Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer

Lara-Guerra, Humberto; Chung, Catherine T.; Schwock, Joerg; Pintilie, Melania; Hwang, David M.; Leighl, Natasha B.; Waddell, Thomas K.; Tsao, Ming-Sound

doi:10.1016/j.lungcan.2011.10.020

« Previous Next »Lung Cancer
Volume 76, Issue 2 , Pages 235-241, May 2012

Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer

Humberto Lara-Guerra
- Division of Thoracic Surgery, University Health Network, Toronto, ON, Canada
- Department of Surgery and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- These authors contributed equally to this work.
- Department of Thoracic and Cardiovascular Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Catherine T. Chung
- Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- These authors contributed equally to this work.
- Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
Joerg Schwock
- Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Melania Pintilie
- Department of Biostatistics, University Health Network and Princess Margaret Hosital, Toronto, ON, Canada
David M. Hwang
- Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Natasha B. Leighl
- Division of Medical Oncology and Haematology, University Health Network and Princess Margaret Hospital, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
Thomas K. Waddell
- Division of Thoracic Surgery, University Health Network, Toronto, ON, Canada
- Department of Surgery and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
Ming-Sound Tsao
- Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Corresponding author at: Department of Pathology, University Health Network, 200 Elizabeth St., Toronto, ON, Canada M5G 2C5. Tel.: +1 416 340 4737; fax: +1 416 340 5517.

Received 20 July 2011; received in revised form 23 October 2011; accepted 25 October 2011. published online 23 November 2011.

Abstract

To define the pathological features associated with response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC, we have evaluated tumor histopathological features and immunohistochemical markers of proliferation (Ki-67) and epithelial mesenchymal transition (EMT) in 36 resected early stage NSCLC from patients treated preoperatively with gefitinib for 28 days. Tumors studied included 7 squamous cell carcinoma, 27 adenocarcinoma (ADC), one adenosquamous carcinoma, and one large cell carcinoma. Six of the ADC harboured an EGFR tyrosine kinase domain (TKD) mutation; five were the sensitizing type. Five ADC with TKD mutation demonstrated non-mucinous lepidic growth pattern as the dominant histological feature. Post-gefitinib treated EGFR TKD mutant tumors demonstrated lower tumor cellularity and proliferative index compared to wild type ADC and non-ADC cases, features correlating with clinical response. Responding tumors also showed large areas of fibrosis, within which focal residual viable tumor cells were noted. However, there was no significant correlation between the degree of fibrosis and radiological changes in tumor size. Expression of EMT markers was not associated with significant change in tumor size. The results suggest that radiologically assessed response to EGFR TKI in NSCLC is related to loss of tumor cellularity and reduced tumor cell proliferation, but residual viable tumor cells may persist even after prolonged treatment. Neoadjuvant studies in early stage NSCLC offer a unique opportunity to evaluate pathological and biomarker changes induced by targeted drugs.

Keywords: Neoadjuvant therapy, Tyrosine kinase domain, Mutation, Gefitinib, Response biomarker, Proliferation marker, Fibrosis, Inflammatory infiltrate