Cancer Survivorship—Genetic Susceptibility and Second Primary Cancers: Research Strategies and Recommendations

Lois B. Travis 1 2 Charles S. Rabkin 1 2 Linda Morris Brown 1 2 James M. Allan 1 2 Blanche P. Alter 1 2 Christine B. Ambrosone 1 2 Colin B. Begg 1 2 Neil Caporaso 1 2 Stephen Chanock 1 2 Angela DeMichele 1 2 William Douglas Figg 1 2 Mary K. Gospodarowicz 1 2 Eric J. Hall 1 2 Michie Hisada 1 2 Peter Inskip 1 2 Ruth Kleinerman 1 2 John B. Little 1 2 David Malkin 1 2 Andrea K. Ng 1 2 Kenneth Offit 1 2 Ching-Hon Pui 1 2 Leslie L. Robison 1 2 Nathaniel Rothman 1 2 Peter G. Shields 1 2 Louise Strong 1 2 Toshiyasu Taniguchi 1 2 Margaret A. Tucker 1 2 Mark H. Greene 1 2 0 7086, MSC 7238 , Bethesda, MD 20892 ( 1 Affiliations of authors: Division of Cancer Epidemiology and Genetics (LBT , CSR, LMB, BPA, NC, SC, MH, PI, RK, NR, MAT, MHG) , Center for Cancer Research (WDF), National Cancer Institute, National Institutes of Health, Department of Health and Human Services , Bethesda, MD; University of York , York , UK ( JMA); Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, NY (CBA); Memorial Sloan-Kettering Cancer Center , New York, NY (CBB , KO); University of Pennsylvania, Philadelphia (AD); The Princess Margaret Hospital, University of Toronto , Ontario , Canada ( MKG); Center for Radiological Research, Columbia University , New York , NY (EJH); Labo- ratory of Radiobiology, Harvard School of Public Health , Boston, MA (JBL); The Hospital for Sick Children , Toronto, Ontario , Canada ( DM); Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute (AKN) , Boston, MA; St. Jude Children's Research Hospital , Memphis , TN (C-HP); University of Minnesota, Minneapolis (LLR); Lombardi Cancer Center , Washington , DC (PGS); University of Texas M. D. Anderson Cancer Center, Houston (LS); Fred Hutchinson Cancer Research Center , Seattle, WA (TT). and Genetics , Radiation Epidemiology Branch, National Cancer Institute , 6120 Executive Blvd., EPS 2 Journal of the National Cancer Institute , Vol. 98, No. 1, January 4, 2006 Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled Cancer Survivorship-Genetic Susceptibility and Second Primary Cancers. These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer. [J Natl Cancer Inst 2006;98:15-25] - The 5-year relative survival rate after a diagnosis of cancer has increased steadily over the last few decades to reach almost 64% in the mid-1990s (1). As of 2001, there were almost 10 million cancer survivors in the United States, representing 3.5% of the population. Because of advances in early detection, supportive care, and treatment, the number of cancer survivors has tripled since 1971 and is growing by 2% each year (2). This growing and heterogeneous population provides important opportunities for clinical and epidemiologic research into cancer biology, long-term treatment effects, and prevention. One of the most serious events experienced by cancer survivors is the diagnosis of a new cancer. The number of second- or higher-order cancers is burgeoning and accounted for about 16% of incident cancers in 2003 (1). Also, second cancers have become a leading cause of death among long-term survivors of Hodgkin lymphoma (35). Second cancers can reflect the late sequelae of treatment; the influence of lifestyle factors, environmental exposures, and host factors; and combinations of influences, including geneenvironment and genegene interactions (Fig. 1). The research community has made great strides in elucidating treatment-associated risks for second cancer and documenting doseresponse relations between specific chemotherapeutic agents and/or therapeutic radiation and site-specific risk; however, the identification of patient subgroups that might be at heightened susceptibility of developing cancer or other adverse sequelae has not been systematically addressed. Although there are few data on the molecular underpinnings of genetic susceptibility to the development of late effects in the growing population of cancer survivors, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) serve as a strong research platform into the study of geneenvironment and genegene interactions. To date, however, there has been no concerted effort to provide future research direction in the complex area of molecular mechanisms of second cancer development. Thus, there is a Second Cancers: Etiology Interactions and other influences Fig. 1. Risk factors for second primary cancers (refer to text). Many influences, some of which are diagrammed here, may contribute to the development of multiple primary cancers, including interactions between exposures. From Travis LB. Acta Oncologica 2002;41:323333. Reproduced with permission from Taylor and Francis, Stockholm, Sweden. lack of relevant clinical research to provide evidence-based patient management guidelines and little consensus on either the infrastructure or study designs needed to comprehensively investigate late effects. Because molecular markers to gauge patient prognosis and predict tumor response to treatment are under investigation (68), it seems timely that attempts to customize therapy could also incorporate factors that might predict the susceptibility of patients to both acute and chronic toxicity, including second primary cancers. Prospective identification of patients genetically susceptible to the late complications of cancer treatment (9) could result in opportunities to individualize therapy to maximize therapeutic benefit and to minimize serious late toxicity (10). The goal of this commentary is to provide perspective on the research agenda, design considerations, and infrastructure that are needed to understand the underlying genetic mechanisms of late neoplastic e (...truncated)