Role of BRCA1 mutation screening in the management of familial ovarian cancer

CURRENT DEVELOPMENT Role of BRCA1 mutation screening in the management of familial ovarian cancer Andrew Berchuck, MD," Frank Cirisano, MD,aJohnathan M. Lancaster, MB, BCh, e a Joellen M. Schildkraut, PhD,b Roger W. Wiseman, PhD,' Andrew Futreal, PhD '

c

d

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Jeffrey R. Marks, PhDc Durham and Research Triangle Park, North Carolina Families with multiple cases of ovarian cancer have long been observed, and in the past prophylactic oophorectomy has been advocated for women with a history of ovarian cancer in two first-degree relatives. It is now thought that >90% of familial ovarian cancer is due to inherited mutations in the BRCA1 breast-ovarian cancer susceptibility gene on chromosome 17q. BRCA1 testing is being performed in several academic medical centers on a research basis and is also now commercially available. With the ability to identify inherited mutations in BRCA1, prophylactic oophorectomy and other interventions intended to decrease cancer mortality can be offered specifically to women who carry a mutation, but the optimal strategy for decreasing cancer mortality in BRCA1 families has not yet been determined. To facilitate further clinical and basic research in this field, our group and others have established multidisciplinary hereditary breast-ovarian cancer clinics that offer a wide range of services including BRCA1 testing, genetic counseling, and cancer prevention and treatment. (Am J Obstet Gynecol 1996;175:738-46.) Key words: BRCA1 gene, familial ovarian cancer, breast cancer

In the 1970s Lynch et al.' at Creighton University and Fraumeni et al. 2 at the National Cancer Institute identified several families in which multiple cases of epithelial ovarian cancer had occurred. A higher than expected incidence of breast cancer also was noted in some of these families3 ; transmission of cancer in these women appeared to be consistent with a dominant pattern of inheritance. Piver et al. 4' 5 at Roswell Park Memorial Institute in Buffalo encountered similar families and in 1981 initiated a registry to study the characteristics of families with multiple cases of ovarian cancer. Several hundred families were accessioned, including that of Gilda Radner, the comedienne who died of ovarian cancer in 1989. Her autobiography It's Always Something movingly recounts her battle with ovarian cancer and has raised public awareness of the disease. The Roswell Park Registry was posthumously named in her honor.6 Studies from the Gilda Radner Familial Ovarian Cancer Registry and other groups furthered our understandFrom the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology," and the Departments of Cancer Control," Surgery,' and Genetics,d Duke University Medical Center, and the Laboratory of Molecular Carcinogenesis,NationalInstitute ofEnvironmental Health Sciences, National Institutes of Health.e Supported by grantsNo. CA 55640 and Breast CancerSPORE (No. CA 68438) from the National CancerInstitute and the Lawrence Goodman Ovarian CancerResearch Fund. Reprint requests:Andrew Berchuck, MD, Division of Gynecologic Oncology, Box 3079 Duke University Medical Center, Durham, NC 27710. 6/1/74288

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ing of familial ovarian cancer in the 1980s. First, the initial suggestion of an autosomal dominant pattern of inheritance was supported by an analysis of significant numbers of large pedigrees.6 In addition, familial ovarian cancer was noted to have an earlier age of onset.6 7 Although the median age of ovarian cancer in the Surveillance Epidemiology and End Results Program registry was 61 years, the median age for familial cases was in the mid to late 40s. Early onset of disease was interpreted as further evidence of the hereditary nature of this syndrome. The clinical characteristics of familial ovarian cancers were noted to be similar to those of women without a family history, however. Familial cancers were typically advanced-stage papillary serous adenocarcinomas and survival was poor.6 Because of the presumed autosomal dominant mode of inheritance and poor survival, the Gilda Radner Familial Ovarian Cancer Registry and others recommended prophylactic oophorectomy at age 35 years in families in which two first-degree relatives (mother, sister, daughter) had already been affected. 6 ' 8, 9 Several systematic population-based epidemiologic studies also suggested that heredity contributes to the development of some ovarian cancers. Schildkraut and Thompson ° examined the family histories of ovarian cases and controls who had been identified in conjunction with the Cancer and Steroid Hormone Study in the early 1980s. The risk of ovarian cancer in first- and second-degree relatives of women with ovarian cancer were found to be increased 3.6- and 2.9-fold, respectively, com-

