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L.C. Heukamp



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    MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA04.05 - P53 Non-Disruptive Mutation is a Negative Predictive Factor for OS and PFS in EGFR M+ NSCLC Treated with TKI (ID 5879)

      16:00 - 17:30  |  Author(s): L.C. Heukamp

      • Abstract
      • Presentation
      • Slides

      Background:
      P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

      Methods:
      484 patients diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either Miseq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 97%.

      Results:
      484 consecutive patients were studied. The overall EGFR M+ rate was 17.8% (86/484) in all patients, 84.9% (73/86) showing common mutations of exon 19 or 21. In 21/86 (24.4%) patients’ p53 analysis was not successful. P53 disruptive mutations were demonstrated in 24.6% (16/65) of successfully tested patients, and p53 non-disruptive mutation occurred in 27.7% (18/65) whereas p53 WT configuration was found in 47.7% (31/65). Median OS was 28 months in p53 disruptive mutation and 44 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p<0.023). PFS on 1[st] line TKI therapy was 14 months in p53 disruptive mutation, 27 months in p53 WT and 10 months in p53 non-disruptive mutation (p<0.040). Similar results were shown in the EGFR common mutation subgroup. 11/16 (68.8%) patients with a disruptive p53 M+ and 25/29 (86.2%) patients with a p53 WT constellation achieved an objective response on the 1[st] line TKI therapy compared to 7/13 (53.8%) patients with a non-disruptive p53 status. The patients with an unknown p53 status achieved an objective response on the 1[st] line TKI therapy of 82.4.8% (14/17).

      Conclusion:
      Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 M+ status. P53 mutational status is predictive when disruptive and non-disruptive p53 M+ are differentiated. A p53 WT constellation has a positive effect on OS and PFS. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03b-022 - Outcome in Molecularly Defined NSCLC within the NOWEL Network: The Influence of Sequential 2nd and 3rd Generation TKI in EGFR mt+ and ALK+ pts (ID 5902)

      14:30 - 15:45  |  Author(s): L.C. Heukamp

      • Abstract
      • Slides

      Background:
      Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with a proved mutation. Targeted therapies achieve a better quality of life, a higher PFS and ORR and in some cases increased OS. The aim of the study was therefore to systematically analyze retrospective data from three cancer centers in the north of Germany. The study compares these three cancer centers in reference to the test rate and the therapeutic success of targeted therapy.

      Methods:
      1383 patients from the three cancer centers diagnosed with non-small lung cancer stage IV (UICC 7) were examined. Methods for the detection of mutations included Sanger Sequencing, hybridization based COBAS testing as well as hybrid cage next generation sequencing. Clinical characteristics including smoking status were available for more than 92% of the patients.

      Results:
      880 consecutive patients from the three cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The overall mutation testing rate was 63.6% (880/1383). EGFR mutations were found in 18.4% (86/467)/ 13.1% (38/289)/ 11.3% (14/124) in the Pius-Hospital, Bremen-Ost or Hamburg Harburg respectively, ALK in 3.9% (18/467)/ 1.7% (5/289)/1.6% (2/124) yielding an overall EGFR M+ rate of 15.7% (138/880) and overall ALK M+ rate of 2.9% (25/880). Median OS was 43 (n=86) vs. 25 (n=38) vs. 16 (n=14) months (Pius vs. Bremen vs. Hamburg) (p<0.035). PFS on the 1[st] line TKI therapy was 25 (n=77) vs. 22 (n=31) vs. 10 (n=13) months respectively. Pts receiving 3[rd] generation TKI (Osimertinib n=12) had a significantly longer OS than pts not receiving 3[rd] gen. TKI (n=134). PFS on 3[rd] gen TKI was significantly longer than for other therapies (p<0.020). Median OS in ALK mutated patients was 31 (n=18) vs. 17 (n=5) vs. 10 (n=2) months (Pius vs. Bremen vs. Hamburg). Median OS of pts treated with Crizo alone (n=14) was 18 months, pts treated sequentially with Crizo and Ceritinib (n=6) 31 months, median OS without Crizotinib (n=4) was 17 months.

      Conclusion:
      The results illustrate differences between the three Lung Cancer Centers in the north of Germany. Significant differences in OS were observed, depending on the center and a significant difference in PFS between the therapy with Osimertinib and other therapies could be established. The differences mentioned could depend on the selection of the patients and their clinical characteristics. The clinical characteristics should be observed in detail.

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      P2.03b-081 - Comparison of Genomic Alterations Derived from Matched Tumor Tissue and Liquid Biopsy (ID 6010)

      14:30 - 15:45  |  Author(s): L.C. Heukamp

      • Abstract

      Background:
      In the last decade, translational research led to the identification of oncogenic drivers and the successful development of targeted inhibitors. Today, especially patients with lung carcinoma with a non-squamous histology benefit from targeted inhibition, for example of EGFR, ALK, ROS1, MET. However, in many cases tumor material is limited and does not allow for complete molecular diagnostics or, in a relapse setting, a re-biopsy may not be possible. Thus, reliable and comprehensive detection of genomic alterations by non-invasive means, such as liquid biopsies are required. In addition, repeated analysis of cell-free tumor DNA allows for disease monitoring while, at the same time, displaying the tumor heterogeneity.

      Methods:
      At NEO New Oncology we have developed two hybrid-capture based NGS assays, designed for the detection of genomic alterations in tissue or blood with high sensitivity and specificity. NEOplus is applied to FFPE tumor tissue and detects somatic alterations in a panel of more than 90 cancer related genes. NEOliquid is specifically designed for detection of genomic alterations from cell-free DNA of liquid biopsies and covers a panel of 39 clinically relevant genes. To evaluate the performance of liquid biopsies in the routine setting, we applied both NEO tests on matched FFPE and blood samples to correlated results.

      Results:
      Overall, a selection of matched FFPE and blood samples of more than 60 patients with non-squamous histology were analyzed. We were able to identify the same therapy relevant genomic alterations in FFPE and blood samples in a majority of the cases. Discrepancies in mutation spectrum of the blood and tissue sample were due to insufficient tumor DNA in cfDNA as well as tumor heterogeneity across multiple tumor manifestations.

      Conclusion:
      By comparing 60 matched tissue and blood sample we were able to identify concordant mutations across a broad spectrum of genes.