Role In Precision Medicine Research Articles

Towards precision medicine: from quantitative imaging to radiomics.

Radiology (imaging) and imaging-guided interventions, which provide multi-parametric morphologic and functional information, are playing an increasingly significant role in precision medicine. Radiologists are trained to understand the imaging phenotypes, transcribe those observations (phenotypes) to correlate with underlying diseases and to characterize the images. However, in order to understand and characterize the molecular phenotype (to obtain genomic information) of solid heterogeneous tumours, the advanced sequencing of those tissues using biopsy is required. Thus, radiologists image the tissues from various views and angles in order to have the complete image phenotypes, thereby acquiring a huge amount of data. Deriving meaningful details from all these radiological data becomes challenging and raises the big data issues. Therefore, interest in the application of radiomics has been growing in recent years as it has the potential to provide significant interpretive and predictive information for decision support. Radiomics is a combination of conventional computer-aided diagnosis, deep learning methods, and human skills, and thus can be used for quantitative characterization of tumour phenotypes. This paper discusses the overview of radiomics workflow, the results of various radiomics-based studies conducted using various radiological images such as computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET), the challenges we are facing, and the potential contribution of radiomics towards precision medicine.

Alcohol-Induced Epigenetic Changes in Cancer.

Chronic, heavy alcohol consumption is associated with serious negative health effects, including the development of several cancer types. One of the pathways affected by alcohol toxicity is the one-carbon metabolism. The alcohol-induced impairment of this metabolic pathway results in epigenetic changes associated with cancer development. These epigenetic changes are induced by folate deficiency and by products of the ethanol metabolism. The changes induced by long-term heavy ethanol consumption result in elevations of homocysteine and S-adenosyl-homocysteine (SAH) and reductions in S-adenosylmethionine (SAM) and antioxidant glutathione (GSH) levels, leading to abnormal promoter gene hypermethylation, global hypomethylation, and metabolic insufficiency of antioxidant defense mechanisms. In addition, reactive oxygen species (ROS) generated during the ethanol metabolism induce alterations in DNA methylation patterns that play a critical role in cancer development. Specific epigenetic changes in esophageal, hepatic, and colorectal cancers have been detected in blood samples and proposed to be used clinically as epigenetic biomarkers for diagnosis and prognosis of these cancers. Also, genetic variants of genes involved in one-carbon metabolism and ethanol metabolism were found to modulate the relationship between alcohol-induced epigenetic changes and cancer risk. Furthermore, alcohol metabolism products have been associated with an increase in NADH levels, which lead to histone modifications and changes in gene expression that in turn influence cancer susceptibility. Chronic excessive use of alcohol also affects selected members of the family of microRNAs, and as miRNAs could act as epigenetic regulators, this may play an important role in carcinogenesis. In conclusion, targeting alcohol-induced epigenetic changes in several cancer types could make available clinical tools for the diagnosis, prognosis, and treatment of these cancers, with an important role in precision medicine.

Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope

The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in several B cell malignancies and autoimmune diseases. G6 is an anti-idiotypic monoclonal Ab that selectively binds to IGHV1-69 heavy chain germline gene 51p1 alleles that have been implicated in these Ab responses and disease processes. Here, we determine the co-crystal structure of humanized G6 (hG6.3) in complex with anti-influenza hemagglutinin stem-directed broadly neutralizing Ab D80. The core of the hG6.3 idiotope is a continuous string of CDR-H2 residues starting with M53 and ending with N58. G6 binding studies demonstrate the remarkable breadth of binding to 51p1 IGHV1-69 Abs with diverse CDR-H3, light chain, and antigen binding specificities. These studies detail the broad expression of the G6 cross-reactive idiotype (CRI) that further define its potential role in precision medicine.