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Fig. 1. Familial ovarian cancer pedigree with BRCA1 mutation. Age of each family member and type of cancer is noted. Slashes, Individuals who have died of cancer; arrow, proband who was treated for ovarian cancer at Duke University. Her 40-year-old sister elected to have prophylactic oophorectomy and mastectomy. Individuals denoted Mhave germline BRCA1 mutation that leads to a truncated 75 amino acid protein product, whereas individuals denoted WT have normal wild-type BRCA1 genes.

pared with women with no family history of ovarian cancer. In addition, analysis of the data revealed that a family history of either ovarian or breast cancer increased the risk of both cancers in first-degree relatives."'-" Identification of the BRCA1 breast-ovarian cancer susceptibility gene At the same time that awareness of familial ovarian cancer was growing, other groups were beginning studies that sought to elucidate the genetic basis of hereditary breast cancer. In 1990 Hall et al.' 4 at the University of California, Berkeley, reported genetic linkage studies that suggested that many cases of familial breast cancer were caused by a gene on the long arm of chromosome 17. The following year Narod et al. 5 reported that families with both breast and ovarian cancer also showed linkage to chromosome 17 q. Linkage analysis involves examination of genetic markers on each chromosome that frequently vary with respect to their precise deoxyribonucleic acid (DNA) sequence. If DNA samples are obtained from siblings and their parents, it generally can be determined whether a given allele of one of these genetic markers was inherited from the mother or the father. With linkage analysis it was shown that transmission of cancer in a given breast-ovarian cancer family was closely linked to inheritance of a specific allele of the marker D17S74 on chromosome 17 q.'4 5 Although this marker was not the breast-ovarian cancer susceptibility gene, it represented a genetic locus in the vicinity of the causative gene. Several groups then undertook the arduous task of attempting to identify the causative gene among the dozens of other genes that reside in the 17q21 region. In 1994 a collaborative group from the University of Utah and the National Institute of Environmental Health Sci-

ences in North Carolina reported the presence of mutations in a candidate gene from this region in affected members of breast-ovarian cancer families.'6 Most of the mutations in this gene (BRCA1) yield a truncated protein product, and mutational analysis of this gene in >100 independent cancer families has confirmed that it is a genuine breast-ovarian cancer susceptibility gene (Fig. 1).' 7 Published data suggest that women in these families have approximately a 90% to 100% lifetime risk for breast or ovarian cancer.' 8 It is possible that these estimates are artificially high because of ascertainment bias in which families with highly penetrant mutations are more likely to be identified on the basis of a strong family history, however. The sequence of the BRCA1 gene is unlike that of other known genes with the exception of a putative zinc finger DNA binding domain' 6 and a granin consensus sequence." BRCA1 expression has been shown to increase during cell cycle progression,2' suggesting that it may act to regulate transcription of genes involved in cellular proliferation. Although the function of BRCA1 is unknown, the recent report of a phenotypically normal woman who inherited two mutant copies of this gene indicates that BRCA1 is not requisite for growth and development As is the case for other genes that cause hereditary cancers, BRCA1 is expressed in tissues other than those in which it causes cancer. 6 The incidence of prostate and colon cancers has been found to be increased by approximately threefold and fourfold, respectively,22 but these are the only other malignancies in which a higher-than-expected incidence has been noted in families with BRCA1 mutations. Several lines of evidence suggest that BRCA1 is a member of the tumor-suppressor gene family. First, most other

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hereditary cancer syndromes in which a genetic basis has been demonstrated, such as retinoblastoma, Wilms' tumor,2s and Li-Fraumeni syndrome, 24 have been shown to be the result of inheritance of a mutant copy of a tumorsuppressor gene. Because these genes act in a recessive fashion, the remaining normal copy of the gene generally must be damaged if tumorigenesis is to occur. In this regard, it has been shown that the normal copy of BRCA1 is invariably deleted in breast and ovarian cancers that arise in women who inherit a mutant BRCA1 gene.2 5 The finding that transfection of normal BRCA1 genes into breast and ovarian cancers inhibits growth also is consistent with the hypothesis that BRCA1 is a tumor-suppressor gene.26

