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M. Sebastian
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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
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.12 - Proteomic Profiling of Pulmonary Cancer with Squamous Cell Histology (ID 1377)
17:55 - 18:00 | Author(s): M. Sebastian
- Abstract
Background:
Pathologic differentiation of neoplastic lesions in the lung with squamous cell histology is challenging as appropriate diagnostic immunohistochemical biomarkers are lacking. In particular patients with head and neck cancer and a smoking history can develop both lung metastases and primary lung cancer. Differentiation of primary lung cancer and lung metastases of head and neck cancer is clinically important for therapy and risk stratification. Furthermore, molecular targeted therapies for squamous cell carcinoma of the lung are largely lacking to date. Recent genetic studies uncovered multiple genetic subgroups of squamous cell carcinoma of the lung and moreover potential drug targets. However, the correlation between protein-expression/signaling activation patterns and genetic alterations is strongly influenced by co- and post-transcriptional as well as post-translational regulation. We characterized a broad panel of primary patient-derived formalin-fixed squamous cell carcinomas from lung and head and neck cancer by quantitative mass spectrometry to identify proteomic diagnostic biomarkers, signaling patterns and potential novel drug targets.
Methods:
Proteins were extracted from formalin-fixed paraffin-embedded (FFPE) microdissected patient-derived cancer tissues by using the “filter-aided sample preparation (FASP)” method. Purified proteins were subsequently mixed with a cancer-matched isotope labeled quantification standard (Super-SILAC standard) that allows for identification and quantification of thousands of proteins and their phosphorylation sites by high-end mass spectrometry. Using bioinformatics we determined the protein expression and signaling patterns. The biomarkers discovered were validated by immunohistochemistry in additional independent tumor tissues.
Results:
In this study we quantitatively characterized the proteomes of 60 primary patient-derived non-small cell lung cancer specimens with squamous cell histology and 25 squamous cell carcinomas from the head and neck region derived from patients that developed lung tumors with similar histology in the course of their disease. Using the Super-SILAC-based mass spectrometric approach we were able to identify and quantify around 2500 proteins per sample. Unsupervised clustering- and principal component analyses revealed that the detected protein expression patterns show a strong correlation with the cellular origin of the analyzed carcinomas. Furthermore, secondary lesions with similar histological morphology in the lung in patients with squamous cell carcinoma of the head and neck region could be classified as primary or metastatic cancer according to their protein expression profiles.
Conclusion:
Collectively, this study provides a large set of proteomic biomarkers that can be used to improve lung cancer diagnostics in the future. In particular the differential diagnosis of squamous cell carcinoma/metastases in the lung, that has so far been difficult due to the lack of biomarkers, will be improved by the biomarker panels presented here. Moreover, the expression and activation patterns of kinases discovered in our study is of interest regarding potential novel lung cancer therapies as overexpression or hyperactivation of certain kinases can potentially contribute to the malignant phenotype of lung cancer cells.
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P2.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 210)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.02-034 - Induction Therapy with Intercalated TKI and Chemotherapy in NSCLC with Activating EGFR Mutation in Stages II-IIIB: NeoIntercal (ID 2255)
09:30 - 09:30 | Author(s): M. Sebastian
- Abstract
Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. 1[st] and 2[nd] generation agents lead to response rates of up to 70% in metastatic EGFRM+ NSCLC. Recently, new light has been shed on intercalated regimens of chemotherapy and TKI have shown improved PFS as well as OS in the metastatic setting in an unselected Asian population (Wu et al. 2013 The Lancet Oncology 14 (8): 777-86). Response is a predictor of PFS and OS in limited and locally advanced NSCLC. Chemotherapy induction alone leads to pCR rates of no more than 15%. No data have been generated for induction therapy including EGFR TKI in EGFRM+ NSCLC. Four cases treated in one center have demonstrated the feasibility and tolerability of an intercalated induction therapy concept (Lüers et al. 2013 Abstract WCLC).
Methods:
Therefore, NeoIntercal a single arm phase II study has been initiated in 9 centers in Germany. In a first step, patients with stage II to IIIB staged according to local standards will be screened for EGFR mutations by a ring certified pathologist. EGFRM+ patients will receive gefitinib 250 mg / die p.o. on d-12 to -1 (d1 = first day of first cycle of chemotherapy) followed by 3 cycles of taxane and platinum containing chemotherapy with intercalated gefitinib on d4-d20 of each cycle. After 2 cycles, restaging CT is performed and patients are scheduled to undergo surgery during the 4[th] or 5[th] week of the last cycle of CTx-gefitinib. Pathologic response rate is the primary endpoint. If more than 30% of patients achieve pCR (regression grades IIB and III according to Junker) in the mediastinal lymph nodes, it is planned to additionally enroll 28 patients in the 2[nd] part of the study. Secondary endpoints include OS, PFS, relapse rate and pattern, toxicity and feasibility. A liquid biopsy project is included in the study to correlate EGFR mutation status from tumor biopsy results with ctDNA plasma analysis. Furthermore, therapy effects will be monitored by liquid biopsy.
Results:
Study preparation and recruitment of clinical trial centers is nearly completed and the enrollment of the first patient is planned for 3Q2015. An interim analysis will be performed approximately 12 months after enrollment initiation with data from 21 patients. Should the interim analysis be positive and an additional 28 patients are included, the study is scheduled to end in approximately 2019 after a follow up period of 24 months.
Conclusion:
According to our knowledge, NeoIntercal is the first study in the neoadjuvant setting with curative intent applying an intercalating combination of chemotherapy and targeted therapy. The NeoIntercal study group believes that this study will potentially contribute to the improvement of EGFRM+ NSCLC therapy.
