The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example.

OBJECTIVE: To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non-small cell lung cancer (NSCLC). DATA SOURCES: Journal articles and the "grey" literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: A broad appraisal of the titles and abstracts of articles on gefitinib and tyrosine kinase inhibitors in lung cancer was undertaken to identify pertinent concepts and relevant publications for further analysis. Articles deemed particularly relevant were retrieved for detailed appraisal. Dossiers on the licensing of gefitinib from the Food and Drug Administration Web site and major published reviews were retrieved. Relevant pharmacogenetic issues were identified and the clinical studies addressing these were evaluated. DATA SYNTHESIS: Initial promising trial data for gefitinib in NSCLC led to its conditional marketing approval. When the drug's efficacy was not confirmed in a pivotal Phase 3 trial, its prescribing was restricted. Subsequent discovery of activating mutations in the tyrosine kinase domain of EGFR led to further retrospective and prospective evaluation of the drug in patients with those mutations. The new evidence was sufficiently robust to persuade the drug regulators to license the drug as first-line treatment for patients with locally advanced or metastatic NSCLC who test positive for those mutations. CONCLUSIONS: Pharmacogenetic evidence has played a key role in rescuing gefitinib for front-line treatment of NSCLC. This case-example portends what will be increasingly likely scenarios in the regulation and clinical validation of targeted drug therapies.

A toolkit for incorporating genetics into mainstream medical services: Learning from service development pilots in England.

BACKGROUND: As advances in genetics are becoming increasingly relevant to mainstream healthcare, a major challenge is to ensure that these are integrated appropriately into mainstream medical services. In 2003, the Department of Health for England announced the availability of start-up funding for ten 'Mainstreaming Genetics' pilot services to develop models to achieve this. METHODS: Multiple methods were used to explore the pilots' experiences of incorporating genetics which might inform the development of new services in the future. A workshop with project staff, an email questionnaire, interviews and a thematic analysis of pilot final reports were carried out. RESULTS: Seven themes relating to the integration of genetics into mainstream medical services were identified: planning services to incorporate genetics; the involvement of genetics departments; the establishment of roles incorporating genetic activities; identifying and involving stakeholders; the challenges of working across specialty boundaries; working with multiple healthcare organisations; and the importance of cultural awareness of genetic conditions. Pilots found that the planning phase often included the need to raise awareness of genetic conditions and services and that early consideration of organisational issues such as clinic location was essential. The formal involvement of genetics departments was crucial to success; benefits included provision of clinical and educational support for staff in new roles. Recruitment and retention for new roles outside usual career pathways sometimes proved difficult. Differences in specialties' working practices and working with multiple healthcare organisations also brought challenges such as the 'genetic approach' of working with families, incompatible record systems and different approaches to health professionals' autonomous practice. 'Practice points' have been collated into a Toolkit which includes resources from the pilots, including job descriptions and clinical tools. These can be customised for reuse by other services. CONCLUSIONS: Healthcare services need to translate advances in genetics into benefits for patients. Consideration of the issues presented here when incorporating genetics into mainstream medical services will help ensure that new service developments build on the body of experience gained by the pilots, to provide high quality services for patients with or at risk of genetic conditions.

Genetics education for health professionals: strategies and outcomes from a national initiative in the United Kingdom.

The National Health Service (NHS) National Genetics Education and Development Centre was established by the Department of Health in 2004 to help drive and co-ordinate genetics education for health professionals working outside specialist genetic services. This paper reviews the experiences and lessons learned to date. At the outset, it was clear that understanding the learning ethos, preferred delivery methods and attitudes towards genetics of different NHS healthcare groups was vital. We collected evidence by undertaking needs assessments with educators, practitioners and patients. We have determined the genetics knowledge, skills and attitudes which they said were needed and translated these into learning outcomes and workforce competences in a continuum of education. Beginning with core concepts introduced (and examined) pre-registration, the continuum continues with development of concepts post-registration as appropriate for role, leading to practical application and assessment of competences in the workplace. These are supported by a portfolio of resources which draw heavily on patient based scenarios to demonstrate to staff that genetics is relevant to their work, and to convince educators and policy makers that genetic education is likely to result in real clinical benefit. A long term educational policy, inclusive of learners, educationalists and their institutions must be evidence based, flexible and responsive to changes in workforce structure, provision of clinical services and conceptual and financial commitments to education. The engagement of national policy, regulatory and professional bodies is vital (www.geneticseducation.nhs.uk).

Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2.

Chordomas are rare sacrococcygeal/sacral, sphenooccipital/clivus, and spinal tumors whose molecular etiology remains relatively understudied. As several anecdotal reports had described chordomas in individuals with tuberous sclerosis complex (TSC), a multisystem hamartoma syndrome, we hypothesized that the genes that cause TSC may have an etiological role in chordomas. In two cases of sacrococcygeal chordomas in individuals with TSC, one with a germ-line TSC2 mutation and the other with a germ-line TSC1 mutation, we confirmed somatic inactivation of the corresponding wild-type allele by loss of heterozygosity analysis and immunohistochemistry. These data provide the first evidence of a pathogenic role by TSC genes in sacrococcygeal chordomas.