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Some public health issues in the current state of genetic testing for breast cancer in Australia

Some public health issues in the current state of genetic testing for breast cancer in Australia Abstract: Two genes associated with a high breast cancer risk (BRCAl and BRCA2) have been discovered recently from study of large breast-cancer-dense kindreds. It is problematic to make inferences from these atypical families to the general population. Nevertheless, it appears that about 1 to 2 per cent of all breast cancer may be due to rare dleleterious mutations in BRCAl or BRCA2. The majority of breast cancer families with fewer than four cases are likely to have cancers not attributable to these genes. There may be more common mutations in other genes (such as A T M , HRASI) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases. At this early stage of cancer genetics, the risks associated with particular mutations are not known, there are no proven and acceptable strategies for women with an inherited susceptibility to ameliorate risk or improve prognosis, and risk estimates appropriate for Australian women with a family history of breast cancer are not established, although data from the United States may overestimate risk. Information is needed from population-based studies, such as the Australian Breast Cancer Family Study (Hopper et al. Breast 1994; 3: 79-86), but 100 per cent mutation detection in large cancer genes is difficult and expensive. Development of a systematic, research-oriented, evidence-based approach to genetic testing in Australia is recommended. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database. (AustN Z.fPublic Health 1996; 20: 467-72) HE possibility that there are inherited genetic factors that place some women at an increased or high risk for breast cancer has been thought likely for some time, on the basis of two general observations. First, women with one or more close relatives with a personal history of breast cancer are more likely to develop breast cancer themselves. This increased risk is greater if the relatives are the mother or a sister, if cancer developed at an early age or was bilateral, or more than one relative on the same side of the family was affected. Family history is one of the stronger and well-established risk factors for breast cancer, and even though the increased risk is on average a modest 1.5-fold to twofold, there must exist strong underlying familial risk factors.’ Finding the familial risk factors for breast cancer could be an important step forward in breast cancer prevention, and is a major aim of studies in genetic epidemiology.‘ Although the high-risk cancer susceptibility genes are obvious candidates, they may explain less than half the familial aggregation of breast cancer. Dietary and other life-style factors are also familial, and there may be interactions between genes, and between genetic and environmental factors. Second is the existence of rare extended multigenerational families in which there are multiple cases of breast cancer (see below). Whereas somatic mutations, or faults, develop in the chromosomes of tissue cells as a result of dam- age (such as background ionising radiation or the effect of carcinogens) and these have the potential to occur in anyone, Knudson’s two-hit hypothesis proposes that some people inherit a defect at a critical place in their genome on one chromosome and this defect occurs in all of their cells.3If in just one of these cells the other chromosome of that pair should also become defective in this critical region, that cell may go on to initiate a malignant tumour. These people are said to have inherited a germ-line mutation, which places them at an increased risk of developing cancer (susceptibility); which cancer depends on where the inherited germ-line mutation is, and a number of other yet-to-be-elucidated factors. Correspondence to Dr John L. Hopper, Department of Public Health and Community Medicine, University of Melbourne, 200 Berkeley Street, Carlton, Vic 3053. Fax (03) 9347 6136. BRCAl and BRCA2 The International Breast Cancer Linkage Consortium pooled data from over 200 extended breast cancer kinships from across the world. Almost all families contained at least two breast cancer cases, and most had at least four. More than a quarter also contained at least one case of ovarian cancer. These large, multigenerational and highly unusual families have extreme cancer histories, as can be seen from their pedigree diagrams published in a series of papers in the April 1993issue of the AmericanJournal o Human Genetics. The diagnosis in affected women f was usually at a young age, and there were sometimes one or more cases of ovarian cancer in female relatives, or even breast cancer in a male relative. These features reflect that the families were ascertained for breast cancer gene searching. VOL. AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 F 20 NO. 5 HOPPER To date, these families have been used to discover two high-risk autosomal dominant genes (that is, inheriting just one defective copy of the gene from either parent is sufficient to place a woman at high risk, according to the two-hit hypothesis above). The gene BRCAI was cloned (that is, its genetic sequence and exact place on chromosome 17 was discovered) in 1994.' It is a large and complex gene composed of 22 coding regions (exons). Over 100 different deleterious mutations have so far been identified, and the total may go as high