Abstract P6-09-16: Identification of proliferation related derivers and their roles in precision medicine for breast cancers: A retrospective multidimensional comparative, integrated genomic, transcriptomic, and protein analysis

Abstract Backgound and Aim: The best test to guide the choice of systemic therapy for breast cancer (BC) has not yet been identified. We did this study to identify factors that drive proliferation features in BC and assess their association with clinical outcomes after systemic therapy. Methods: We applied an artificial neural network-based integrative data mining approach to three cohorts of patients with untreated lymph node (LN)-negative BC (Wang et al; n=286, Desmedt et al; n=198 and Schmidt et al; n=200). The results were validated in four cohorts of BC patients (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), The Cancer Genome Atlas-Breast Cancer project [TCGA-BRCA; n= 970] and Molecular Taxonomy of Breast Cancer International Consortium [METABRIC cohort; n=1980]. Genes that featured prominently in our interactome map of proliferation have been chosen to take them forward to investigate their clinicopathological relevance of their gene copy number aberrations (CNAs), mRNA transcript expression, and protein expression and their associations with breast cancer-specific survival (BCSS), distant relapse-free survival (DRFS) and pathological complete response (pCR) in ten international cohorts of BC (n>12000 patients). Findings: ESR1, SPAG5, EGFR, BCL2, and FOXA1 were among the 39 common gene probes that were predictive across most proliferation features and datasets. In TCGA-BRCA cohort, SPAG5 gene mutation, gain/amplification and loss at the Ch17q11.2 locus were detected in 43 (4.4%), 177 (18.2%) and 180 (18.8%) of 970 patients, respectively and 65 (31%) of 479 ER-positive /HER-positive patients showed gain/amplification of SPAG5 gene. In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced BCSS compared with lower expression (METABRIC: HR 1·27, 95% CI 1·02–1·58, p=0·034; untreated LN-negative cohort: 2·34, 1·24–4·42, p=0·0090; and Nottingham-cohort: 1·73, 1·23–2·46, p=0·0020). In patients with ER-negative/HER2-negative or ER-positive/HER2-negative BC, high SPAG5 transcript expression was associated with an increased pCR compared with low SPAG5 transcript expression after receiving anthracycline neoadjuvant chemotherapy (AC-NeoACT) [(Multicentre phase 2 clinical trial cohort; n=136; OR 2·47, 95% CI 1·17–5·21, p=0.016) and (MD Anderson- taxane+AC-NeoACT cohort; n=287; OR 3·16, 95% CI 1·46–6·84, p=0.003); respectively]. In patients with ER-positive/HER2-negative BC who received taxane+AC-NeoACT followed by adjuvant tamoxifen (Adj-Tam) for 5 years (MD Anderson- taxane+AC-NeoACT cohort; n=287), high and low SPAG5 transcript expression had similar DRFS (HR 1·40, 95% CI 0.76–2·58, p=0.282). Whereas in ER-positive/HER2-negative BC patients who received only adj-Tam (n=298), high SPAG5 transcript expression was associated with reduced DRF at 5 years compared with lower expression (HR 1.98, 95% CI 1.19–3.27, p=0.008). Interpretation: The transcript and protein products of SPAG5 are independent prognostic and predictive biomarkers that might have clinical utility as biomarkers for combination cytotoxic chemotherapy sensitivity in ER-positive/HER-negative BC. Citation Format: Abdel-Fatah TMA, Agarwal D, Zafeiris D, Pongor L, Györffy B, Rueda OM, Moseley PM, Green AR, Liu D-X, Pockley AG, Rees RC, Caldas C, Ellis IO, Ball GR, Chan SYT. Identification of proliferation related derivers and their roles in precision medicine for breast cancers: A retrospective multidimensional comparative, integrated genomic, transcriptomic, and protein analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-16.

Extracellular Vesicles: A Brief Overview and Its Role in Precision Medicine.

