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Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2019 ASCO Annual Meeting but not presented at the Meeting, can be found online only.

The HGF-MET signaling pathway is enriched in LUAC brain metastases.

Sub-category:
Metastatic Non-Small Cell Lung Cancer

Category:
Lung Cancer—Non-Small Cell Metastatic

Meeting:
2019 ASCO Annual Meeting

Abstract No:
e20597

Citation:
J Clin Oncol 37, 2019 (suppl; abstr e20597)

Author(s): Maria A Velez, Zachary A. Yochum, Uma R. Chandran, Anish Chakka, Saveri Bhattacharya, Aswin Somasundaram, William LaFramboise, Gerald Wallweber, Roy Ravanera, Brenda F Kurland, Sanja Dacic, Laura P. Stabile, Timothy F. Burns; Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pharmacology & Chemical Biology and Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA; Department of Biomedical Informatics, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA; Department of Medical Oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA; Department of Pathology, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA; Monogram Biosciences/LabCorp of America, South San Francisco, CA; Monogram Biosciences/Laboratory Corporation of America, South San Francisco, CA; Department of Biostatistics, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA; Department of Pharmacology & Chemical Biology, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA; Department of Pharmacology & Chemical Biology and Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, PA

Abstract Disclosures

Abstract:

Background: Brain metastases occur in over 40% of non-small cell lung cancer (NSCLC) patients leading to a poor prognosis. c-Met (MET) is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. We have previously shown that the EMT transcription factor, TWIST1 is required for proliferation in MET driven NSCLC. Therefore, the HGF/MET/TWIST1 pathway may be a significant determinant of metastatic potential to the brain. Methods: We evaluated 125 lung adenocarcinoma (LUAC) brain metastases for MET amplification by FISH as well as other molecular alterations using targeted next generation sequencing in a subset of brain metastases (N = 74) and primary LUAC (N = 171) samples including 13 paired primary and brain sets. MET activation was examined in paired tumors using a HGF-MET proximity binding, dual-antibody assay (VeraTag; Monogram Biosciences). TWIST1 and EMT markers in the paired sets were measured by immunohistochemistry. Results: Compared to primary LUAC, we found that 17 pathogenic variants including TP53, SMAD4, RB1, RET, APC,ALK, FGFR3, EGFR, STK11 and MET alterations were significantly more common in LUAC brain metastases (adj. p values ≤ 0.02). Specifically, MET amplification was significantly enriched in LUAC brain metastases (23/125, 19%) compared to 2-4% in non-brain metastatic and primary sites. Among paired samples, 2/13 brain metastases had MET amplification that was not found in the primary tumor. MET mutations were also present in 16/74 brain cases (22%) compared to 9% (16/171) observed in the lung. VHL mutations were associated with MET altered cases compared to non-MET altered cases. MET expression was increased in the majority of brain metastases compared to the paired LUAC and there were 3 cases with brain specific MET activation. We found that TWIST1 was induced by HGF and determined response to MET TKIs in vitro. Among paired samples, TWIST1 was increased in brain metastases compared to primary LUAC in a subset of cases. Further analyses of TWIST1 and EMT markers is ongoing. Conclusions: Over a third of brain metastases have MET alterations compared to primary LUAC and may be responsive to MET inhibitors.

 
Other Abstracts in this Sub-Category:

 

1. Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.

Meeting: 2019 ASCO Annual Meeting Abstract No: 102 First Author: Ferdinandos Skoulidis
Category: Lung Cancer—Non-Small Cell Metastatic - Metastatic Non-Small Cell Lung Cancer

 

2. Real-world outcomes of patients with advanced non-small cell lung cancer (aNSCLC) and autoimmune disease (AD) receiving immune checkpoint inhibitors (ICIs).

Meeting: 2019 ASCO Annual Meeting Abstract No: 110 First Author: Sean Khozin
Category: Lung Cancer—Non-Small Cell Metastatic - Metastatic Non-Small Cell Lung Cancer

 

3. RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).

Meeting: 2019 ASCO Annual Meeting Abstract No: 9000 First Author: Kazuhiko Nakagawa
Category: Lung Cancer—Non-Small Cell Metastatic - Metastatic Non-Small Cell Lung Cancer

 

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