GENETIC RISK FOR CANCER: A MODEL FOR
CANCER CONTROL

The Family Risk Assessment Program (FRAP) offers education, risk assessment, and evaluation of screening and prevention programs for individuals with a family history of cancer. This program serves as a research base for ongoing studies of the biological, genetic, and environmental factors that influence disease risk.

The availability of clinical genetic testing for cancer susceptibility genes has heightened the need to explore directions in genetic risk assessment and counseling. The challenges of disseminating genetic information to the lay and professional communities are being addressed through a series of educational interventions using state-of-the-art computer technology.

The Cooperative Family Registry for Breast Cancer Studies (CFRBCS), now in its third year, is an international collaborative effort among the Fox Chase Cancer Center, the Northern California Cancer Center, the Huntsman Cancer Institute, the Memorial Sloan-Kettering Cancer Center, the Ontario Cancer Treatment and Research Foundation, and the University of Melbourne Department of General Practice and Public Health. The CFRBCS was initiated by the National Cancer Institute to provide the scientific community with a resource for multi-disciplinary studies of breast cancer. The registry includes a large computerized database with both genetic and environmental risk information from a racially and ethnically diverse set of families with a history of breast cancer. Data in the registry was obtained from the analysis of tissue and blood samples obtained from study participants.

Our estimated accrual is 1,000 families over the course of the grant period. Together, the six institutions plan to recruit 5,000 families. Recruitment at Fox Chase is conducted through existing high risk and breast cancer evaluation clinics at Fox Chase, Fox Chase Network hospitals and Cooper Medical Center, as well as through physician referral and self-referral. To date, 505 probands and 787 family members have consented to participate in the CFRBCS. Seven hundred and eighty-five blood samples have been shipped to Coriell Institute for Medical Research (Camden, NJ) for storage.

Our participation in the CFRBCS has provided Fox Chase with the tremendous opportunity to develop a registry-based infrastructure, design a sophisticated family based informatics system, adopt state-of-the-art biospecimen processing, and successfully present the availability of genetic-based research to high risk individuals from several settings. Several national and international research institutions have received approval from the CFRBCS Advisory Committee to use CFRBCS data and biospecimens for research purposes. These studies include: "Population-Based Estimation of the Penetrance of Protein-Truncating Mutations in BRCA1 and BRCA2," "Mutations in the ATM Gene and the Risk of Breast Cancer," "Study Design Issues for Investigating Both Genetic and Environmental Risk Factors in a Case-Control Study," "Estrogen- and Carcinogen-Metabolism Genes and Risk of Breast Cancer," "A Prospective Study of Prognosis in Heritable and Familial Breast Cancer," and "Genetic Susceptibility to Risk Factors for Breast Cancer."

Among the factors associated with breast and ovarian cancer, none, other than gender and age, alters the magnitude of risk more than a family history of these diseases. Three mutations, 185delAG (on the BRCA1 gene), 5382insC (on the BRCA1 gene), and 6174delT (on the BRCA2 gene), predisposing to hereditary breast and ovarian cancer have been detected in Jews of Eastern European descent. A supplemental grant to the CFRBCS has made possible a three-year study by Fox Chase investigators to examine the prevalence of the three mutations in the BRCA1 and BRCA2 genes. The study sample will include 900 Jewish individuals unselected for family history. Initial screening for the three recurrent mutations will be accomplished by heteroduplex analysis. In addition, for participants whose family history is suggestive of an inherited pattern of breast/ovarian cancer, the entire coding region and all of the intron/exon boundaries of BRCA1 will be examined.

We are also examining women's perceptions of genetic testing and the psychological factors associated with potential mutation carrier status. Participants complete the Beck Depression Inventory, the Revised Impact of Events Scale, and Risk and Cancer at baseline, post counseling, one-month post disclosure and four months post-disclosure. An integral part of this study is the provision of education and personalized cancer risk counseling. To date, 321 women have contacted Fox Chase expressing interest in our research. Two hundred and one women have attended an education session. Of these, 193 availed themselves of cancer risk counseling and donated blood for genetic testing. One hundred and three relatives have also consented to participate in the study. Mutation analysis has been completed for 286 individuals and 175 have received results. Thirty-three are BRCA1 positive, 13 are BRCA2 positive, 20 are true negative and 220 are indeterminate.

Future research will focus on the decision-making process as it pertains to primary and secondary prevention following receipt of BRCA1 and BRCA2 genetic carrier status. Coping strategies of those who have received BRCA1 and BRCA2 mutation carrier status is of great interest and will also be the focus of future research efforts.