Precision medicine has emerged as an approach to tailor therapies for an individual at the time of diagnosis and/or treatment. This emergence has been fueled by the ability to profile nucleic acids, along with proteins and lipids isolated from biofluids, a method called "liquid biopsy ," either by or in combination of one of the following components: circulating tumor cells (CTCs), cell-free DNA (cfDNA), and/or extracellular vesicles (EVs) . EVs are membrane-surrounded structures released by cells in an evolutionarily conserved manner. EVs have gained much attention from both the basic and clinical research areas, as EVs appear to play a role in many diseases; however, the well-known case is cancer. The hallmark of EVs in cancer is their role as mediators of communication between cells both at physiological and pathophysiological levels; hence, EVs are thought to contribute to the creation of a microenvironmental niche that promotes cancer cell survival, as well as reprogramming distant tissue for invasion. It is important to understand the mechanistic and functional aspects at the basic science level of EVs to get a better grasp on their role in healthy and disease states. EVs range from 30-1000nm membrane-enclosed vesicles that are released by many mammalian cell types and present in a variety of biofluids. EVs have emerged as an area of clinical interest in the era of Precision Medicine, from their role in liquid biopsy (tissue biopsy free) approach for screening, assessing tumor heterogeneity, monitoring therapeutic responses, and minimal residual disease detection to EV-based therapeutics . EVs' diagnostic and therapeutic exploitation is under intense investigation in various indications. This chapter highlights EV biogenesis , composition of EVs, and their potential role in liquid biopsy diagnostics and therapeutics in the area of cancer.

PUB051 Comprehensive Analysis of Chromosomal Alterations Involving CDKN2A and 22q in Malignant Pleural Mesothelioma

The promise of personalized genomic medicine relies on the identification and clinical management of patients on the basis of specific genomic alterations that drive clinically heterogenous malignancies. While recent large cohort studies of malignant pleural mesothelioma (MPM) tumors have confirmed that CDKN2A and NF2 are among the most commonly mutated genes, the clinical and biological significance of these molecular alterations remains incompletely characterized. Herein, we explore whether loss of CDKN2A and/or 22q define molecular subclasses in a large cohort of MPM patients. FISH analysis was performed using the Vysis LSI9p21/CEP9 Dual Color Probe Set (Abbott Molecular, Des Plaines, IL) for the p16 locus at 9p21, CEP9 at the chromosome 9 centromeric region, and Vysis TUPLEI/LSI ARSA Dual color Probe set (Abbott) for TUPLEI at 22q11.2, and ARSA at 22q13. At least 50 nuclei were observed per tumor. Aberrations observed in ≥ 2% of nuclei was considered abnormal, based on normal mesothelial cell controls. Loss of CDKN2A or 22q was explored in relation to demographic, pathological and clinical factors using Fisher’s exact test. Overall survival (OS) was estimated using the Kaplan–Meier method and compared between groups using the logrank test. CDKN2A and 22q FISH data along with patient’s clinical information were collected from 592 MPM patients. Loss of CDKN2A was detected in 329 (56%), and of 22q in 326 (55%) patients. CDKN2A loss was significantly more common among men (p=0.0027) compared to women, and among men older than 60 compared to younger men (p = 0.0005). Loss of CDKN2A was also significantly correlated with self-reported asbestos exposure (p=0.0419), preoperative anemia (p=0.0007), and epitheliod tumor histology (p<0.0001). Loss of 22q was unrelated to most clinical factors explored, being only marginally associated with N2-N3 lymph node status compared to N0-N1 (p=0.0429). Survival analysis showed that patients with CDKN2A loss, with (n=228) or without (n=101) concurrent loss of 22q, demonstrated reduced OS compared to patients with either wild-type copy number of both markers (n=165; p<0.0001) or loss of 22q only (n=98; p < 0.0001). This study demonstrates a previously unappreciated relationship between demographic, clinical, pathological and outcome characteristics of MPM in association with CDKN2A versus 22q loss. The pattern of alteration involving these chromosomal regions may, therefore, suggest the possibility of distinct molecular subgroups. Further analyses are needed to demonstrate its potential role in precision medicine.

The Promises of Quantitative Proteomics in Precision Medicine

Precision medicine approach has a potential to ensure optimum efficacy and safety of drugs at individual patient level. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models could play a significant role in precision medicine by predicting interindividual variability in drug disposition and response. In order to develop robust PBPK/PD models, it is imperative that the critical physiological parameters affecting drug disposition and response and their variability are precisely characterized. Currently used PBPK/PD modeling software, for example, Simcyp and Gastroplus, encompass information such as organ volumes, blood flows to organs, body fat composition, glomerular filtration rate, etc. However, the information on the interindividual variability of the majority of the proteins associated with PK and PD, for example, drug metabolizing enzymes, transporters, and receptors, are not fully incorporated into these PBPK modeling platforms. Such information is significant because the population factors such as age, genotype, disease, and gender can affect abundance or activity of these proteins. To fill this critical knowledge gap, mass spectrometry-based quantitative proteomics has emerged as an important technique to characterize interindividual variability in the protein abundance of drug metabolizing enzymes, transporters, and receptors. Integration of these quantitative proteomics data into in silico PBPK/PD modeling tools will be crucial toward precision medicine.

