Research Papers:

A window of opportunity study of potential tumor and soluble biomarkers of response to preoperative erlotinib in early stage non-small cell lung cancer

Adrian G. Sacher, Lisa W. Le, Humberto Lara-Guerra, Thomas K. Waddell, Shingo Sakashita, Zhuo Chen, Lucia Kim, Tong Zhang, Suzanne Kamel-Reid, Alexandra Salvarrey, Gail Darling, Kazuhiro Yasufuku, Shaf Keshavjee, Marc de Perrot, Frances A. Shepherd, Geoffrey Liu, Ming Sound Tsao and Natasha B. Leighl _

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Oncotarget. 2016; 7:25632-25639. https://doi.org/10.18632/oncotarget.8350

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Adrian G. Sacher1,5, Lisa W. Le2, Humberto Lara-Guerra3, Thomas K. Waddell3, Shingo Sakashita4, Zhuo Chen1, Lucia Kim4, Tong Zhang4, Suzanne Kamel-Reid4, Alexandra Salvarrey1,3, Gail Darling3, Kazuhiro Yasufuku3, Shaf Keshavjee3, Marc de Perrot3, Frances A. Shepherd1, Geoffrey Liu1, Ming Sound Tsao3, Natasha B. Leighl1

1Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

3Division of Thoracic Surgery, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

4Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

5Division of Hematology and Oncology, Columbia University/New York-Presbyterian Hospital, New York, New York, USA

Correspondence to:

Natasha B. Leighl, e-mail: [email protected]

Keywords: erlotinib, NSCLC, preoperative window study

Received: May 04, 2015     Accepted: March 10, 2016     Published: March 25, 2016


Background: Erlotinib is highly active in EGFR mutant NSCLC, but may benefit some with wild-type tumors. We examined pre-operative erlotinib in early stage NSCLC to assess response and correlation with potential biomarkers.

Results: Twenty-five patients were enrolled; 22 received erlotinib treatment and were evaluable (median follow-up 4.4 years). Histology was predominantly adenocarcinoma although 31% had squamous carcinoma. PET response was observed in 2 patients (9%), both with squamous carcinoma. Most (20/22) had stable disease (RECIST), with frequent minor radiographic regression and histologic findings of fibrosis/necrosis including in squamous histology. Only two had EGFR mutations identified, one with minor radiographic response and the other stable disease after 4 weeks of EGFR TKI. High pre-treatment serum levels of TGF-α correlated with primary resistance to erlotinib (p = 0.02), whereas high post-treatment soluble EGFR levels correlated with response (p = 0.03). EGFR, PTEN, cMET and AXL expression did not correlate with tumor response.

Methods: Clinical stage IA–IIB NSCLC patients received erlotinib 150 mg daily for 4 weeks followed by resection. Tumor response was assessed using CT, PET and pathological response. Tumor genotype was established using Sequenom Mass ARRAY; EGFR, PTEN, cMET and AXL expression was assessed by immunohistochemistry, circulating markers of EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) by ELISA and EGFR, MET copy number by FISH.

Conclusions: Erlotinib appears to demonstrate activity in EGFR wild-type tumors including squamous carcinoma. Further research is needed to characterize those wild-type patients that may benefit from EGFR TKI and predictive biomarkers including TGF-α, EGFR copy and others.

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