as 300 or more. In late 1995 BRCA2 was cloned.5 It is also very large, about twice the length of BRCAl. Women who have inherited deleterious mutations in either BRCAl or BRCAP have a high risk of developing breast cancer. The age-specific cumulative risk of cancer, or penetrance, was estimated by statistical analyses using genetic markers prior to the cloning of these genes,6x and not by studying individuals with known mutations. It is thought to increase from less than 5 per cent at age 30 years, to about 15 per cent at age 40 years, 50 per cent at age 50 years and 75 per cent at age 60 years, and reaches a maximum of around 85 per cent by age 80 years (Figure 1; the lack of precision of these estimates is also indicated). The risk does not reach 100 per cent; there exist women who are known mutation carriers but who have not developed cancer by the age of 80. Different mutations could have different penetrances. Furthermore, the mutations in these families are probably those more likely to cause cancer, and at an earlier age, than the mutations occurring in the general p o p ~ l a t i o n that is, these families are ;~ likely to be unrepresentative because thay have been chosen specifically to have a preponderance of earlyonset breast cancer. If this possible overestimation of risk is ignored, for a woman with a deleterious BRCAI or BRCAZ mutation who has not yet developed breast cancer, her risk of developing cancer in the next decade can be approximated from Figure 1. The 10-year conditional risk is relatively low at about 5 per cent for an unaffected 20-year-old, and 10 per cent for an unaffected 30-year-old. That is, cancer-free genetically (D Figure 1 : Age-specific cumulative risks, with 95% confidence intervals, for breast or ovarian cancer in female B R C A 1 mutation carriers based on linkage analyses in cancer-dense families susceptible women under the age of 30 years have a small chance of developing breast cancer in their next decade of life. However, this risk increases rapidly to about 40 per cent for an unaffected 40year-old, and 50 per cent for an unaffected 50-yearold, but reduces to about 20 per cent for women who have reached older ages without developing breast cancer. Therefore, most of those women who have inherited these defective genes, and who go on to develop breast cancer, would be expected to do SO in their 40s and 50s. Some mutations in BRCA1 carry an increased risk of ovarian cancer: and perhaps other cancers, such as those of the colon, rectum and p r ~ s t a t ewhile ,~ mutations in BRCAZ may confer an increased risk of breast cancer in males, and possibly ovarian and other cancers in females8 The spectrum of cancers caused by BRCA1 and BRCAP has yet to be charactensed on a population basis. The risk of ovarian cancer in women with BRCAI mutations has been estimated from the Consortium data to be about 15 per cent by age 50 years and 40 per cent by age 70 years6 Although these risks may be overestimates for the reasons discussed above, they are important. Survival from ovarian cancer i s poor, reflecting the difficulty of detection at an early stage. For a woman with BRCAl mutations who has had breast cancer, her risk of developing either a second primary in the contralateral breast or ovarian cancer appears to be similar to the risk of a first primary (shown in Figure l).' Mathematical modelling suggests that about 1 in 800 women have inherited a high-risk mutation.'" The true population frequency can be found, in principle, by screening a population-based sample of women, but this is impractical at present, except for particular mutations, such as the 185delAG in BRCAI which appears to be relatively common at about 1 per cent in Jews of Ashkenazi descent." Based on mathematical models, it has been. estimated that 5 per cent of cases diagnosed before the age of 40 years, 2 per cent of those diagnosed between the ages of 40 and 49 years, and 1 per cent of those diagnosed at or after the age of 50 years, s could be attributable to the high-risk genes.'" A most breast cancer occurs in postmenopausal women, about 1 per cent to 2 per cent of all breast cancers might be due to the high-risk mutations in BRCAI and BRCA2, and perhaps other yet-to-beidentified high-risk genes. The issue of how much breast cancer is due to particular genes can be resolved only by thorough mutation searches in population-based samples. Cancer genes are large and complex, however, and hundreds of different sequences, or variants, are possible. For some of these variants it can be inferred from the DNA sequence that they will lead to the formation of a truncated protein. These can be considered to be disease-causing muations, especially if they can be shown to run through families in tandem with affected individuals. For others, it may be clear from the sequence that they will not affect the gene's function, or they may be common among AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 vot. 20 NO 5 F GENETIC TESTING F R BREAST CANCER O people without the disease (these are called polymorphisms). For some variants, however, it is not clear what effect they will have, and it is difficult to determine whether they cause disease. Therefore, it is important that mutation searches involve both affected and unaffected individuals, and have the capacity to study DNA from family members. Such a study is being undertaken on material collected by the Australian Breast Cancer Family Study" (see pages 471-2, 'Progress'). as a80.7 Y a5- 0.4 0.3 - Other genes