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Genetic Predisposition Testing: Taking the Lead
GYNECOLOGIC ONCOLOGY ARTICLE NO.
67, 121–122 (1997)
GO974882
EDITORIAL Genetic Predisposition Testing: Taking the Lead Michael G. Muto, M.D. Familial Ovarian Cancer Center, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02155
The identification of germline mutations predisposing women to the development of ovarian cancer is of extraordinary importance. For the first time there is the real prospect that molecular genetics will open the door to understanding the pathogenesis of this lethal disease. By identifying individuals at high risk for developing ovarian cancer, we have the opportunity to develop and test risk reduction strategies ranging from chemoprevention to prophylactic surgery. We can more appropriately target sonographic screening and serum tumor markers to those individuals genuinely at risk. We will be able to better identify precursor lesions and ultimately further refine our understanding of the biologic behavior of this malignancy. Finally, as the function of the BRCA1 and BRCA2 gene products are elucidated, there is hope that we may be able to replace or repair these products, thereby achieving the ultimate goal of all gynecologic oncologists, the primary prevention of ovarian cancer. We must, however, be very careful not to let our intellectual excitement cloud our clinical judgment. It is clearly our responsibility, as stewards of women’s cancer care, to take a leadership position in defining the role of genetic testing and to rationally apply it. Many have argued that genetic ovarian cancer is rare, representing only 1–3% of all cases, and therefore not immediately relevant to our clinical practice. Not so as illustrated by Beller et al.’s lead article in this issue of Gynecologic Oncology [1]. Among Ashkenazi Jewish women with ovarian cancer, there is a 48% chance that the disease is associated with a germline mutation in either BRCA1 or BRCA2. Beller et al.’s observation is not unexpected. Modan et al. had previously reported a 39% mutation rate in BRCA1 among affected Israeli women [2]. In a population-based cohort of prospectively collected Jewish women with ovarian cancer in Boston we found a combined mutation rate of 44% [3]. Beller et al.’s observation, therefore, is likely to be correct. His recommendation that genetic testing be considered and discussed with any Jewish women with ovarian cancer, regardless of age at onset or family history, is very prudent.
Given the high mutation rate in Jewish cases, is it then reasonable to expand our scope and offer testing to unaffected Jewish women? Here the controversy grows, because we must face a disturbing inconsistency in the data. We know that 1–3% of Ashkenazi women carry a germline mutation in BRCA1 or BRCA2. Women who carry a BRCA1 mutation and have a family history consistent with breast ovarian cancer syndrome have a 40 – 60% lifetime risk of developing ovarian cancer. One would therefore logically expect that the overall rate of ovarian cancer among Ashkenazim would be very high. This seems not to be true. American and Israeli Jews have rates of ovarian cancer similar to those in the general population. In addition, as Beller et al. have shown, many of his BRCA1 and BRCA2 carriers have no significant family history. Struewing’s observation among Ashkenazim in Baltimore confirms this observation. It seems that the penetrance of the BRCA1 and BRCA2 mutations is variable and that the lifetime risk of developing ovarian cancer may be as low as 10% in an unaffected Jewish population without a family history [4]. Until a better understanding of the factors that impact on penetrance is achieved, general population screening, even among Ashkenazim, is not justified. Currently, a substantial number of women who are candidates for BRCA1 or BRCA2 genetic testing decline to be tested for a variety of reasons. First, these tests are very expensive and, if positive, could result in a loss of employment or health insurance. Until there is legal protection against genetic discrimination at the State level, there will be strong pressure to avoid testing. Second, there is great confusion about the predictive value of these tests, among both patients and their physicians. Finally, and in my opinion most importantly, we as gynecologic oncologists have no well-defined strategy to prevent the development of ovarian cancer. In the absence of effective primary prevention or early detection, patients will continue to think twice about testing. If we are to take the lead in the era of genetic testing, we must be willing to accept the responsibility for managing patients who are likely to develop ovarian cancer, as well as those who already have. Managing high-risk patients forces us
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0090-8258/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.
