I appreciate the opportunity to describe the purposes and achievements of the Metropolitan NY Registry and the five other sites contributing to the Cooperative Family Registry for Breast Cancer Studies [CFRBCS]. The initial goal of the CFRBCS, funded by the National Cancer Institute in 1995, was to encourage participation of key members of cancer-prone families. The families invited to join the Registry have been identified through high-risk clinics and population-based cancer registries. The role of family-based research for etiologic studies, specifically of the interactions of genetic risk with environmental exposures, was defined and potential multidisciplinary projects were described.
A major challenge for the CFRBCS Steering Committee was to develop a universal consent form to meet the Institutional Review Board [IRB] criteria of the six CFRBCS international sites. The consent form appropriately informs participants of the interdisciplinary research that will be conducted using the data and biospecimens they contribute and that findings from these studies may benefit their own families as well as society at large. The consent form also assures the protection and maintenance of confidentiality of all family members while minimizing any risks that may be associated with their participation. 
 Daly MB. Offit K. Li F. Glendon G. Yaker A. West D. Koenig B. McCredie M. Venne V. Nayfield S. Seminara D. Participation in the cooperative family registry for breast cancer studies: issues of informed consent. J. Nat. Cancer. Inst. 92:452-6 (2000)
Each participant has been asked to provide medical history, family and lifestyle information as well as blood and urine samples. Permission to obtain sections of tumor tissue is also requested of participants with a history of breast or ovarian cancer or whose affected relative is deceased. These data and biospecimens provide a valuable resource for qualified scientists who are studying avenues to prevent, diagnosis, and treat breast cancer. To ensure the appropriate use of the invaluable and limited biospecimens, senior breast cancer researchers of the Advisory Committee evaluate the merits of each submitted research proposal. Approved projects are then assessed by the Research Monitoring and Ethics Review Panel to assure that standards of medical ethics are maintained and the confidentiality of data is guaranteed.
Family-based genetic studies necessitate the participation of three or more relatives per family; therefore, women and men with and without a history of cancer are included. Although the need for enrollment of families rather than isolated individuals within families has created a sense of community among participants who share our common goals, some individuals have hesitated to encourage their relatives to participate. Some hesitancy has been due to the perception that genetic studies are qualitatively different from other types of medical research contributing to fear of genetic discrimination. To reassure participants and to protect their privacy a Certificate of Confidentiality has been obtained from the Department of Health and Human Services prohibiting names or identifying characteristics from ever being released for any purpose.
Due to the rapid progress of scientific research, especially in the field of genetics, the exact nature of future studies using the Registry resources could not be fully described to individuals considering participation. Therefore, a commitment was made by the CFRBCS team of investigators to inform Registry participants of ongoing research and results through biannual newsletters and educational seminars. [Current issue from NY is attached] Through these mechanisms participants are also advised of additional research opportunities in which their active participation might provide personal benefit while contributing to cancer prevention options, improved screening modalities and enhanced therapeutic modalities.
Our international CFRBCS now includes more than 6,000 families of whom 1,150 were recruited by the New York Registry team. To identify a diverse population of cancer-prone families from the New York metropolitan area, several of the researchers contributing to the Long Island case-control study also collaborated in forming the NY Registry. Families at high risk were defined as having one or more first or second degree relatives with: early onset breast cancer, a history of both breast and ovarian cancer, male breast cancer, or three or more older aged relatives with breast or ovarian cancer. These criteria for the NY Registry have enabled recruitment of a genetically diverse cohort of families with a spectrum of risk with potentially inherited susceptibility to breast cancer.
Data and biospecimens are collected from all participating relatives using common instruments and laboratory protocols. Coded personal health information, dietary intake, treatment for breast and/or ovarian cancer, and pedigree data are routinely transmitted to CFRBCS Informatics Center. Biospecimens including blood and tumor tissue samples are banked at each collaborating site following rigid quality control procedures. Annual follow-up with all participants has been conducted to maintain an accurate record of cancer history and current status of participating family members as well as those who have not agreed to join.
Data files from all six Registry sites are merged and made available to approved investigators by the CFRBCS Informatics Center. Code numbers enable linking of family and personal history data with genetic analyses; personal identifiers are never available. The development of research proposals has progressed concurrently with family recruitment. The banked data and specimens are now being used by New York colleagues as well as investigators across the country in many interdisciplinary studies to assess the risk of breast cancer and breast cancer prognosis associated with susceptibility genes and the interaction of these genes with environmental exposures.