Role of BRCA1 in sporadic ovarian cancers Most women who have ovarian cancer do not have a strong family history suggestive of a hereditary syndrome. It is thought that, like other common forms of human cancer, most ovarian cancers occur as a result of acquired alterations in oncogenes, tumor-suppressor genes, and other genes that regulate cellular growth and DNA repair. Our group and others have shown that alterations in the p5 3 , HER-2/neu and c-myc genes are a frequent feature of sporadic ovarian cancers.2 7 28 Because several tumor-suppressor genes that cause hereditary cancer syndromes are also frequently mutated in sporadic cancers,23 it was thought that acquired mutations in BRCA1 might be common in sporadic ovarian cancers. The finding that half of ovarian cancers have deletions on chromosome 17 q was also suggestive of a role for BRCA1 in sporadic cases. 29 ' S Initially Futreal et al.3 examined the BRCA1 gene in 12 ovarian cancers from Duke University that were selected for DNA sequencing on the basis of having lost one copy of BRCA1. A mutation was noted in one cancer but was also present in normal DNA obtained from that patient's white blood cells. Thus the only mutation seen represented an inherited defect, as had been noted in breastovarian cancer families. Similarly, Takahashi et al. 32 found mutations in 7 of 115 ovarian cancers but all were germline mutations. In two other studies, however, acquired somatic mutations in BRCA1 were found in 4 of 47 and 1 of 17 ovarian cancers.3 . 34 Because somatic mutations have been seen in only 3% (5/191) of cases, it appears unlikely that inactivation of the BRCA1 gene plays a major role in the development of sporadic ovarian cancers. There is some evidence to suggest that inactivation of BRCA1 might occur in sporadic cancers by way of mechanisms that alter the production, degradation, or cellular localization of the protein, however. 35 36

Screening women with familial cancer for BRCA1 mutations Several university medical centers have opened clinics to meet the needs of families suspected of having an

increased susceptibility for cancer as a result of inherited mutations in BRCA1 or other genes. Multidisciplinary teams in these clinics will need to address challenges in cancer diagnosis, treatment and prevention, genetics, psychology, and social implications. The involvement of genetic counselors is critical because they are specifically trained in the process of educating patients regarding the complex principles of medical genetics and patterns of inheritance.3s The protocol for managing individuals with suspected genetic susceptibility to cancer should be similar to the approach long used by genetic counselors for other inherited disorders. This includes (1) performing a pedigree analysis to determine if a genetic disorder likely exists in a family, (2) nondirective counseling and education to arrive at a decision whether the individual wishes to undergo genetic testing, (3) genetic testing, (4) disclosure of results by a multidisciplinary team, (5) determination of cancer risk for both carriers and noncarriers, (6) discussion of options for management, (7) psychologic counseling with regard to carrier status, and (8) follow-up counseling. The importance of follow-up counseling by a genetic counselor or other team member cannot be overemphasized because profound psychologic consequences are not unusual after genetic testing. Although hereditary breast-ovarian cancer clinics have been established, several obstacles must be overcome before BRCA1 testing becomes widely available to women with a family history of ovarian or breast cancer. Because mutations occur throughout this relatively large gene, which encodes a protein of 1863 amino acids, the most reliable method of detecting BRCA1 mutations is to sequence the entire coding region (Fig. 2). With the polymerase chain reaction ample material can be generated to facilitate automated DNA sequencing, but analysis of the entire BRCA1 gene is a labor-intensive process. In addition, although splice site mutations in the BRCA1 gene that result in loss of entire exons from the final product are rare,1 6 because these mutations lie outside the coding region they could be missed with DNA sequencing. In view of the labor-intensive nature of DNA sequencing, single-stranded conformation analysis has been used to screen segments of the BRCA1 gene for alterationS.17 3840 It has been shown that mutations in BRCA1 and other genes cause the single strands of DNA that comprise the gene to migrate abnormally when electrophoresed (Fig. 3). If abnormal migration of a BRCAI gene fragment is noted with single-stranded conformation analysis, this area of the gene can then be subjected to DNA sequencing to identify the specific mutation. Unfortunately, not all mutations cause sufficient alteration of the single-stranded conformation of BRCA1 to produce shifted bands on analysis, and the sensitivity of single-stranded conformation analysis for detection mutations in BRCA1 is probably only approximately 80% to

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I ,' Fig. 2. Automated DNA sequencing of mutation. In normal tissue on left, arrow denotes heterozygous germline A/C denoted by N. In matching cancer sample on right, arrow denotes presence of only mutant C. ThisA to C transversion in antisense strand results in ATG to AGG change in sense strand, which changes codon 1775 from methionine to arginine. (Reprinted with permission from Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 1994;266:121. Copyright 1994 American Association for the Advancement of Science.)