122
EDITORIAL
to focus our attention on primary prevention and early detection, areas sorely in need of new and innovative ideas. REFERENCES 1. Beller U, Halle D, Catane R, Kaufman B, Hornreich G, Levy-Lahad E: High-frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67:123–126, 1997
2. Modan B, Gak E, Bar Sade-Bruchim R, Hirsh-Yechezkel GT, Lubin F, Ben-Baruch G, Beller U, Fishman A, Dgani R, Menczer J, Papa M, Friedman E: High frequency of BRCA 1 185delAG mutation in ovarian cancer in Israel. JAMA 276:1823–1825, 1996 3. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA: The risk of cancer associated with specific mutations of BRCA1 1 and BRCA 2 among Ashkenazi Jews. N Engl J Med 336:1401–1408, 1997 4. Lu KH: personal communication, September 1997
67, 121–122 (1997)
GO974882
EDITORIAL Genetic Predisposition Testing: Taking the Lead Michael G. Muto, M.D. Familial Ovarian Cancer Center, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02155
The identification of germline mutations predisposing women to the development of ovarian cancer is of extraordinary importance. For the first time there is the real prospect that molecular genetics will open the door to understanding the pathogenesis of this lethal disease. By identifying individuals at high risk for developing ovarian cancer, we have the opportunity to develop and test risk reduction strategies ranging from chemoprevention to prophylactic surgery. We can more appropriately target sonographic screening and serum tumor markers to those individuals genuinely at risk. We will be able to better identify precursor lesions and ultimately further refine our understanding of the biologic behavior of this malignancy. Finally, as the function of the BRCA1 and BRCA2 gene products are elucidated, there is hope that we may be able to replace or repair these products, thereby achieving the ultimate goal of all gynecologic oncologists, the primary prevention of ovarian cancer. We must, however, be very careful not to let our intellectual excitement cloud our clinical judgment. It is clearly our responsibility, as stewards of women’s cancer care, to take a leadership position in defining the role of genetic testing and to rationally apply it. Many have argued that genetic ovarian cancer is rare, representing only 1–3% of all cases, and therefore not immediately relevant to our clinical practice. Not so as illustrated by Beller et al.’s lead article in this issue of Gynecologic Oncology [1]. Among Ashkenazi Jewish women with ovarian cancer, there is a 48% chance that the disease is associated with a germline mutation in either BRCA1 or BRCA2. Beller et al.’s observation is not unexpected. Modan et al. had previously reported a 39% mutation rate in BRCA1 among affected Israeli women [2]. In a population-based cohort of prospectively collected Jewish women with ovarian cancer in Boston we found a combined mutation rate of 44% [3]. Beller et al.’s observation, therefore, is likely to be correct. His recommendation that genetic testing be considered and discussed with any Jewish women with ovarian cancer, regardless of age at onset or family history, is very prudent.
Given the high mutation rate in Jewish cases, is it then reasonable to expand our scope and offer testing to unaffected Jewish women? Here the controversy grows, because we must face a disturbing inconsistency in the data. We know that 1–3% of Ashkenazi women carry a germline mutation in BRCA1 or BRCA2. Women who carry a BRCA1 mutation and have a family history consistent with breast ovarian cancer syndrome have a 40 – 60% lifetime risk of developing ovarian cancer. One would therefore logically expect that the overall rate of ovarian cancer among Ashkenazim would be very high. This seems not to be true. American and Israeli Jews have rates of ovarian cancer similar to those in the general population. In addition, as Beller et al. have shown, many of his BRCA1 and BRCA2 carriers have no significant family history. Struewing’s observation among Ashkenazim in Baltimore confirms this observation. It seems that the penetrance of the BRCA1 and BRCA2 mutations is variable and that the lifetime risk of developing ovarian cancer may be as low as 10% in an unaffected Jewish population without a family history [4]. Until a better understanding of the factors that impact on penetrance is achieved, general population screening, even among Ashkenazim, is not justified. Currently, a substantial number of women who are candidates for BRCA1 or BRCA2 genetic testing decline to be tested for a variety of reasons. First, these tests are very expensive and, if positive, could result in a loss of employment or health insurance. Until there is legal protection against genetic discrimination at the State level, there will be strong pressure to avoid testing. Second, there is great confusion about the predictive value of these tests, among both patients and their physicians. Finally, and in my opinion most importantly, we as gynecologic oncologists have no well-defined strategy to prevent the development of ovarian cancer. In the absence of effective primary prevention or early detection, patients will continue to think twice about testing. If we are to take the lead in the era of genetic testing, we must be willing to accept the responsibility for managing patients who are likely to develop ovarian cancer, as well as those who already have. Managing high-risk patients forces us
121
0090-8258/97 $25.00 Copyright © 1997 by Academic Press All rights of reproduction in any form reserved.
122
EDITORIAL
to focus our attention on primary prevention and early detection, areas sorely in need of new and innovative ideas. REFERENCES 1. Beller U, Halle D, Catane R, Kaufman B, Hornreich G, Levy-Lahad E: High-frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67:123–126, 1997
2. Modan B, Gak E, Bar Sade-Bruchim R, Hirsh-Yechezkel GT, Lubin F, Ben-Baruch G, Beller U, Fishman A, Dgani R, Menczer J, Papa M, Friedman E: High frequency of BRCA 1 185delAG mutation in ovarian cancer in Israel. JAMA 276:1823–1825, 1996 3. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA: The risk of cancer associated with specific mutations of BRCA1 1 and BRCA 2 among Ashkenazi Jews. N Engl J Med 336:1401–1408, 1997 4. Lu KH: personal communication, September 1997