It has been estimated that about 10% of breast and ovarian cancer cases are hereditary. Mutations in the BRCA1 gene on chromosome 17 and in the BRCA2 gene on chromosome 13 may account for a significant proportion of these hereditary cases. Genetic screening for mutations in BRCA1 and BRCA2 is already being incorporated into clinical practice to enhance prevention and control strategies for high-risk individuals. Many articles have been published examining decision-making about undergoing genetic testing and the impact of results on individuals receiving such information. Relatively little attention has been paid to looking at the communication of genetic knowledge within families or at what percentage of individuals receiving test results inform their at-risk relatives of their carrier status. We have designed a survey to assess the pattern of communication within families one month after an individual receives test results. Results were analyzed to detect barriers or levels of distress encountered when communicating their genetic results to their at-risk relatives. Reasons for not sharing test results with certain family members were also explored.

Through these studies, we have shown that individuals are disclosing their test results to their relatives, and that there is a level of difficulty and anxiety in explaining this information, particularly to their own children. Further studies will be needed to monitor the impact of genetic test information notification and to aid in the development of guidelines for helping probands disseminate genetic test information to their relatives. Health care professionals and cancer risk counselors may have to explore with their patients undergoing genetic testing what difficulties exist within the family unit that may prevent their patients from sharing genetic testing information. Mechanisms to evaluate the effectiveness of intervention techniques will help monitor degrees of difficulties experienced by the probands and access by the at-risk relatives to genetic counseling and testing.

With funding from the NCI and the National Action Plan on Breast Cancer, FRAP has developed an interactive multimedia program (IMP) to facilitate cancer risk counseling among individuals with a family history of breast and ovarian cancer. The program is designed to improve comprehension of personal cancer risk and psychological adjustment regarding cancer risk counseling, as well as enhance genetics knowledge and satisfaction with decision-making regarding genetic testing. The IMP, which uses compact disc interactive (CD-i) technology, offers a variety of media (text, narration, still graphics, animation and full motion video) to present information. The interactive design requires active participation, facilitates repetition, and allows the participant to self-tailor the receipt of information to match her own learning needs. The program covers the role of family history and heredity in cancer risk assessment, familial cancer patterns, genetic testing for cancer susceptibility genes, and information on screening and prevention. A full motion video segment features women sharing their personal experiences about their decision to undergo cancer risk assessment, genetic testing, and preventive surgery.

This project, funded by the Department of Defense, established a breast cancer high-risk registry among the Fox Chase Network hospitals. Through on-going recruitment, research can be conducted among women with familial breast and/or ovarian cancer. This infrastructure project provided training, genetic educational resources, DNA and tissue collection procedures, genetic testing protocols and on-going administrative support to offer cancer risk assessment programs at community hospitals. Ten out of 13 Network institutions implemented the program. On average, three hospitals per year operationalized the program requiring six to eight months for start up. Over 500 women received education regarding breast cancer risk resulting in 164 women from 106 families joining the registry. Of those families, over 70% met criteria for high risk based on their family history with 50% providing biologic samples for the registry. Seven families participated in genetic testing research and received results. The Breast Cancer Risk registry has demonstrated that with sufficient resources and support it is feasible to create a community-based infrastructure for genetic research. This registry will provide an on-going opportunity to further epidemiologic and molecular research related to breast cancer, and to evaluate educational and counseling strategies for breast cancer risk assessment at the community level.

With the availability of genetic predisposition testing for cancer, a variety of health professionals are needed to meet the education and counseling needs of individuals seeking cancer risk information. Nurses, accustomed to risk assessment models in preventive health care, are well positioned with appropriate training in cancer genetics to become members of cancer risk assessment and counseling teams. A three-year educational research study evaluated knowledge outcomes of training oncology nurses in cancer risk counseling. Four separate training sessions were conducted with 164 nurses utilizing didactic instruction and skill building workshops on topics including genetic principles of inheritance, the molecular carcinogenesis of cancer genetics, inherited patterns of cancer, obtaining and evaluating a cancer family history, cancer risk models, medical management of high risk populations, and the psychosocial, legal and ethical implications of genetic risk information. To measure outcomes in knowledge, a 27 item, pre/posttest was developed from questions submitted by lecturers corresponding to lecture content.

Fox Chase Cancer Center was a participating site in the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Breast Cancer Prevention Trial (BCPT). The results of the preliminary data collected showed that Tamoxifen reduced the risk of invasive breast cancer, thus prompting the NSABP's decision to close the trial early. Our participants enrolled in the BCPT were unmasked to protocol therapy in April 1998 and the study was closed. The participants were informed via telephone over a three-day period. A follow-up letter detailing the preliminary results of the trial and their protocol assignment was mailed to each of the 44 participants within the month. The participants continue follow-up per the protocol every six months until year seven of the study. There have been no adverse events or deaths during the last year. Those women assigned to the Tamoxifen arm who have not completed five years of treatment continue to take study medication. Results of the study have been published (1).