90%, even when performed in a laboratory with extensive experience. An additional problem is that the specificity of single-stranded conformation analysis is <100% because not all shifted bands represent disease causing mutations. Sometimes DNA sequencing reveals that a shifted band represents a polymorphism, which is a normal variant that occurs in the population at a low frequency. Unlike the 80% to 90% of disease causing mutations in BRCA1, which leads to truncated protein products, these polymorphisms generally either do not change the amino

acid encoded or result in a conservative change that does not appreciably affect the function of the BRCA1 protein. Although several polymorphisms have been well characterized, 6 it is unclear whether some alterations in the BRCA1 gene that result in substitution of a single amino acid represent polymorphisms or true disease-causing mutations. Approximately 85% of the reported alterations in BRCA1 are either nonsense mutations in which a single nucleotide substitution produces a stop codon or frameshift mutations in which one or more nucleotides are deleted, producing a stop codon somewhere downstream." In either case the result is production of a smaller-than-usual BRCA1 protein. In view of this, another approach to identifying BRCA1 mutations involves

Fig. 3. Analysis of BRCA1 gene with single-stranded conformation analysis. Mobility shift is seen in cancer in lane 3. This is same cancer in which BRCA1 mutation was demonstrated by DNA sequencing in Fig. 2.

translating BRCA1 ribonucleic acid into protein and then performing electrophoresis to determine whether there is an alteration in its size. The protein truncation test appears to be a relatively efficient screening tool for detecting BRCA1 mutations (Fig. 4).41 As with the other techniques, the protein truncation test does have limitations. Missense mutations that only change a single amino acid are undetectable, but these alterations represent only about 10% of BRCA1 mutations. Likewise, the sensitivity is limited for mutations that result in either very small peptides that migrate off the bottom of the gel or very large products whose mobility differs little from the wild-type protein. For example, one of the most frequently identified mutations to date, 185delAG, produces a short 39 amino acid peptide that is difficult to detect by the protein truncation test. By use of complementary DNA-based primers the entire BRCA1 coding region can be screened by protein truncation test with as few as five polymerase chain reaction templates. An additional advantage is that splice site mutations that would not be detected by sequencing the coding region of the gene should be detectable. Because a straightforward BRCA1 test with high sensitivity and specificity is not available and the estimated

carrier frequency in the general population is estimated to be 1 in 800, population screening for BRCA1 mutations is impractical. A possible exception is suggested by a recent study of 850 Ashkanazi Jews, which revealed that approximately 1 in 100 carried an identical mutation in codon 185 (deletion AG) of the gene.42 Because the major-

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Fig. 4. Analysis of BRCA1 gene with protein truncation test. BRCA1 protein in lane 3 has migrated further down gel because it has been truncated and is smaller than normal. Presence of BRCA1 mutation was confirmed by DNA sequencing. WT; Wild type; MUT mutation.

ity of the six million Jews in the United States are of Ashkanazi heritage, perhaps testing for the codon 185 mutation should be offered to this entire population. It may be premature to advocate population screening for BRCA1 mutations when it remains unproved that intervention can decrease cancer incidence or mortality, however. Women with concerns regarding a family history of breast or ovarian cancer have been invited to attend the hereditary cancer clinic at Duke University. After a comprehensive family history is obtained, in some cases it is determined that the likelihood of that individual carrying a BRCA1 mutation is too low to justify genetic testing. For example, on the basis of experience to date, it is estimated that the probability of finding a BRCAI mutation in a woman >50 years old who is the only individual in her family with ovarian or breast cancer is significantly <3%. 7 In contrast, in families with two cases of breast cancer and two cases of ovarian cancer, the probability of finding a BRCA1 mutation is approximately 90%." Although the decision as to who should undergo mutational screening is straightforward at these extremes, most patient family histories place them in an intermediate risk group. One significant opportunity in the familial cancer clinic is to reassure women with an insignificant family history or a negative BRCA1 test that they do not appear to be at high risk for ovarian or breast cancer. The importance of this has been underscored by our impression that there is not necessarily a correlation between the level of an individual's anxiety and the actual cancer risk. When careful analysis of a pedigree suggests a significant probability of the presence of a BRCA1 mutation, our preferred approach is to use single-stranded conformation analysis and the protein truncation test to screen the DNA of women in the family who have had breast or ovarian cancer. Genetic analysis usually is performed with white blood cells from peripheral blood, but surgical tissue samples preserved in paraffin blocks may also serve as a source of DNA from decreased family members. If a

