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Q. Zhou



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    JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)

    • Event: WCLC 2015
    • Type: Joint Chinese/ English Session
    • Track: Other
    • Presentations: 2
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      JCHS.03 - Development of New Drugs by Chinese Pharmaceutical Companies (ID 3453)

      07:55 - 08:15 AM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCHS.08 - Role of T790M Mutation in EGFR-TKI Rechallenge for Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 3525)

      09:25 - 09:35 AM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.

      Methods:
      We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.

      Results:
      EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.

      Conclusion:
      EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.

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    MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI03.09 - Role of T790M Mutation in EGFR-TKI Rechallenge for Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 1031)

      05:35 - 05:40 PM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.

      Methods:
      We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.

      Results:
      EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Figure 1 Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.



      Conclusion:
      EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.

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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI08.06 - Prognostic Significance of FGFR1 Amplification in Patients with Lung Squamous Cell Carcinoma (ID 814)

      05:20 - 05:25 PM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      The Fibroblast Growth Factor Receptor(FGFR) pathway especially FGFR1 gene copy number gain have attracted continuous attention of researchers for several years. Whereas due to different test methods and distinguishing criteria whether FGFR1 amplification related to patients smoking status or prognosis is still controversial.

      Methods:
      We used fluorescence in situ hybridization (FISH) to detect the gene copy number in paraffin-embedded tissue sections from 200 cases of pulmonary squamous cell carcinoma patients who underwent surgery in Guangdong Lung Caner Institute(GLCL) from 2008 to 2013. All samples had been identified as primary squamous cell carcinoma by postoperative pathology and informed consent. A tumor is defined as FGFR1 amplification positive when FISH results meet one of the following criteria after reviewing at least 100 tumor cells: (1) FGFR1/CEP-8 ratio≥2; (2) mean number of FGFR1 signals≥6; or if (3) ≥10% tumor cell containing more than 15 FGFR1 signals or large clusters. Among them, sample accord with the 3rd standard was defined as focal amplification.

      Results:
      Figure 1 We used fluorescence in situ hybridization (FISH) to detect the gene copy number in paraffin-embedded tissue sections from 200 cases of pulmonary squamous cell carcinoma patients who underwent surgery in Guangdong Lung Caner Institute(GLCL) from 2008 to 2013. All samples had been identified as primary squamous cell carcinoma by postoperative pathology and informed consent. A tumor is defined as FGFR1 amplification positive when FISH results meet one of the following criteria after reviewing at least 100 tumor cells: (1) FGFR1/CEP-8 ratio≥2; (2) mean number of FGFR1 signals≥6; or if (3) ≥10% tumor cell containing more than 15 FGFR1 signals or large clusters. Among them, sample accord with the 3rd standard was defined as focal amplification.



      Conclusion:
      Our results suggested that FGFR1 focal amplification might be an independent risk factor for patients overall survival. Patients with FGFR1 amplification were more likely to disease recurrence. Clinical characteristic including smoking status were not found in association with FGFR1 amplification, suggesting patients with FGFR1 amplification might not be fully enriched through only clinical factors.

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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI16.13 - A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901) (ID 2762)

      05:55 - 06:00 PM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      For non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, preclinical data showed the superiority of exon 19 mutations to exon 21 mutations in both response to EGFR tyrosine kinase inhibitors (TKIs) and survival. Meanwhile, retrospective studies demonstrated that erlotinib was significantly superior to gefitinib in progression-free survival (PFS) for advanced NSCLC patients with EGFR mutations. However, no randomized controlled trials compared erlotinib to gefitinib in advanced NSCLC patients with EGFR exon 19 or 21 mutations.

      Methods:
      We conducted a randomized controlled trial (CTONG 0901;NCT01024413) comparing erlotinib to gefitinib in advanced NSCLC harboring EGFR exon 19 or 21 mutations from July 2009 to July 2014. Eligible patients were randomized to receive erlotinib (150 mg, qd) or gefitinib (250 mg, qd) at the ratio of 1:1 in any line settings. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), post-progression survival (PPS), and toxicities.

