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Pao W.,Vanderbilt Ingram Cancer Center
Nature Reviews Cancer | Year: 2010

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease. © 2010 Macmillan Publishers Limited. All rights reserved.


Lovly C.M.,Vanderbilt University | Pao W.,Vanderbilt University | Pao W.,Vanderbilt Ingram Cancer Center
Science Translational Medicine | Year: 2012

Mutated anaplastic lymphoma kinase (ALK) drives the development of multiple tumor types, and ALK tyrosine kinase inhibitors such as crizotinib have been validated as targeted therapeutics. Unfortunately, as with other oncogene-driven tumors, therapeutic resistance invariably develops. In Science Translational Medicine, two recent studies provide new insight into mechanisms of resistance to ALK tyrosine kinase inhibitors and possible strategies to overcome this resistance.


Camidge D.R.,Aurora University | Pao W.,Vanderbilt Ingram Cancer Center | Sequist L.V.,Harvard University
Nature Reviews Clinical Oncology | Year: 2014

The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment of acquired resistance in NSCLC, focusing on EGFR mutant and ALK rearrangement-positive disease, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms of acquired resistance may be pharmacological (that is, failure of delivery of the drug to its target) or biological, resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain control of the disease in the acquired resistance setting, including the use of radiation to treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel approaches that have already proven successful include the development of second-generation and third-generation inhibitors and the combination of some of these inhibitors with antibodies directed against the same target. With our increased understanding of the spectrum of acquired resistance, major changes in how we conduct clinical research in this setting are now underway. © 2014 Macmillan Publishers Limited. All rights reserved.


Pao W.,Vanderbilt Ingram Cancer Center | Girard N.,University of Lyon
The Lancet Oncology | Year: 2011

Treatment decisions for patients with lung cancer have historically been based on tumour histology. Some understanding of the molecular composition of tumours has led to the development of targeted agents, for which initial findings are promising. Clearer understanding of mutations in relevant genes and their effects on cancer cell proliferation and survival, is, therefore, of substantial interest. We review current knowledge about molecular subsets in non-small-cell lung cancer that have been identified as potentially having clinical relevance to targeted therapies. Since mutations in EGFR and KRAS have been extensively reviewed elsewhere, here, we discuss subsets defined by so-called driver mutations in ALK, HER2 (also known as ERBB2), BRAF, PIK3CA, AKT1, MAP2K1, and MET. The adoption of treatment tailored according to the genetic make-up of individual tumours would involve a paradigm shift, but might lead to substantial therapeutic improvements. © 2011 Elsevier Ltd.


In 2009, ASCO and the Oncology Nursing Society (ONS) published standards for the safe use of parenteral chemotherapy in the outpatient setting, including issues of practitioner orders, preparation, and administration of medication. In 2011, these were updated to include inpatient facilities. In December 2011, a multistakeholder workgroup met to address the issues associated with orally administered antineoplastics, under the leadership of ASCO and ONS. The workgroup participants developed recommended standards, which were presented for public comment. Public comments informed final edits, and the final standards were reviewed and approved by the ASCO and ONS Boards of Directors. Significant newly identified recommendations include those associated with drug prescription and the necessity of ascertaining that prescriptions are filled. In addition, the importance of patient and family education regarding administration schedules, exception procedures, disposal of unused oral medication, and aspects of continuity of care across settings were identified. This article presents the newly developed standards.


Cmelak A.J.,Vanderbilt Ingram Cancer Center
Critical Reviews in Oncology/Hematology | Year: 2012

Curative treatment for patients with locally advanced squamous cell carcinomas of the head and neck (SCCHN) is complex and multidisciplinary. Our understanding of the optimal management of this disease has improved over the years, incorporating refined surgical approaches, better radiotherapy delivery methods, and greater use of systemic therapies. Investigation into shifting epidemiology patterns has uncovered two biologically and clinically distinct diseases: the smoking-related entity and the increasingly common malignancy associated with human papilloma virus (HPV). Prognosis favors the latter, driving newer investigations into dose de-intensification to limit toxicities in patients with HPV-driven disease, and alternatively intensifying treatment to improve tumor control in those with a significant smoking history. In this review, I describe the most recent progress in the multi-modal integration of radiotherapy and chemoradiotherapy, and the role of targeted agents and personalized therapy, and conclude with a discussion of the relevance of these innovations with respect to HPV tumor status. © 2012 Elsevier Ireland Ltd.