In summary, Tamoxifen reduced the risk of invasive breast cancer by 49%. Risk was also reduced in women with a history of lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia and in those with any category of predicted five-year risk. Tamoxifen reduced the risk of non-invasive breast cancer by 50%. It reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen.

Tamoxifen administration did not alter the average annual rate of ischemic heart disease. However, a reduction in hip, radius and spine fractures was observed. The rate of endometrial cancer was increased in the Tamoxifen group. This increased risk occurred predominantly in women aged 50 years and older. All endometrial cancers in the Tamoxifen group were Stage I. No endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian or other tumors were observed in the Tamoxifen group. The rates of stroke, pulmonary embolism and deep-vein thrombosis were elevated in the Tamoxifen group. These events occurred more frequently in women aged 50 years or older.

Fox Chase Cancer Center has recently been chosen as one of the centers to conduct a Study of Tamoxifen and Raloxifene (STAR), a breast cancer prevention trial that will compare the protective benefit of Tamoxifen to that of Raloxifene a new selective estrogen receptor modifier (SERM).

1.   FISHER, B., COSTANTINO, J.P., WICKERHAM, D.L., REDMOND, C.K., KAVANAH, M., CRONIN, W.M., VOGEL, V., ROBIDOUX, A., DIMITROV, N., ATKINS, J., DALY, M., WIEAND, S., TAN-CHIU, E., FORD, L., WOLMARK, N., and other National Surgical Adjuvant Breast and Bowel Project Investigators. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl. Cancer Inst. 90(18):1371-1388, 1998.

BRUNET, J-S., GHADIRIAN, P., REBBECK, T.R., LERMAN, C., GARBER, J.E., TONIN, P.N., ABRAHAMSON, J., FOULKES, W.D., DALY, M., WAGNER-COSTALAS, J., GODWIN, A., OLOPADE, O.I., MOSLEHI, R., LIEDE, A., FUTREAL, P.A., WEBER, B.L., LENOIR, G.M., LYNCH, H.T., NAROD, S.A. Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J. Natl. Cancer Inst. 90:761-766, 1998.

DALY, M.B. Trials and tribulations of community interventions. Report of chair of symposia held at ASPO's annual meeting, March 4-6, 1998. Cancer Epidemiol. Biomark. Prev. 7:558, 1998.

DALY, M., OBRAMS, G.I. Epidemiology and risk assessment for ovarian cancer. Semin. Oncol. 25(3):255-264, 1998.

DIEFENBACH, M.A., MILLER, S.M., DALY, M.B. Specific worry about breast cancer predicts mammography use in women at risk for breast and ovarian cancer. Health Psychol. (in press).

REDSTON, M., NATHANSON, K.L., YAN, Z.Q., NEUHAUSEN, S.L., SATAGOPAN, J., WONG, N., YANG, D., NAFA, D., ABRAHAMSON, J., OZCELIK, H., ANTIN-OZERKIS, D., ANDRULIS, I., DALY, M., PINSKY, L., SCHRAG, D., GALLINGER, S., KABACK, M., KING, M-C., WOODAGE, T., BRODY, L.C., GODWIN, A., WARNER, E., WEBER, B., FOULKES, W., OFFIT, K. The APC I1307K allele and breast cancer risk. Nature Genet. 20:13-14, 1998.

SAUTER, E.R., BABB, J., DALY, M., ENGSTROM, P.F., EHYA, H., MALICK, J., DIAMANDIS, E. Prostate-specific antigen production in the female breast: Association with progesterone. Cancer Epidemiol. Biomark. Prev. 7, 315-320, 1998.

SHODA, Y., MISCHEL, W., MILLER, S.M., DIEFENBACH, M., DALY, M. B., ENGSTROM, P.F. Psychological interventions and genetic testing: Facilitating informed decisions about BRCA1/2 cancer susceptibility. J. Clin. Psychol. in Med. Settings 5(1):3-17, 1998.

DALY, M., FARMER, J., HARROP-STEIN, C., MONTGOMERY, S., ITZEN, M., COSTALAS, J.W., ROGATKO, A., MILLER, S., BALSHEM, A., GILLESPIE, D. Exploring family relationships in cancer risk counseling using the genogram. Cancer Epidemiol. Biomark. Prev. 8(4 Pt. 2):393-398, 1999.

^§    Fox Chase researcher

^a   K. McGlynn: National Cancer Institute, DCEG/EEB, Bethesda, MD 20892-7374

^b   G. Grana: Cooper Hospital/University Medical Center, Camden, NJ 08103

^c   J. Beck: Coriell Institute for Medical Research, Camden, NJ 08103

Illustrations or unpublished data in these reports should not be used without permission of the author.

Fox Chase Cancer Center

Scientific Report 1998