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BRCA1 mutation is suspected on this initial screen, DNA sequencing is used to confirm the presence of a significant sequence change and to determine its location. It is then relatively easy to screen other women in the family for this specific mutation. In addition, male family members should consider testing because BRCA1 mutations are associated with an increased risk of colon and prostate cancer. Half of children of male BRCA1 carriers would also be predicted to carry the mutant gene, but there is debate as to whether parents have the right to test their children for genetic diseases such as hereditary breastovarian cancer or Huntington's disease that do not manifest until adulthood. Because of these concerns, our current policy is not to test individuals <20 years old. Many of the women who attend the familial cancer clinic because of concerns regarding an increased risk of cancer have not yet had ovarian or breast cancer. It is not optimal to begin BRCA1 analysis of a family by testing these women, however. Failure to find a BRCA1 mutation in an unaffected individual might mean that the familial aggregation of ovarian or breast cancer occurred by chance or other genetic alterations. Alternatively, if these cancers were due to BRCA1, this would escape detection if the individual in whom the test was performed did not inherit a mutant copy of the gene. Although less desirable, testing unaffected individuals may be unavoidable in some circumstances if affected individuals in a family are unavailable or unwilling to be tested. It is not unusual for some family members to decline BRCA1 testing. Sometimes refusal to be tested is due to irrational fears or ignorance, but individual decisions to decline testing after having received appropriate educational material and counseling must be respected. It is important for zealous health care providers to remember that it has not been proved that cancer mortality can be prevented in BRCA1 carriers. For some individuals the depression that might accompany knowledge that they carry the mutation is reasonable justification to decline testing. In families with multiple cases of ovarian or breast cancer in which BRCA1 mutations are not found, linkage analysis is performed to determine whether the disease is linked to chromosome 17 q. Because this analysis ideally requires DNA from several unaffected and affected family members, it cannot always be performed, however. Although it is believed that >90% of hereditary ovarian cancer is due to mutations in BRCA1, 4 ' 44 a small fraction of familial ovarian cancer is probably due to other genes. Occasionally ovarian cancer occurs in Lynch II cancer families, but colon and endometrial cancer are the hallmarks of this syndrome. The Lynch II syndrome is due to inherited mutations in a family of DNA repair genes (MSH2, MLH1, PMS1, PMS2).45 Analysis of these genes is appropriate in pedigrees in which colon cancer predominates. A significant fraction of breast cancer families do not have BRCA1 mutations but do show linkage to chro-