Rexer B.N.,Vanderbilt Ingram Cancer Center | Arteaga C.L.,Vanderbilt Ingram Cancer Center
Cancer Research | Year: 2013

The combination of a PI3K inhibitor with trastuzumab has been shown to be effective at overcoming trastuzumab resistance in models of HER2+ breast cancer by inhibiting HER2-PI3K-FOXO-survivin signaling. In this review the potential clinical implications of these findings are discussed. © 2013 American Association for Cancer Research.


Pao W.,Vanderbilt Ingram Cancer Center
Proceedings of the American Thoracic Society | Year: 2012

This brief report summarizes Dr. Pao's talk at the 54th Annual Meeting of the Thomas L. Petty Aspen Lung Conference, in Aspen, Colorado, on June 11, 2011. In this talk, Dr. Pao discussed three main topics: (1) DETECT (DNA Evaluation of Tumors for Enhanced Cancer Treatment), (2) MyCancerGenome.org (web-based decision support), and (3) DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment). Copyright © 2012 by the American Thoracic Society.


Boice Jr. J.D.,Vanderbilt Ingram Cancer Center
Journal of Radiological Protection | Year: 2012

For nearly 100 years, epidemiologic studies of human populations exposed to ionising radiation have provided quantitative information on health risks. High dose deterministic (tissue reaction) effects result when sufficient numbers of functioning cells are killed, such as in bone marrow depression that can lead to death. Lower dose stochastic effects are probabilistic in nature and include an increased risk of cancer later in life and heritable genetic defects, although genetic conditions in the children of irradiated parents have yet to be convincingly demonstrated. Radiation studies are of diverse populations and include not only the Japanese atomic bomb survivors, but also patients treated with radiation for malignant and non-malignant disease; patients exposed for diagnostic purposes; persons with intakes of radionuclides; workers occupationally exposed; and communities exposed to environmental and accidentally released sources of radiation. Much is known about radiation and its risks. The major unanswered question in radiation epidemiology, however, is not whether radiation causes cancer, but what the level of risk is following low dose (<100mSv) or low dose rate exposures. Paracelsus is credited with first articulating that the 'poison is in the dose', which for radiation epidemiology translates as 'the lower the dose, the lower the risk' and, an important corollary, the lower the dose, the greater the difficulty in detecting any increase in the number of cancers possibly attributable to radiation. In contrast to the Chernobyl reactor accident, the Fukushima reactor accident has to date resulted in no deterministic effects and no worker deaths. Estimates to date of population doses suggest very low uptakes of radioactive iodine which was a major determinant of the epidemic of thyroid cancer following childhood exposures around Chernobyl. The estimates to date of population doses are also much lower (and the distribution much narrower) than the doses for which cancer excesses have been detected among atomic bomb survivors after 60 years of follow-up. Studies of populations exposed to low doses are also limited in their ability to account for important lifestyle factors, such as cigarette smoking and medical x-ray exposures, which could distort findings. Studies of the Fukushima population should be and are being considered for reassurance and health care reasons. Apart from as regards the extreme psychological stress caused by the horrific loss of life following the tsunami and the large-scale evacuation from homes and villages, such studies have limited to no chance of providing information on possible health risks following low dose exposures received gradually over time - the estimated doses (to date) are just too small. © 2012 IOP Publishing Ltd.


Carney P.H.,Vanderbilt Ingram Cancer Center
Seminars in Oncology Nursing | Year: 2014

Objectives: To provide oncology nurses with an overview of clinical decision support (CDS) and explore opportunities for genomic CDS interventions. The nation's first personalized cancer decision support tool, My Cancer Genome, is presented as an exemplar of a novel CDS tool. Data Sources: Published nursing and medical literature and the internet for an exemplar. Conclusion: CDS is a sophisticated health information technology that can translate and integrate genomic knowledge with patient information, providing recommendations at the point of care. Implications for Nursing Practice: Nurses, as key stakeholders, must have an understanding of CDS interventions and their application to fully participate in all stages of CDS development and implementation. © 2014 Elsevier Inc.

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