Enviro-geno-pheno state approach and state based biomarkers for differentiation, prognosis, subtypes, and staging

Finding biomarkers for differentiation, prognosis, subtypes, and staging takes a key role in precision medicine, usually featured by association analysis on geno-measures and pheno-measures. Recent efforts turn to identifying the role of a biomarker under certain condition or in a particular environment, represented by a set of enviro-measures. This paper proposes to consider the joint domain of geno-measures, pheno-measures, and enviro-measures, in which one element (i.e., each triple jointly taken by the three measures) represents a possible behaviour of the bio-system under investigation. A collection of elements that locate adjacently and share a common system status represents a ‘state’, and the system is characterised by a number of such states learned from samples. Instead of directly using one or a set of geno-measures as a biomarker, such an enviro-geno-pheno state (E-GPS) is considered as a biomarker, indicating ‘health/normal’ versus ‘risk/abnormal’ together with its associated enviro-geno-pheno conditions. Association analyses for differentiation, prognosis, subtypes, and staging can be performed between such E-GPS biomarkers and those measures representing clinical phenotypes and treatments, made either on one state or cross multiple states. Moreover, potential applications are suggested for analyses of expression data, sequencing data, and their integrative uses.

Precision or Personalized Medicine for Cancer Chemotherapy: Is there a Role for Herbal Medicine.

Although over 100 chemotherapeutic agents are currently available for the treatment of cancer patients, the overall long term clinical benefit is disappointing due to the lack of effectiveness or severe side effects from these agents. In order to improve the therapeutic outcome, a new approach called precision medicine or personalized medicine has been proposed and initiated by the U.S. National Institutes of Health. However, the limited availability of effective medications and the high cost are still the major barriers for many cancer patients. Thus alternative approaches such as herbal medicines could be a feasible and less costly option. Unfortunately, scientific evidence for the efficacy of a majority of herbal medicines is still lacking and their development to meet FDA approval or other regulatory agencies is a big challenge. However, herbal medicines may be able to play an important role in precision medicine or personalized medicine. This review will focus on the existing and future technologies that could speed the development of herbal products for treatment of resistant cancer in individual patients. Specifically, it will concentrate on reviewing the phenotypic (activity based) rather than genotypic (mechanism based) approach to develop herbal medicine useful for personalized cancer chemotherapy.

Abstract No. 488 - The interventional radiologist’s role in precision medicine

Abstract No. 488 - The interventional radiologist’s role in precision medicine

Abstract A18: Exploration of Florida blacks' understanding of precision medicine for cancer care and treatment

Abstract Background and Objective: African-Americans in the US have the highest cancer mortality rates. Recognizing the need to address this disparity via technological and scientific innovation, In January 2015, President Obama introduced the Precision Medicine Initiative in his State of the Union Address. Allocating $215 million dollars in the 2016 budget, precision medicine should address these cancer health disparities. Yet, little is known about self-identified African-Americans/Blacks' knowledge of precision medicine. Strategy: The objective is to understand Floridan African American men and women's knowledge of Precision Medicine and ability to successfully explain underlying concepts relative to the Precision Medicine Initiative. Using a cross-sectional design, Florida Blacks' were recruited at health forums, barbershops, salons, and churches in the state of Florida. Participants completed a self-administered survey that asked about their demographics, knowledge of precision medicine and ability to explain PMI concepts. Participants who completed the study were given either a $5 gift card of a shirt. Results: A total of 132 participants completed the self-administered survey. Majority of the participants were female (64%) and Native U.S Blacks (85% African American of African descent). 62% were college trained and 71% were currently employed. 7% of participants had been diagnosed with cancer before and roughly 62% of them had private insurance. Well over 70% of participants have never heard of the concepts precision medicine, and pharmacogenomics. Over 50% of participants had never heard of personalized medicine, individualized medicine, and genomic sequencing. Participants were more familiar with the terms clinical trials, abnormal genes, hereditary risk, and genetic abnormality. They were also able to successfully describe the four terms that they were more familiar with. 73% participants stated that they did not know whether or not the use of precision medicine would improve cancer care and treatment. Conclusion: The findings suggest that majority of participants are unaware of precision medicine. There was little to no understanding about the role of precision medicine in cancer care and treatment. There is a great need to educate minority populations about the Precision Medicine Initiative and identify facilitators and barriers to engagement in order to address health disparities effectively and efficiently. Citation Format: Christina L. Redwine, Folakemi Odedina, Debra Lyon, Jennifer Nguyen. Exploration of Florida blacks' understanding of precision medicine for cancer care and treatment. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A18.