involved with breast cancer The autosonnal dominant Li-Fraumeni syndrome is the familial clustering of childhood bone and soft tissue sarcomas of an early onset, and breast cancer is sometimes observed in these very rare families, about half of which have mutations in the Tp53 gene." Perhaps 1 in 10 000 individuals in the population carry Tp53 mutations, and this gene may account for up to 1 per cent of breast cancer cases diagnosed before the age of 35 years, but a negligible amount iin older ages because few mutation carriers survive past middle age. The risk of breast cancer in women with Tp53 mutations is thought to be between 30 and 40 per cent by age 45 years. There is considerable uncertainty in the figures.I4 The ATM gene for the recessively inherited condition ataxia-telangiectasia on chromosome 11 was cloned recer1t1y.I~ Persons who inherit two defective copies, one from each parent, develop the disease, and sufferers of ataxia-telangiectasia are at high risk of breast cancer. Although it is far from well established, there is some evidence from families with ataxia-telangiectasia that individuals who carry one defective copy of the ATM gene may be at a threefold or more increased risk of breast cancer.'"' These carriers are relatively common. Perhaps 1 in 200 to 1 in LOO women have inherited this moderately increased genetic risk, and it may account for from 2 to 7 per cent of breast cancer in the population, although again there is much uncertainty about this.I4 Like BRCAl and BRCAZ, the ATM gene is very long and complex, and mutations can occur all along its length. The rare alleles at the HRASl locus are thought to be associated with about a 70 per cent increase in risk of breast cancer." Somewhere in the order of 1 in 10 women have these rare alleles, and a risk of about 20 to 30 per cent by age 70 years, so about 3 to 8 per cent of all breast cancer could be attributable to this gene.14 It is not clear whether the mismatch repair genes involved with nonpolyposis colorectal cancer syndromes increase the risk of breast cancer. The involvement in breast cancer of other genes, such as the androgen and oestrogen receptor genes and genes involwd in the metabolic detoxification of some environmental carcinogens and steroid hormones, is currently under investigation. Therefore, although the mutations in BRCAI and BRCAZ are associated with a high risk of breast cancer, and are more evident in cases with an earlier onset and consequently a greater loss of years of life, they are rare, and cause a very small proportion of Age (yean) Figure 2: The approximate age-specific cumulative risks of breast cancer for women who carry deleterious mutations in different genes, and the Australian population average. breast cancer overall. In contrast, more common mutations in a set of other genes, of which ATM and HRASl possibly belong, which confer a more modest increase in risk could account for a greater proportion of breast cancer, especially among older cases (Figure 2). Risks associated with a family history Family history is not a well-defined term (just which family members are considered, and how strong is the history?) and cannot be used alone to identify unambiguously families in which the high-risk genes are causing cancer. There is imprecision in the risks associated with a family history of cancer. They do not take into account how far back people know their family history, or the number of sisters and aunts a woman may have, let alone whether their true cancer status is known. Genetic susceptibility can be passed down through the father's side as well as the mother's, but it is only rarely evident in terms of cancer in male relatives. Family history does not imply a genetic cause; it can also be a consequence of nongenetic risk factors shared by relatives, and chance alone will produce a large proportion of family clusters. To assess a familial risk properly, it is necessary to know about any cancer in all first- and seconddegree male or female relatives on both sides of the family. Every report of cancer in a relative should be confirmed, if possible. Family history needs to be updated on a regular basis, as it can change with time as relatives age, and as more information comes to light about relatives. Historically, risk estimates from case-control studies have been open to recall bias because reports of cancer in relatives were not verified." Cohort studies, such as the Nurses' Health Studylgand the Iowa Women's Health Study,2"population-based studies using cancer registries," and case-control studies in which reports of cancer in relatives were validated,22 have indicated that the earlier studies may have overestimated familial risks. That is, whereas it had been thought that in general an average woman's risk was doubled or more by having an affected mother (relative risk (RR)22.0), it is now more probable that this increase is closer to 50 per cent (RR-1.5). The increased risk associated with an VOL. AUSTRALIAN AND NEW ZEALAND JOURNAL O PUBLIC HEALTH 1996 F NO. HOPPER affected mother was thought to be threefold or more (RR23.0) or more if the mother had been diagnosed at a young age (for example, before the age of 45 years), but it may be closer to twofold (RR=2.0). In Australia, breast cancer develops in about 7.5 per cent of women who reach the age of 75 years; that is 1 in 13 women.23In the United States (US) this figure is closer to 10 per cent; that is, one-third higher. Therefore, risk estimates based on baseline rates in the US and the case-control studies in which cancer in relatives was not verified could be giving up to double the absolute risk of breast cancer that would be appropriate for Australian women with a family history.24 Moreover, tables based on the Gail model, derived for selecting eligible women for the Tamoxifen Prevention Trial, possibly overestimate absolute risk for Australian women because the data are from a study of white women in the US willing to have annual examination^.