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mosome 13 q.46 Recently this second breast cancer susceptibility gene (BRCA2) on chromosome 13q12 was identified.4 7 A notable attribute of many BRCA2 families is the occurrence of male breast cancer. Ovarian cancer does not appear to be a prominent feature of these families, but there may be some exceptions. It is estimated that BRCA1 is responsible for approximately half of hereditary breast cancer, whereas mutations in BRCA2 cause an additional 40%. The remaining 10% of hereditary breast cancer is associated with germline mutations in p5 3, the ataxia-telangiectasia gene the HNPCC genes and rarely others.4 8 Thus far most BRCA1 testing has been performed in a research setting. Before BRCA1 testing at Duke University, individuals sign a detailed consent form that has been approved by our Investigational Review Board. The consent form requests permission to obtain blood for genetic testing, permission to test for BRCA1 mutations, and permission to inform the subject of the results of BRCA1 testing. This multifaceted consent form allows some patients who do not wish to be informed of their BRCA1 status to contribute to research studies. BRCA1 testing is also now available commercially, but some groups, including the American Society of Human Genetics, have suggested that the test should be confined to a research setting until guidelines for its proper use have been established.4 9 Strategies for prevention of ovarian cancer in women who inherit BRCA1 mutations The ability to identify mutations in the BRCA1 gene represents a major advance in the management of familial ovarian cancer. The breast cancer linkage consortium has shown that >90% of breast-ovarian cancer families that contained cases of ovarian cancer in addition to breast cancer were linked to chromosome 17q. 4 3' 44, 50. 31 In most cases it should now be possible to identify mutations in the BRCA1 gene in these families. Prevention of ovarian cancer can be focused on those women who carry the mutant gene, whereas those who carry two normal copies of BRCA1 can be reassured that they are not at increased risk. Only a minority of cases of familial ovarian cancer need be managed as we have in the past, by simply recommending prophylactic oophorectomy on the basis of a strong family history. 6 8, 9 There is some debate in the literature as to whether the age of onset of ovarian cancer is actually younger in women who inherit a mutant BRCA1 gene.' 8 It is clear, however, that familial ovarian cancer often strikes during the fourth and fifth decades of life and the estimated lifetime risk of ovarian cancer is 60% in BRCA1 carriers.' 8 It has been suggested that the likelihood of developing ovarian cancer may differ between various BRCA1 mutations, with ovarian cancer being less prevalent in families that carry mutations affecting the 3' end of the gene, 7 ' 52

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but too few women have been studied thus far to allow firm conclusions. One of the primary reasons for performing BRCA1 testing is the hope that ovarian cancer mortality can be reduced in carriers, but the optimal strategy for achieving this goal remains unclear. Available methods of early detection such as transvaginal ultrasonography and serum CA 125 are not sufficiently specific for population screening because of the relatively low prevalence of ovarian cancer relative to benign gynecologic conditions that lead to false-positive screen results. It is conceivable that this may be less of a problem in BRCA1 carriers, who have a higher prevalence of ovarian cancer. Although prospective studies are needed to determine the value of pelvic examination, transvaginal ultrasonography, and CA 125 in BRCA1 carriers, in the interim the use of these modalities seems reasonable, particularly in young women who wish to maintain fertility. In view of the lack of evidence that screening tests can reliably detect ovarian cancer while it is still localized and curable, prophylactic oophorectomy has been advocated as a strategy to decrease ovarian cancer mortality in BRCA1 carriers. Oophorectomy can now be performed laparoscopically in an outpatient setting and most women do not view removal of the ovaries as cosmetically mutilating or have significant loss of self-esteem. Finally, estrogen replacement can be administered either orally or transdermally, thereby avoiding the deleterious side effects of premature menopause, including severe hot flushes, urogenital atrophy, osteoporosis, and an increased risk of cardiovascular disease.53 Although there is some concern that estrogen replacement might increase the risk of breast cancer in these women, this risk already approaches 85% in women with BRCA1 mutations.'8 Furthermore, in most cases the amount of estrogen used for replacement in women with premature menopause is lower than that which would have been produced endogenously had the ovaries not been removed. One concern regarding prophylactic oophorectomy is the observation that a small fraction of women subsequently have intraperitoneal carcinomatosis indistinguishable macroscopically or microscopically from advanced ovarian cancer. 54 55 In at least a few of these cases careful retrospective examination of the ovaries has revealed the presence of microscopic foci of cancer that were not appreciated at the time of the initial pathologic examination. This may occur because a single section is all that usually is examined in a normal-appearing ovary. When prophylactic oophorectomy is performed, the pathologist should be alerted as to the indication for surgery and multiple sections should be examined from each ovary to exclude the presence of occult carcinoma. Another possible explanation for the occurrence of carcinomatosis after oophorectomy is that the pelvic peritoneum shares the same embryologic origin as the ovarian epithelium. It is conceivable that some cases of peri-