      Results:
      The last follow-up was on March 30, 2015. Totally, 256 patients (148 with exon 19 mutations and 108 with exon 21 mutations), of whom 165, 83 and 9 were in the first, second or further-line settings respectively, were randomized to receive erlotinib or gefitinib. Median PFS was 12.4 (95%CI: 10.6~14.1) months in erlotinib arm and 10.4 (95%CI: 8.8~11.9) months in gefitinib arm, HR=0.80 (0.61~1.05), p=0.100; ORR, median PPS and OS were 56.3% versus 52.3% (p=0.530), 6.9 (95%CI: 4.3~9.5) versus 6.9 (95%CI: 4.5~9.2) months (p=0.784), and 22.4 (95%CI: 17.9~27.0) versus 20.5 (95%CI: 17.1~23.8) months (HR=0.90 [0.67~1.22]; p=0.496) respectively. There were no significant differences in toxicities between the two arms, p>0.05. In the four subgroups (the first-line, second or further-line setting, exon 19 and 21 mutations), except for median PFS being 11.4 versus 7.9 months (HR=0.58 [0.37~0.90], p=0.015) in the second or further-line setting, no significant differencs were observed in median PFS and OS respectively between the two arms, p>0.05. Receiving erlotinib or gefitinib treatment, EGFR exon 19 mutant patients were superior to those with exon 21 mutations in terms of ORR (62.2% versus 43.5%, p=0.003), median PPS (9.1 [95%CI: 7.0~11.2] versus 4.6 [95%CI: 3.4~5.8] months, p=0.011 ) and OS (24.8 [95%CI: 20.9~28.8] versus 17.7 [95%CI: 15.1~20.3] months, HR=0.66 [0.48~0.89], p=0.006) respectively, even though there was no significantly difference in median PFS (11.4 [95%CI: 9.6~13.2] versus 11.1 [95%CI: 9.4~12.9] months, HR=0.80 [0.60~1.05], p=0.101). Multivariant Cox regression analysis showed that subsequent EGFR TKIs, combination of subsequent EGFR TKIs and local treatment, as well as subsequent chemotherapy were prognostic factors for OS, p<0.05.

      Conclusion:
      Erlotinib was not significantly superior to gefitinib in advanced NSCLC with either exon 19 or 21 mutations in response and survival, with similar toxicities. However, EGFR exon 19 mutant patients had remarkably increased ORR, PPS and OS than those with exon 21 mutations after taking erlotinib or gefitinib. Subsequent treatments after failure to EGFR TKIs were significantly prognostic factors for OS.

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    MINI 26 - Circulating Tumor Markers (ID 148)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI26.13 - Serial ctDNA Assessment of Response and Resistance to EGFR-TKI for Patients with EGFR-L858R Mutant Lung Cancer from a Prospective Trial (ID 3107)

      05:50 - 05:55 PM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Plasma circulating tumor DNA (ctDNA) has been widely accepted as a form of liquid biopsy to detect EGFR mutations in NSCLC for its high concordance rate with tumor tissues. There are some retrospective studies about the ctDNA quantitative changes of EGFR mutations in EGFR-TKI treatment, but there is no report about serial ctDNA assessment of response and resistance to EGFR-TKI by detecting the dynamic changes of EGFR mutations during the whole course of EGFR-TKI treatment based on prospective clinical trial.

      Methods:
      Based on a randomized trial initiated to compare erlotinib with gefitinib in advanced NSCLC harboring EGFR exon 21 L858R mutation in tumor tissues (CTONG0901, NCT01024413), we prospectively collected serial plasma samples as preplanned schedule (baseline, one week after treatment, one month after treatment and then every 8 weeks until disease progression) and quantitatively detected EGFR L858R mutation in ctDNA by using fluorescence quantitative polymerase chain reaction. We made a serial ctDNA assessment of response and resistance to EGFR-TKI and its correlation with survival outcomes. Four patients’ serial plasma samples were selected to undergo next generation sequencing (NGS).

      Results:
      From 108 patients enrolled in the trial, serial plasma of 80 patients were collected as schedule and tested the quantity of L858R. As a whole, the quantity of L858R decreased to the lowest level when patients achieved best response to EGFR-TKI and increased to the highest level when disease progressed. Further analysis by Ward's Hierarchical Clustering Method showed that the dynamic changes of quantity of L858R could be categorized into two groups, Ascend Group and Stable Group (Figure 1A). Median progression-free survival (PFS) was 11.1 months (95%CI=6.6-15.6) and 7.5 months (95%CI=1.4-13.6) in two groups, respectively (HR=0.57, 95%CI=0.34-0.97, P=0.035) (Figure 1B). Median overall survival was 20.1 months (95%CI=15.7~24.5) vs. 16.4 months (95%CI=13.3~19.6) (HR=0.73, 95% CI =0.38~1.38, P=0.322). In multivariate Cox proportional hazards regression analysis, changing group was independent predictive factor for PFS. In plasma samples of 4 patients underwent NGS, similar dynamic changing characteristics were confirmed and more genetic mutations were found. Detailed data will be presented on site.Figure 1



      Conclusion:
      This is the first report about serial ctDNA assessment of response and resistance to EGFR-TKI by detecting the dynamic changes of EGFR mutation based on a prospective clinical trial. The quantity of plasma L858R has different changing patterns during EGFR-TKI treatment and higher L858R mutation abundance on EGFR-TKI resistance is correlated with longer PFS.