^^ It is therefore suggested that, in advising Australian women about their familial risk using tables based on data from the US, risk should be quoted as lying within a range that goes from 50 to 75 per cent of the published risk. This will help adjust for the above issues, while conveying the approximate nature of all familial risk estimates. Issues in genetic testing At this relatively early stage of breast cancer genetics, some issues about genetic testing are as yet unresolved. Although it is now technically possible to determine whether a person has inherited high-risk mutations, genetic testing requires specialised laboratory techniques, and is expensive and timeconsuming, especially if it is to cover all possible genetic errors. Currently, only a few Australian laboratories can conduct such specialised testing, and even then 100 per cent mutation detection is not yet available. It is not known just how many genes confer a high risk. Therefore, a woman with a strong family history, yet for whom no mutations of any of the known breast cancer genes can be found, cannot be assured that she has not inherited an increased risk. Even within a cancer family in which the causative mutation has been identified, women shown not to carry that mutation can still develop breast cancer-they will be at about the average population risk, depending on their life-style risk profile. It is not known whether different mutations confer different risks of breast cancer, or different prognoses in affected women. There is a suggestion yet to be confirmed that mutations at the 5-prime end of the BRCAI gene may be more likely to lead to ovarian cancer than those at the 3-prime end.26 It is not clear that there are proven and acceptable established strategies to inform women with an inherited susceptibility of what to do to ameliorate the risk of breast cancer. One strategy is a radical double mastectomy, but this is not a 100 per cent guarantee, owing to the possibility that cancer may develop in residual breast tissue, or that undetected cancer may have already spread into the lymph sys470 tem. More frequent screening starting at a young age would appear prudent, but mammography is less effective in younger (premenopausal) women when their breasts are more dense (less fatty and translucent). Furthermore, it is possible that increased radiation may pose risks in women with genetic instability, such as those with mutations at either ATM or Tp53.I7It is not known if women with BRCAI or BRCA2 mutations are at an increased risk owing to radiation. Breast self-examination is of unproven benefit in this context. Other nonionising screening modalities, such as ultrasound and magnetic resonance imaging, are being investigated. Ultrasound does not have sufficient sensitivity and specificity to warrant use as a screening technique. Magnetic resonance imaging is expensive, and there are no clinical data to assess its long-term efficiency. It cannot be used to detect microcalcification, and its future use is likely to be in cancer staging, the assessment of treatments, and as a supplement for detecting cancer in women with dense breasts. Although life-style strategies based on putative risk factors for breast cancer, such as not delaying first childbirth, limiting use of oral contraceptives, and breast-feeding, may seem prudent, there are no data (yet) to support such advice for women with an inherited susceptibility. Some of these factors may have no effect, or even a reverse effect, in women with an inherited susceptibility. For example, there is evidence that the effects of some reproductive factors are different among women with a family history of breast cancer from among women without a family h i s t ~ r y . ~International collaborative efforts ’,~~ will be needed to clarify these issues. There are no prospective data on which to inform affected women with an inherited susceptibility of what to do to improve prognosis. Prospective studies are being initiated in the US and elsewhere, and Australian groups are planning to collaborate. Finally, only cancers in families with four or more cases of breast or ovarian cancer are more likely than not to be due to the rare high-penetrance genes.’O This is important for deciding which families should be referred to cancer family clinics for counselling and possibly genetic testing. Currently, only a very small proportion of women may be appropriate for genetic testing. Furthermore, genetic testing should be offered only with pre- and post-test counselling. This is to inform potential participants, prior to making an informed decision to go through with testing, about the limitations of testing and the consequences of being found to carry, or not carry, a high-risk mutation, taking into account the family’s cancer history. It is also essential in order to help individuals cope with the results of their tests, even if they are found not to carry a high-risk mutation. Recommendations for developing a systematic, research-oriented,evidence-basedapproach to genetic testing Recommendations for a coordinated Australian approach (Figure 3) were detailed in a report to the National Health and Medical Research Council VOL. AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 F 20 NO 5 GENETIC TESTING F R BREAST CANCER O 1 . To identify Australian public and private groups which are, or are planning to become, active in relation to breast cancer family clinics, genetic testing, genetic counselling, and associated reseo rc h. 2. To en:iure the above groups establish common information, ethical procedures and guidelines in order to advise, counsel and test appropriate women and families. 