SAGE-Hindawi Access to Research Pathology Research International Volume 2011, Article ID 312346, 8 pages doi:10.4061/2011/312346 Review Article From the Bench to Bedside: Biological and Methodology Considerations for the Future of Companion Diagnostics in Nonsmall Cell Lung Cancer Anastasios Dimou,1 Kevin Harrington,2 and Kostas N. Syrigos3 1 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA 2 Section of Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, UK 3 3rd Department of Medicine, University of Athens Medical School, 11527 Athens, Greece Correspondence should be addressed to Anastasios Dimou, tasodimo6@hotmail.com Received 11 January 2011; Revised 9 May 2011; Accepted 14 June 2011 Academic Editor: Elizabeth Wiley Copyright © 2011 Anastasios Dimou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Companion diagnostics are an emerging and exciting ﬁeld in the care of oncology patients. These tests accompany standard diagnostic investigations in cancer patients and function as an aid in treatment decision making. A great number of new compounds are under clinical and laboratory testing in nonsmall cell lung cancer (NSCLC). As the variety of therapeutic options expands in the various settings of the disease, it becomes apparent that speciﬁc and sensitive molecular tests are necessary to deﬁne the subsets of patients who are going to derive clinical beneﬁt. Testing for epidermal growth factor receptor (EGFR) somatic mutations for the appropriate administration of tyrosine kinase inhibitors is just the beginning. Anaplastic lymphoma kinase (ALK) fusion protein detection and molecular histology classiﬁcation are promising candidate predictors for clinical beneﬁt from crizotinib and pemetrexed, respectively. This paper summarizes such diagnostics and discusses unanswered questions concerning underlying biology and standardization issues. 1. Introduction Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide [1]. Adenocarcinoma, squamous cell, and large cell carcinoma are the major histologic types. The majority of patients are diagnosed with metastatic disease and their treatment options are limited to systemically administered modalities often at the cost of signiﬁcant adverse events. With regard to clinical beneﬁt to toxicity ratio, tailoring treatment to every patient with NSCLC has emerged as a long-term goal. Recent advances in understanding tumor biology have provided new treatment targets as well as exciting insights into designing treatment plans according to unique molecular proﬁles. Companion diagnostics are tests that accompany diag- nostic investigations in cancer patients and determine whether speciﬁc drugs should, or should not, be admin- istered. The history of such tests can be traced back to the estrogen receptor in breast cancer: patients with this disease beneﬁt from antiestrogen treatment if their tumors express the receptor [2, 3]. In addition, patients with breast cancer receive trastuzumab if their tumors express HER2, a transmembrane receptor of the HER family [4]. Other examples include testing for KRAS mutations before prescribing cetuximab treatment in colorectal cancers [5] and testing for the presence of the Philadelphia chromosome for imatinib treatment in chronic and refractory or relapsed acute myeloid leukemias (AMLs) [6]. A companion diagnos- tic test should be highly reproducible and accurate, as well as rigorously standardized and validated before, it is widely recommended for clinical application. This paper summarizes recent progress in companion diagnostics in NSCLC. In particular, testing for epidermal growth factor receptor (EGFR) mutations and for anaplastic lymphoma kinase (ALK) fusion proteins is discussed. Those genetic alterations have been linked to response to tyrosine