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    ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL16.07 - Intratumor Heterogeneity of EGFR Activating Mutations Analyzed in Single Cancer Cells in Advanced NSCLC Patients (ID 2311)

      11:50 - 12:01 PM  |  Author(s): Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can achieve dramatic response in EGFR activating mutation positive lung cancer patients. However, the duration of treatment is quite different. Some patients experienced longer progression-free survival (PFS) of more than 1 year, whereas some had PFS of shorter than 6 months. Our previous study showed that the relative EGFR mutation abundance in tumor tissues could predict benefit from EGFR-TKIs treatment. However, it still remains controversial whether the intratumor heterogeneity of EGFR activating mutation exists. This study explored the intratumor heterogeneity of EGFR activating mutation at the level of single cancer cell.

      Methods:
      Single H1975 cells which harbor EGFR exon 21 L858R mutation were isolated by flow cytometry (FCM). The whole DNA extracted from a single cell was submitted to perform nested polymerase chain reaction (PCR) amplification of EGFR exon 21. The amplified products from nested PCR were sequenced to evaluate the feasibility of single-cell analysis for EGFR exon 21. Then, six patients diagnosed with lung adenocarcinoma whose fresh frozen specimens harbored EGFR exon 21 mutation tested by direct sequencing were chosen. All of them received gefitnib treatment and the PFS of three patients was longer than 14 months (Group A) while the PFS of other three patients was shorter than 6 months (Group B). By using the established method based on single H1975 cells, EGFR exon 21 mutational status was analyzed in single tumor cells which were captured from tumor sample by Laser Capture Microdissection (LCM). At least 20 tumor cells were captured from each tumor sample. X[2] test was used to compare the amplification rate of nested PCR and EGFR mutational rate between the two groups.

      Results:
      A total of 104 individual H1975 cells were obtained to detect EGFR exon 21 mutational status through the application of single-cell nested PCR. The amplification rate and allele drop-out rate were 96.2% and 7.0%. A total of 135 tumor cells from six samples were captured. The amplification rate of nested PCR was 84.3% (59/70) in Group A and 93.8% (61/65) in Group B. There was no statistical difference between the two groups (X[2] =3.119, P=0.077). The mutational rate of EGFR exon 21 L858R was 89.5% (17/19), 89.5% (17/19), and 81.0% (17/21) in the three patients in Group A and 72.2% (13/18), 68.4% (15/22), and 66.7% (14/21) in the three patients in Group B respectively. The total mutational rate was 86.4%(51/59)in Group A, which was significantly higher than the total mutational rate 68.9%(42/61)in Group B (X[2] =5.321, P=0.021).

      Conclusion:
      It is feasible to perform EGFR mutation detection in single cancer cells. The intratumoral heterogeneity of EGFR activating mutation in lung adenocarcinoma does exist based on the analysis in single cancer cells and the abundance of EGFR activating mutation is relevant to the benefit from EGFR-TKIs treatment.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-051 - Biomarker Analyses from a Phase II Trial of Nab-Paclitaxel/Carboplatin vs Emcitabine/Carboplatin in Advanced Squamous Cell Lung Cancer (ID 2846)

      09:30 - 09:30 AM  |  Author(s): Q. Zhou

      • Abstract
      • Slides

      Background:
      The administration of nab-paclitaxel/carboplatin (nab-PC) as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) was efficacious and resulted in a significantly improved objective overall response rate (ORR) versus solvent-based PC in a phase Ⅲ trial. However, our phase Ⅱ trial (NCT01236716; CTONG1002), which compared the efficacy and safety of first-line nab-PC with gemcitabine/carboplatin (GC) in advanced squamous cell carcinoma of the lung, only showed a marginally improved ORR caused by first-line nab-PC. Meanwhile, the matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) and caveolin-1 are potential biomarkers for advanced NSCLC patients receiving nab-PC. Therefore, we retrospectively aimed to explore their predictive and prognostic value using immunohistochemistry (IHC).

