%). Remarkably, we detected a rare ALK gene fusion that has not been yet described: IRF2BP2(1)-ALK(20). The concurrent alterations identified by expanded genomic analysis are shown in an OncoPrint figure comparing both groups. The most frequent concomitant alteration was TP53 mutation: 62% in ALK-positive and 69% ALK-negative (p> 0.05). Regarding gene amplifications, we identified three ALK-positive cases with copy number alterations of which we highlight MYC in two of these cases. Interestingly, a high TMB was significantly associated with ALK-negative cases with a median of 19.9 mut/Mb compared to 7.0 mut/Mb in ALK-positive (p= 0.001).

      figure abstract wclc alk tmb.png

      Conclusion

      We have studied the presence of ALK fusion genes with a novel NGS panel that showed excellent correlation with standard techniques. ALK fusions can be interpreted as early strong drivers to carcinogenesis due to the low frequency of concurrent alterations. It remains to determine the clinical impact of these alterations in larger series.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-34 - Next-Generation Sequencing Implementation in Non-Small Cell Lung Cancer Molecular Diagnosis (ID 2337)

      10:15 - 18:15  |  Author(s): Pedro Rocha

      • Abstract
      • Slides

      Background

      Currently, all patients with advanced non-small cell lung cancer (NSCLC) require EGFR, ALK, ROS1 and BRAF molecular characterization. Next-generation sequencing (NGS) allows the simultaneous analysis of these biomarkers optimizing both the sample and the economic cost. The purpose of this study was to compare NGS results with those obtained using single gene analysis in a prospective clinical setting.

      Method

      During 12 months, 50 paraffin-embedded samples from patients with advanced NSCLC (46 adenocarcinomas and four NSCLC-NOS) were prospectively analyzed in our institution. Molecular characterization was carried out using the NGS Oncomine Solid Tumor DNA and Fusion Transcript Kits for hotspot mutations and gene fusions (Thermo Fisher) and results were compared with Therascreen EGFR RGQ PCR Kit (Qiagen), and Vysis ALK and ROS1 Break Apart FISH Probe Kits (Abbott Molecular, ZytoVision).

      Result

      All samples studied by NGS for hotspot mutations were assessable and we detected pathogenic alterations in 90% (n= 45). Regarding targetable alterations, we identified nine patients harboring EGFR mutations (18%), in agreement with real-time PCR (except for one case which had an exon 20 insertion not interrogated by Therascreen), and one patient with a BRAF mutation (2%). We highlight the presence of TP53 mutations in 27 cases (54%), KRAS in 16 cases (32%) and STK11 in three cases (6%). TP53 mutations were concomitant with other alterations in 70% of the cases (n= 19), without being significantly associated with any of them. Gene fusion analysis by NGS was assessable in 80% of the samples (n= 40): six samples had insufficient RNA quality and four had not enough material. We detected only one case with an ALK rearrangement (2%), confirmed by FISH.

      Conclusion

      NGS technology for NSCLC molecular diagnosis could be considered as the initial screening test although the success rate in gene fusion assessment is closely related to RNA paraffin-embedded evaluation. NGS also detected other genomic alterations that allowed referral of patients to clinical trials.

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