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toneal carcinomatosis in BRCAl carriers may arise from the surrounding peritoneal lining. Although oophorectomy does not provide absolute protection, in the Gilda Radner Registry carcinomatosis developed in only 6 of 324 (2%) women who had undergone prophylactic oophorectomy.55 Another strategy that has been suggested to decrease risk of ovarian cancer in women with germline BRCA1 mutations is use of oral contraceptives. 6 It has been shown that long-term oral contraceptive pill use decreases the risk of ovarian cancer in the general population by as much as 60%.56 Other factors such as high parity and breast-feeding, which like the pill inhibit total lifetime ovulations, also decrease ovarian cancer risk. 56 Epidemiologic, studies are now underway to determine whether factors that inhibit ovulation decrease ovarian cancer risk in BRCA1 carriers. The finding that oral contraceptive users in the Gilda Radner registry had a lower incidence of ovarian cancer than nonusers is encouraging, however.6 Oral contraceptives might be a particularly attractive alternative for young women who have not yet completed childbearing but, as with estrogen replacement, there is some concern that oral contraceptive use might increase the risk of breast cancer.53 Prevention of breast cancer mortality in BRCA1 carriers presents different issues because these cancers are much more readily detected at an early stage than are ovarian cancers. As a result, breast cancer 5-year survival in the United States is 70% compared with only 30% for ovarian cancer. Furthermore, unlike oophorectorry, mastectomy with reconstruction causes marked alterations in self-esteem and body image. Although some women will continue to choose mastectomy, close surveillance with mammography and breast self-examination may prove equally effective in reducing mortality in view of the. good prognosis for women with early breast cancer.57 Chemoprophylaxis of breast cancer with antiestrogens such as tamoxifen is another strategy being considered. Support for this approach comes from studies that have shown that tamoxifen decreases the incidence of second primary breast cancers in the contralateral breast. s A disadvantage of this strategy would be the potential for symptoms of estrogen deficiency. Although tamoxifen may not be the most attractive alternative for most young women who carry BRCA1 mutations, it might be a reasonable alternative for older women. Social implications of BRCA1 testing Prevention of ovarian and breast cancer in women who are found to carry BRCA1 mutations is an important endeavor, but we also must participate in discussions regarding associated nonmedical implications. Misuse of genetic information potentially could have devastating consequences, including difficulty in securing employment and life or health insurance.59 Because society has not resolved these issues, the right to confidentiality of BRCA1 test results must be respected in familial cancer

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clinics. As the genetic basis for many human diseases is discovered, hopefully this will lead to the concept of "no fault" medical or life insurance in which society would not tolerate discrimination on' the basis of inheritance, which is not under the control of the affected individual. It is not inconceivable that a majority of the population carries one or more disease-predisposing genes, and at least some of these mutations probably confer a selective advantage under certain circumstances. Health care professionals should actively advocate that genetic testing for BRCA1 and other mutations be used constructively to modify risk rather than to stigmatize individuals or deprive them of appropriate care. For example, some insurers have denied payment for prophylactic oophorectomy in the setting of familial ovarian cancer because it is a preventive measure rather than treatment of an illness. In at least one case a strongly proactive group of physicians helped a woman to contest such a judgment and the Nebraska Supreme Court eventually ruled in her favor.60 This is a laudable example of how physicians can step beyond their traditional roles as health care providers and contribute to the debate at a societal level. Prenatal diagnosis of BRCA1 mutations is the issue most likely to have an impact on obstetricians. As the number of presymptomatic individuals identified as BRCA1 mutation carriers rises, we undoubtedly will receive requests for prenatal BRCA1 testing. 6 1 With knowledge of the precise mutation in a parent, prenatal testing using fetal cells is relatively straightforward and a result could be obtained in a few days, allowing for pregnancy termination if desired. Whether a fetus with a BRCA1 mutation should be aborted is a matter that the parents should decide after receiving educational material and unbiased counseling. The justification for aborting a fetus with a mutant BRCA1 gene might seem marginal because that individual likely will be unaffected by cancer for many decades. Conversely, termination of pregnancies that carry mutant BRCA1 genes might be viewed as justified in the context of a society in which thousands of undesired pregnancies are aborted electively every year. For those who object to termination of an affected pregnancy, assisted reproductive techniques have advanced to the point where selective implantation of embryos with normal BRCA1 genes is feasible. As clinics develop to meet the need for BRCA1 and other familial cancer genetic testing, we should strive to provide a full range of services, including expertise in cancer diagnosis, treatment, and prevention; genetics; psychology; and social implications. Hopefully, these clinics also will facilitate prospective clinical trials that will provide the rationale basis for management of these patients in the future. We thank J. Dirk Iglehart, MD, Barbara Rimer, MPH, and Eric Winer, MD, for helpful discussion of many of the concepts presented in this article.

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Volume 175, Number 3, Part 1 AmJ Obstet Gynecol

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