3. To establish and monitor standards for the quality ond accreditation of genetic counselling and testingi. 4. To establish means to update the knowledge and membership of the above groups, and to monitor ond evaluate their conduct. 5 . To prepare appropriate educational information to be distributed to women and professional carers and piactitioners, taking into account the availability and capacity of the groups and the limitations of current knowledge. 6. To ensure that relevant Australian data are collected, maintained and updated, in order to map the demand for genetic testing. 7. To develop a network of breast cancer family clinics and genetic testing laboratories, linked to nationcolly coordinated research groups. breast cancer families, based on a common protocol for collecting genetic and epidemiological information, to facilitate clinical treatment, counselling and research, in accordance with the NHMRC Guidelines for Genetic Registers, and for epidemiological research. Not to make any broad public announcements without first establishing the facilities to cope with the consequences of such pronouncements! 8. To establish a database of persons who are trained and proficient in these specialised activities, operating out of nationally accredited centres. There is a need to accumulate appropriate local data, in terms of the epidemiology, the genetic capabilities, and the psychosocial aspects of genetic testing. Studies of psychosocial factors in relation to genetic screening for cancer families have commenced overseas, and some collaborations with a few Australian groups have been established. Studies examining clinical aspects of the treatment of women with breast cancer who have an inherited susceptibility are being established to consider issues such as sensitivity to radiation and the use of Tamoxifen. The results of the majority of these clinical studies should be directly translatable to Australian women. Ethical and legal issues need to be considered at all levels and continually reconsidered in the light of changing evidence, practice, and public and professional opinion. A major problem in predicting future demands, and in determining what is appropriate testing and counselling policy, is the inability at present to define clearly a ‘high-risk’family based alone on the cancer history of relatives. It is possible that this may become clearer when mutation searches are carried out on population-based samples, and when more breast cancer genes are cloned. In the meantime, the vagueness of the term ‘family history’ is likely to cause unnecessary distress and anxiety to many women and their families. A nationally coordinated approach to breast cancer family clinics is important to ensure that counselling is properly informed, that high standards are achieved, and that uniform information is given, not least because some families will be spread across different centres and different states. Without this, it is likely that demand, fuelled by groups with a financial or other motivation, will lead to piecemeal setting up of clinics without infrastructure or evaluation. The cost to health services and the community may be unnecessarily high, with little public health benefit. Progress Since the recommendations shown in Figure 3 were written substantial progress has been made. The National Breast Cancer Centre and the Australian Cancer Network have been bringing together cancer family clinics, researchers, clinicians, and other groups to establish common guidelines covering consent procedures, risk assessment, clinical management and counselling. These initiatives cover recommendations 1 to 4. With respect to recommendation 5, educational material for health professionals, which identifies three groups of women with respect to familial risk has been developed by the and National Breast Cancer Centre and the Australian Cancer Network, and was distributed in September 1996. Educational material for women is also being developed. The Australian Breast Cancer Family Study, a Figure 3: Recommendations for developing a systematic, evidencebased approach to genetic testing for breast cancer (NHMRC) National Breast Cancer Centre in July 1995,and are in the process of being acted on in collaboration with the Australian Cancer Network. At present, there are only a few genetics services in Australia with experience in breast cancer. The early experience of such clinics, in Australia and overseas, is that the great majority of women seeking genetic testing are not at high risk, and therefore constitute a considerable cost in terms of inappropriate utilisation of scarce professional expertise. The facilities for genetic testing in Australia are at present limited. Laboratories need to conform to high standards using the best possible technologies. The transfer of genetic information to families must be undertaken in an ethically approved manner by AUSTRALIAN AND NEW ZEALAND