Familial aggregation of breast cancer has been recognized for centuries; however, the identification of BRCA1 and BRCA2 indicated the importance of having a cohort of families for studies linking genetic and environmental factors for breast cancer studies. Following identification of specific mutations in BRCA1 and BRCA2 among members of breast cancer families of Ashkenazi heritage, supplemental funds were awarded to four of the six CFRBCS sites including the New York Registry. These funds enabled enhanced recruitment efforts and offer genetic counseling and test results to interested members of this subgroup.
Genetic testing assessed the presence of the three founder mutations including 185delAG and 5382insC on BRCA1 and 6174delT located on BRCA2. A total of 336 mutations carriers among men and women of Ashkenazi heritage have been identified in the 1,417 Ashkenazi families currently participating in the CFRBCS. Of the 1,078 Ashkenazi participants with a history of breast or ovarian cancer, 18% were found to have inherited one the founder mutations. More than 1,220 blood samples from 93 New York Ashkenazi families have been tested for the founder mutations. Of these, 144 carriers have been identified including 120 women and 24 men. In addition to breast and ovarian cancer, some carriers have reported malignancies of other sites including prostate, colon, and melanoma. Sixty-one, 18 men and 43 women, found to have a mutation of either BRCA1 and BRCA2 have not been diagnosed with any cancer; however, most are younger than age 60 and remain at elevated risk. Although genetic counseling with provisions providing genetic test results was offered to all participants of Ashkenazi heritage, approximately 25% requested these services. However, during follow-up calls, additional family members are now expressing interest in learning their carrier status.
Although a large increase in disease risk has been associated with inheritance of mutant alleles of the two known breast cancer susceptibility genes, BRCA1 and BRCA2, these genetic mutations account for only a small proportion of breast cancer cases. Investigators are now recognizing the contribution of "low-risk" genetic variations to breast cancer risk. Single nucleotide polymorphisms (SNPs) which occur frequently in the regulatory and coding regions of genes, may confer an increase in cancer risk or modify the cancer risk induced by other factors. The common occurrence of SNPs in the population could contribute more to cancer incidence than the BRCA1 and BRCA2. SNPs may interact with environmental exposures modifying their independent effects disease risk. Studies of many SNPs are currently being conducted by CFRBCS investigators.
Enrollment of family members is often complicated by the geographic dispersion of living relatives necessitating much recruitment by phone and mail. However, this dispersion may be an asset for studies of suspected environmental contaminants. The metropolitan area includes regions of downstate New York as well as counties of New Jersey and Connecticut close to Manhattan. More than 300 participating families residing on Long Island have a first degree relative living outside the metropolitan area. To assess the impact of geographic dispersion that may implicate environmental exposures in breast cancer patterns within families, studies of paired sisters and parent-offspring sets may provide unique opportunities to assess cancer risk among individuals with shared exposures during formative years and differing geographic environments later in life. In addition, the more than 6,000 enrolled CFRBCS families are widely dispersed geographically providing the opportunity to assess breast cancer risk in relation in environmental exposures, BRCA1/2 mutation status and SNPs. As technology advances enable reliable measures of environmental contaminants, Registry sites could collect additional data and biospecimens to enhance currently banked samples in order to assess risk in relation to the interaction of specific genetic factors and suspected adverse exposures.
The Metropolitan NY Registry and 5 collaborating sites of the CFRBCS have recently been awarded an additional 5 years of support indicating the importance placed on this project by Dr. Richard Klausner, Director of the NCI, and Dr. Barbara Rimer, Director of the Division of Cancer Control and Population Sciences. These funds will support additional recruitment, specifically of minority families, in order to provide adequate numbers for subgroup multidisciplinary studies. Disparities in risk and prognosis of breast cancer will be studied in relation to genetic, environmental, and treatment factors. Continuing follow-up interviews will be conducted providing opportunities to assess specific environmental exposures suspected of increasing breast cancer risk as well as changes in exposures reported at entry to the Registry.
The NY Registry and the collaborating sites of the CFRBCS provide a unique resource for current and future studies of breast cancer risk associated with genetic factors, environmental exposures, life style factors, and personal behaviors. During the next five years the Registry should contribute greatly to identifying avenues for reducing the incidence and enhancing prognosis of breast cancer. I feel privileged to be leading the New York Registry team and to be contributing to breast cancer research supported by the National Cancer Institute.