      Methods:
      From November 2010 to June 2013, 127 untreated patients with locally advanced and metastatic squamous cell carcinoma of the lung were randomly assigned 1:1 to receive first-line nab-PC (nab-P, 135 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w ) or GC (G, 1,250 mg/m[2], d1, d8, q3w; C, AUC = 5, d1, q3w). There were 110 patients evaluable for ORR (nab-PC, 54; GC, 56), 119 evaluable for survival (nab-PC, 57; GC, 62) respectively. However, there were 72 patients with sufficient tissue for IHC of both SPARC and caveolin-1 proteins. Different cut-off values of IHC scoring systems were used to explore predictive and prognostic role of both biomarkers.

      Results:
      The last follow-up was on January 16, 2015. Considering treatment, when the maximum rank method was used for cut-off values, median progression-free survival (PFS) was 7.5 (95%CI: 2.4~12.6) months in higher SPARC-expression arm and 4.3 (95%CI: 2.2~6.3) months in lower SPARC-expression arm for patients treated with GC, HR=0.43 (95%CI: 0.19~0.94), p = 0.030; Median overall survival (OS) was 20.0 (95%CI: 14.7~25.3) months in lower SPARC-expression arm and 10.1 (95%CI: 6.2~14.0) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.41 (95%CI: 1.08~5.40), p = 0.027. When average method was used for cut-off values, median OS was 18.2 (95%CI: 9.6~26.8) months in lower SPARC-expression arm and 8.4 (95%CI: 5.1~11.7) months in higher SPARC-expression arm for patients treated with nab-PC, HR=2.46 (95%CI: 1.07~5.65), p = 0.029. Regardless of treatment, when the maximum rank method was used for cut-off values, median OS was 14.5 (95%CI: 6.8~22.1) months in lower SPARC-expression arm and 8.4 (95%CI: 5.3~11.5) months in higher SPARC-expression arm, HR=0.47 (95%CI: 0.27~0.83), p = 0.007. When average method was used for cut-off values, median OS was 14.4 (95%CI: 9.2~19.5) months in lower SPARC-expression arm and 8.4 (95%CI: 5.4~11.4) months in higher SPARC-expression arm, HR=0.48 (95%CI: 0.27~0.87), p = 0.013. ORR was not correlated with expression of SPARC, p>0.05. However, there were no significant differences in ORR, PFS and OS between higher and lower caveolin-1 expression arms, p>0.05.

      Conclusion:
      SPARC expression could be a negative prognostic factor for OS of patients with advanced squamous cell carcinoma of the lung, but was not a predictive factor for ORR and PFS, except for patients treated with GC. However, caveolin-1 expression had neither predictive nor prognostic value.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-036 - Rare Discrepancies in a Driving Gene Alteration within Histologically Heterogeneous Primary Lung Cancers (ID 2229)

      09:30 - 09:30 AM  |  Author(s): Q. Zhou

      • Abstract
      • Slides

      Background:
      Most lung adenocarcinomas consist of a mixture of histological subtypes among which driving gene mutations occurred with different frequencies. However, little is known about intratumoral heterogeneity within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to clinical practice and personalized treatment.

      Methods:
      Morphologically different tumor areas within the same surgically resected primary tumors were extracted from tissue sections and the gene status in each growth pattern was analyzed. Driving genes, epidermal growth factor receptor (EGFR), KRAS, and rearrangements in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), were assessed by assays of different sensitivity.

      Results:
      Seventy-nine consecutive, surgically resected, adenocarcinomas or adeno-squamouse cell carcinomas harboring a driving gene mutation or rearrangement (EGFR, n = 65; KARS, n = 10; EML4-ALK, n = 4) were selected. For EGFR mutations in adenocarcinomas, ITH occurred in 13.3% (8/60) as determined by direct sequencing, but in only 1.7% (1/60) by ARMS(P= 0.016). A consistent intratumoral EGFR mutation status was found within 5 histologically heterogeneous adeno-squamous cell carcinomas, as shown with ARMS. ITH among KRAS mutations were detected in 20% (2/10) of regions examined by direct sequencing ,whereas a consistent status (10/10) was obtained with HRM. There were no discrepancies in EML4-ALK rearrangements according to FISH for four tumors.

      Conclusion:
      Rare ITHs deriving from EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas were found with methods of high sensitivity. Discrepancies might be due to the abundance of cells harboring driving gene and detection assays.

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