JOURNAL O PUBLIC HEALTH 1996 VOL. 20 NO 5 F HOPPER large locally funded population-based case-control family study of early-onset breast cancer being conducted in Melbourne and Sydney, has been s u p ported and extended in part by a new grant from the National Institutes of Health (US) to establish an international Cooperative Family Registry for Breast Cancer Studies." With respect to recommendation 6, the study should provide accurate and precise estimates of familial risk, and mutation analyses should answer questions about the population characteristics of the cloned genes, BRCA1 and BRCA2. A consortium of Australian groups and family cancer clinics involved in breast cancer genetic research, CONFAB, is being formed to facilitate studies into the genetic epidemiology, biology and aetiology of inherited forms of breast cancer, to develop effective regimens for prevention, surveillance and treatment, and to enable cost-effective genetic testing and counselling to be undertaken in a coordinated way across the country. This will help cover recommendations 6 to 8. Therefore, substantial progress has been made, and given the continuing goodwill and cooperation evident to date, cost-effective and appropriate genetic testing for breast cancer could become a reality. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database. Recommendation 9 relies on the common sense of all individuals and groups involved. Acknowledgments This is an updated, revised, and shortened version of Genetic testing: review of the scientzjic literature, a report commissioned by the NHMRC National Breast Cancer Centre. This work was supported by the National Health and Medical Research Council, the NHMRC National Breast Cancer Centre, and the Victorian Health Promotion Foundation. I would like to thank Dr Douglas Easton, Dr David Goldgar, Dr Richard Cotton, Dr Deon Venter, Dr Margaret McCredie, Dr Graham Giles and Professor Peter Boyle for their assistance, advice and support, and take full responsibility for the information and opinions expressed. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Australian and New Zealand Journal of Public Health Wiley

Some public health issues in the current state of genetic testing for breast cancer in Australia

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Wiley
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Copyright © 1996 Wiley Subscription Services, Inc., A Wiley Company
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1326-0200
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1753-6405
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10.1111/j.1467-842X.1996.tb01623.x
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Abstract

Abstract: Two genes associated with a high breast cancer risk (BRCAl and BRCA2) have been discovered recently from study of large breast-cancer-dense kindreds. It is problematic to make inferences from these atypical families to the general population. Nevertheless, it appears that about 1 to 2 per cent of all breast cancer may be due to rare dleleterious mutations in BRCAl or BRCA2. The majority of breast cancer families with fewer than four cases are likely to have cancers not attributable to these genes. There may be more common mutations in other genes (such as A T M , HRASI) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases. At this early stage of cancer genetics, the risks associated with particular mutations are not known, there are no proven and acceptable strategies for women with an inherited susceptibility to ameliorate risk or improve prognosis, and risk estimates appropriate for Australian women with a family history of breast cancer are not established, although data from the United States may overestimate risk. Information is needed from population-based studies, such as the Australian Breast Cancer Family Study (Hopper et al. Breast 1994; 3: 79-86), but 100 per cent mutation detection in large cancer genes is difficult and expensive. Development of a systematic, research-oriented, evidence-based approach to genetic testing in Australia is recommended. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database. (AustN Z.fPublic Health 1996; 20: 467-72) HE possibility that there are inherited genetic factors that place some women at an increased or high risk for breast cancer has been thought likely for some time, on the basis of two general observations. First, women with one or more close relatives with a personal history of breast cancer are more likely to develop breast cancer themselves. This increased risk is greater if the relatives are the mother or a sister, if cancer developed at an early age or was bilateral, or more than one relative on the same side of the family was affected. Family history is one of the stronger and well-established risk factors for breast cancer, and even though the increased risk is on average a modest 1.5-fold to twofold, there must exist strong underlying familial risk factors.’ Finding the familial risk factors for breast cancer could be an important step forward in breast cancer prevention, and is a major aim of studies in genetic epidemiology.