Carina Heydt

Abstract Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models. Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS. Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.

Abstract Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy. Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

// Matthias Scheffler 1,2,* , Marc Bos 1,2,* , Masyar Gardizi 1,2,* , Katharina König 1,3,* , Sebastian Michels 1,2 , Jana Fassunke 1,3 , Carina Heydt 1,3 , Helen Künstlinger 1,3 , Michaela Ihle 1,3 , Frank Ueckeroth 1,3 , Kerstin Albus 1,3 , Monika Serke 4 , Ulrich Gerigk 5 , Wolfgang Schulte 5 , Karin Töpelt 1,2 , Lucia Nogova 1,2 , Thomas Zander 1,6 , Walburga Engel-Riedel 7 , Erich Stoelben 7 , Yon-Dschun Ko 8 , Winfried Randerath 9 , Britta Kaminsky 9 , Jens Panse 10 , Carolin Becker 10 , Martin Hellmich 11 , Sabine Merkelbach-Bruse 1,3 , Lukas C. Heukamp 1,3,* , Reinhard Büttner 1,3,* and Jürgen Wolf 1,2,* 1 Center for Integrated Oncology Köln Bonn, Cologne, Germany 2 Lung Cancer Group Cologne, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany 3 Institute of Pathology, University Hospital of Cologne, Cologne, Germany 4 Department for Pulmonology and Thoracic Oncology, Lung Clinic Hemer, Hemer, Germany 5 Clinic for Hematology, Oncology and Palliative Care, Malteser Hospital, Bonn, Germany 6 Gastrointestinal Cancer Group Cologne, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany 7 Lung Clinic Merheim, Hospital of Cologne, Cologne, Germany 8 Johanniter Hospital, Evangelical Clinics of Bonn, Bonn, Germany 9 Clinic for Pneumology and Allergology Center for Sleep Medicine and Respiratory Care, Bethanien Hospital, Solingen, Germany 10 Department of Medicine IV, University Hospital RWTH Aachen, Aachen, Germany 11 Institute of Medical Statistics, Informatics, and Epidemiology, University of Cologne, Cologne, Germany * These authors contributed equally to this work Correspondence: Jürgen Wolf, email: // Keywords : Non-small cell lung cancer, PIK3CA, mutation, lung cancer, PI3K Received : October 22, 2014 Accepted : November 25, 2014 Published : November 26, 2014 Abstract Background: Somatic mutations of the PIK3CA gene have been described in non-small cell lung cancer (NSCLC), but limited data is available on their biological relevance. This study was performed to characterize PIK3CA -mutated NSCLC clinically and genetically. Patients and methods: Tumor tissue collected consecutively from 1144 NSCLC patients within a molecular screening network between March 2010 and March 2012 was analyzed for PIK3CA mutations using dideoxy-sequencing and next-generation sequencing (NGS). Clinical, pathological, and genetic characteristics of PIK3CA -mutated patients are described and compared with a control group of PIK3CA -wildtype patients. Results: Among the total cohort of 1144 patients we identified 42 (3.7%) patients with PIK3CA mutations in exon 9 and exon 20. These mutations were found with a higher frequency in sqamous cell carcinoma (8.9%) compared to adenocarcinoma (2.9%, p<0.001). The most common PIK3CA mutation was exon 9 E545K. The majority of patients (57.1%) had additional oncogenic driver aberrations. With the exception of EGFR -mutated patients, non of the genetically defined subgroups in this cohort had a significantly better median overall survival. Further, PIK3CA -mutated patients had a significantly higher incidence of malignancy prior to lung cancer (p<0.001). Conclusion: PIK3CA -mutated NSCLC represents a clinically and genetically heterogeneous subgroup in adenocarcinomas as well as in squamous cell carcinomas with a higher prevalence of these mutations in sqamous cell carcinoma. PIK3CA mutations have no negative impact on survival after surgery or systemic therapy. However, PIK3CA mutated lung cancer frequently develops in patients with prior malignancies.