Abstract No. 486 - Percutaneous cholecystostomy: institutional experience and outcomes

Abstract No. 486 - Percutaneous cholecystostomy: institutional experience and outcomes

Abstract P6-04-13: The role of precision medicine in "real-life" management of breast cancer patients: A survey assessing the current use and attitudes towards tumor molecular sequencing in clinical practice

Abstract Background: Personalized medicine is a rising paradigm in cancer care. The identification of pathways involved in carcinogenesis along with the development of targeted therapies has revolutionized cancer treatment. There is increasing availability of technologies that can interrogate the genomic landscape of the tumor; however, it is still uncertain whether such platforms are used in clinical practice. Methods: We conducted a 28-item survey to investigate the current use of tumor molecular sequencing in the management of breast cancer patients. A link to the online survey was communicated via various platforms such as the European Society for Medical Oncology (ESMO) and European School of Oncology (ESO) newsletter, and via a dedicated mailing by the Breast International Group (BIG) and other academic groups. Descriptive statistical analysis and Fisher's exact tests were applied to explore potential association between the demographic characteristics and responses. Results: A total of 211 physicians from 35 countries participated to the study between the 9 March and 3 June 2015, with 92% fully completed questionnaires. The mean age of the participants was 45 years (range 27-77). The majority of responders were medical oncologists (88%), practicing in Europe (69%) and working in academic institutions (66%). 62% (130/211) of participants had never requested tumor molecular sequencing for breast cancer patients. Working in academic institutions and having more time allocated to research were associated with the use of tumor molecular sequencing (p = 0.007 and 0.009, respectively). For the 81 participants that used tumor molecular sequencing in the past (Table 1), there was a significant association between accessibility and frequency of use (p=0.02). 92% (181/211) of participants claimed that they would probably use tumor molecular sequencing more often if it was more accessible. Lack of funding and lack of access to the technology were the main reasons for poor endorsement. 89% of participants believe that tumor molecular sequencing will play a major role in the management of breast cancer patients in the future. Current weak evidence and poor access to matched targeted therapy are the main concerns against a wider use of these platforms in clinical practice. Table 1. Summary of replies from the 81 participants that used tumor molecular sequencing for breast cancer patientsQuestionResponseN (%)In what percentage of your breast cancer patients has tumor molecular sequencing been performed at least once?≤5%55 (68%) &amp;gt;5%26 (32%)How often do the results lead to enrollment in a clinical trial?≤10%53 (65%) &amp;gt;10%28 (35%)How confident are you in interpreting tumor sequencing results?Not at all/A little17 (21%) Somewhat/Highly64 (79%)Do you consider molecular sequencing platforms accessible?Not at all/A little45 (55%) Somewhat/Highly36 (45%) Conclusion: Our survey indicates that molecular sequencing platforms are sometimes used, albeit not widely in guiding management of breast cancer patients. Poor accessibility may contribute to the low frequency of use, but lack of evidence and poor access to matched targeted therapy are also major concerns. Citation Format: Gingras I, Sonnenblick A, Dolci S, de Azambuja E, Paesmans M, Delaloge S, Piccart MJ, Sotiriou C, Michail I, Azim Jr HA. The role of precision medicine in "real-life" management of breast cancer patients: A survey assessing the current use and attitudes towards tumor molecular sequencing in clinical practice. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-13.

