Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma
Introduction
Lung cancer is the leading cause of cancer-related mortality in both men and women [1], and non-small cell lung carcinoma (NSCLC) accounts for ∼85% of lung cancer cases [2]. Although surgical resection is the choice of curative treatment, the majority of the patients with NSCLC are diagnosed at the advanced, unresectable stage. Historically, the pathologic stage has been used to define groups with similar treatment strategies, and is the most important predictor of survival in patients with NSCLC [3], [4].
However, NSCLC is now considered as a heterogeneous disease based both upon molecular features as well as histologic subtypes [5], [6]. In the last 5 years, it has also become evident that adenocarcinomas are characterized by distinct genomic changes that allow the tumors to be further classified into clinically relevant molecular subsets [7], [8], [9]. A representative is a subset of lung cancer patients with EGFR mutations that showed better response rates and prolonged progression free survival when treated with EGFR tyrosine kinase inhibitors (TKIs) than standard platinum-based chemotherapy [10]. Therefore, a selection of the patients based on a biomarker testing has become an essential prerequisite for the appropriate use of targeted therapies in NSCLC.
Recently, Soda et al. have identified the EML4 (echinoderm microtubule-associated protein like 4)-ALK (anaplastic lymphoma kinase) fusion gene in a subset of NSCLCs [11]. ALK-rearranged lung cancer is a unique NSCLC category that is characterized by ALK gene inversion or translocation, and mutually exclusive from other well-known oncogenic mutations involving EGFR or KRAS. Despite the relatively low frequency of the EML4-ALK fusion [12], [13], [14], [15], ALK-rearranged lung cancer has been considered as a unique subgroup with a striking response to treatment with a small-molecule inhibitor of ALK [16].
For the understanding of this patient group, it is important to characterize the clinicopathologic features and prognostic implications of ALK rearrangement in NSCLC, which has not yet been clarified. Furthermore, the efficient separation of the patients with ALK rearrangement from those with EGFR mutation by molecular tests using small biopsy materials is an emerging issue with great clinical interest. In many clinical situations with lung cancer patients including inoperable and/or unresectable condition, the limitation of the amount of biopsy material raised the question of which molecular test should be prioritized for the appropriate targeted therapy. The clinicopathologic characterization of ALK-rearranged lung cancer in the large-scale cohort may provide a possible answer to the clinically important question.
In this study, we aimed to contribute to (1) clinicopathologic characterization of the ALK-rearranged lung cancer in the surgically resectable patients, and (2) suggestion of a “tissue-saving” algorithm for molecular tests of adenocarcinoma with small lung biopsy samples. To make the clinical features clear, we constructed and analyzed retrospective cohort of the patients with primary lung cancer from two institutions in Korea by excluding the patients with stage 4 disease, previous history of cancer, presurgical chemotherapy or radiotherapy. For the clinicopathologic characterization including prognosis with this rare subgroup, it was inevitable to constitute a large-scale cohort by including parts of the previously reported NSCLC patient set where the correlation between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) was analyzed [12], [13].
Section snippets
Case enrollment
We reviewed the clinical characteristics and pathological specimens from patients diagnosed of NSCLC who underwent surgical resection at Seoul National University Bundang Hospital (SNUBH), from January 2003 to December 2008 and at Asan Medical Center (AMC), Seoul, from January 2000 to December 2003. Patients who did not receive a curative resection and had a previous history of cancer, presurgical chemotherapy or radiotherapy were excluded. We examined formalin-fixed, paraffin-embedded (FFPE)
Clinicopathologic characteristics of surgically resected NSCLC cases from two institutions in Korea
A total of 735 surgically resected stage I–III NSCLC patient samples were included in this study (371 from SNUBH and 364 from AMC). The patients composed of 510 (69.4%) men and 225 (39.6%) women. The histology was adenocarcinoma in 395 (53.7%) patients, squamous cell carcinoma in 292 (39.7%) patients, and other NSCLC in 48 (6.6%) patients. The pathologic stage was I in 388 (52.8%) patients, II in 159 (21.6%) patients, and III in 188 (25.6%) patients. The demographic and clinical characteristics
Discussion
The main clinicopathologic findings of our study were as follows: (1) ALK rearrangement per se was not prognostically significant for disease-free survival or overall survival in surgically resectable, early-stage adenocarcinoma cases; (2) ALK-rearranged lung cancer showed lower tumor stage (T1) in NSCLC (p = 0.02), whereas it tended to harbor lymph node metastasis in adenocarcinoma (p = 0.09) (Table 1, Table 2); (3) ALK rearrangement was more frequently observed in women, adenocarcinoma, and
Conflict of interest statement
The authors report no potential conflicts of interest.
Acknowledgments
This work was supported by grants from the Korea Healthcare technology R&D project, Ministry of Health & Welfare, Republic of Korea (A111405) and the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the government of Korea (2010-0022451).
The authors are indebted to J. Patrick Barron, Professor and Chairman of the Department of International Medical Communication, Tokyo Medical University and Advisory Professor of Seoul National
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These authors contributed equally to this article.