Role of precision medicine in pancreatic cancer

Role of precision medicine in pancreatic cancer

The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations

Pancreatic cancer is one of the most lethal types of cancer due to its heterogeneous nature and the difficulty of detecting lesions in the pancreas during the early stages of tumorigenesis. Until recently, progress has been slow in developing methods to detect pancreatic lesions early. However, recent advances in genetics, biomarkers, imaging, and surgical procedures have aided the early detection of such lesions before the incurable metastatic disease state. Precision medicine has benefited pancreatic cancer patients in such areas as genetics, more targeted approaches to therapy, immunotherapy advances, and the discovery of more ideal biomarkers. In this review, the various studies and trials in these areas were reviewed to illustrate the promise of precision medicine.

Optimal Bayesian adaptive trials when treatment efficacy depends on biomarkers.

Clinical biomarkers play an important role in precision medicine and are now extensively used in clinical trials, particularly in cancer. A response adaptive trial design enables researchers to use treatment results about earlier patients to aid in treatment decisions of later patients. Optimal adaptive trial designs have been developed without consideration of biomarkers. In this article, we describe the mathematical steps for computing optimal biomarker-integrated adaptive trial designs. These designs maximize the expected trial utility given any pre-specified utility function, though we focus here on maximizing patient responses within a given patient horizon. We describe the performance of the optimal design in different scenarios. We compare it to Bayesian Adaptive Randomization (BAR), which is emerging as a practical approach to develop adaptive trials. The difference in expected utility between BAR and optimal designs is smallest when the biomarker subgroups are highly imbalanced. We also compare BAR, a frequentist play-the-winner rule with integrated biomarkers and a marker-stratified balanced randomization design (BR). We show that, in contrasting two treatments, BR achieves a nearly optimal expected utility when the patient horizon is relatively large. Our work provides novel theoretical solution, as well as an absolute benchmark for the evaluation of trial designs in personalized medicine.

Massively parallel DNA sequencing from routinely processed cytological smears.

Data generated by next-generation sequencing technologies have a pivotal role in precision medicine. These high-throughput techniques are preferentially performed on fresh tissue, but there is an increasing need for protocols adapted to materials derived from formalin-fixed, paraffin-embedded tissue and cytology specimens. The aim of this work was to show that cytological material collected from archival smears processed for routine diagnoses could be used for massively parallel sequencing and array-based genomic analysis for further studies. As a proof of concept, data obtained from May-Grünwald Giemsa- and Diff-Quik-stained archival smears were shown to be in keeping with those obtained from matched frozen controls. The quality of DNA extracted from routinely processed smears is compatible with the multitargeted sequencing of a large series of genes of interest with methods such as array-based genomic analysis and whole-exome sequencing.

Subtyping: What It is and Its Role in Precision Medicine

Precision medicine is an emerging approach that considers variability in genes, environment, and lifestyle in order to better treat individuals. This article gives an overview of the diverse approaches to subtyping, from early accounts based on clinical practice to more recent approaches that focus on computationally derived subtypes based on molecular and electronic health record (EHR) data. This field is expansive and growing rapidly; the authors juxtapose approaches taken by different communities and highlight examples of significant open computational problems.

Lung Cancer Genotype-Based Therapy and Predictive Biomarkers: Present and Future

The advent of genotype-based therapy and predictive biomarkers for lung cancer has thrust the pathologist into the front lines of precision medicine for this deadly disease. To provide the clinical background, current status, and future perspectives of molecular targeted therapy for lung cancer patients, including the pivotal participation of the pathologist. Data were obtained from review of the pertinent peer-reviewed literature. First-generation tyrosine kinase inhibitors have produced clinical response in a limited number of non-small cell lung cancers demonstrated to have activating mutations of epidermal growth factor receptor or anaplastic lymphoma kinase rearrangements with fusion partners. Patients treated with first-generation tyrosine kinase inhibitors develop acquired resistance to their therapy. Ongoing investigations of second-generation tyrosine kinase inhibitors and new druggable targets as well as the development of next-generation genotyping and new antibodies for immunohistochemistry promise to significantly expand the pathologist's already crucial role in precision medicine of lung cancer.