‘ Although the high-risk cancer susceptibility genes are obvious candidates, they may explain less than half the familial aggregation of breast cancer. Dietary and other life-style factors are also familial, and there may be interactions between genes, and between genetic and environmental factors. Second is the existence of rare extended multigenerational families in which there are multiple cases of breast cancer (see below). Whereas somatic mutations, or faults, develop in the chromosomes of tissue cells as a result of dam- age (such as background ionising radiation or the effect of carcinogens) and these have the potential to occur in anyone, Knudson’s two-hit hypothesis proposes that some people inherit a defect at a critical place in their genome on one chromosome and this defect occurs in all of their cells.3If in just one of these cells the other chromosome of that pair should also become defective in this critical region, that cell may go on to initiate a malignant tumour. These people are said to have inherited a germ-line mutation, which places them at an increased risk of developing cancer (susceptibility); which cancer depends on where the inherited germ-line mutation is, and a number of other yet-to-be-elucidated factors. Correspondence to Dr John L. Hopper, Department of Public Health and Community Medicine, University of Melbourne, 200 Berkeley Street, Carlton, Vic 3053. Fax (03) 9347 6136. BRCAl and BRCA2 The International Breast Cancer Linkage Consortium pooled data from over 200 extended breast cancer kinships from across the world. Almost all families contained at least two breast cancer cases, and most had at least four. More than a quarter also contained at least one case of ovarian cancer. These large, multigenerational and highly unusual families have extreme cancer histories, as can be seen from their pedigree diagrams published in a series of papers in the April 1993issue of the AmericanJournal o Human Genetics. The diagnosis in affected women f was usually at a young age, and there were sometimes one or more cases of ovarian cancer in female relatives, or even breast cancer in a male relative. These features reflect that the families were ascertained for breast cancer gene searching. VOL. AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 F 20 NO. 5 HOPPER To date, these families have been used to discover two high-risk autosomal dominant genes (that is, inheriting just one defective copy of the gene from either parent is sufficient to place a woman at high risk, according to the two-hit hypothesis above). The gene BRCAI was cloned (that is, its genetic sequence and exact place on chromosome 17 was discovered) in 1994.' It is a large and complex gene composed of 22 coding regions (exons). Over 100 different deleterious mutations have so far been identified, and the total may go as high as 300 or more. In late 1995 BRCA2 was cloned.5 It is also very large, about twice the length of BRCAl. Women who have inherited deleterious mutations in either BRCAl or BRCAP have a high risk of developing breast cancer. The age-specific cumulative risk of cancer, or penetrance, was estimated by statistical analyses using genetic markers prior to the cloning of these genes,6x and not by studying individuals with known mutations. It is thought to increase from less than 5 per cent at age 30 years, to about 15 per cent at age 40 years, 50 per cent at age 50 years and 75 per cent at age 60 years, and reaches a maximum of around 85 per cent by age 80 years (Figure 1; the lack of precision of these estimates is also indicated). The risk does not reach 100 per cent; there exist women who are known mutation carriers but who have not developed cancer by the age of 80. Different mutations could have different penetrances. Furthermore, the mutations in these families are probably those more likely to cause cancer, and at an earlier age, than the mutations occurring in the general p o p ~ l a t i o n that is, these families are ;~ likely to be unrepresentative because thay have been chosen specifically to have a preponderance of earlyonset breast cancer. If this possible overestimation of risk is ignored, for a woman with a deleterious BRCAI or BRCAZ mutation who has not yet developed breast cancer, her risk of developing cancer in the next decade can be approximated from Figure 1. The 10-year conditional risk is relatively low at about 5 per cent for an unaffected 20-year-old, and 10 per cent for an unaffected 30-year-old. That is, cancer-free genetically (D Figure 1 : Age-specific cumulative risks, with 95% confidence intervals, for breast or ovarian cancer in female B R C A 1 mutation carriers based on linkage analyses in cancer-dense families susceptible women under the age of 30 years have a small chance of developing breast cancer in their next decade of life. However, this risk increases rapidly to about 40 per cent for an unaffected 40year-old, and 50 per cent for an unaffected 50-yearold, but reduces to about 20 per cent for women who have reached older ages without developing breast cancer. Therefore, most of those women who have inherited these defective genes, and who go on to develop breast cancer, would be expected to do SO in their 40s and 50s. Some mutations in BRCA1 carry an increased risk of ovarian cancer: and perhaps other cancers, such as those of the colon, rectum and p r ~ s t a t ewhile ,~ mutations in BRCAZ may confer an increased risk of breast cancer in males, and possibly ovarian and other cancers in females8 The spectrum of cancers caused by BRCA1 and BRCAP has yet to be charactensed on a population basis. The risk of ovarian cancer in women with BRCAI mutations has been estimated from the Consortium data to be about 15 per cent by age 50 years and 40 per cent by age 70 years6 Although these risks may be overestimates for the reasons discussed above, they are important. Survival from ovarian cancer i s poor, reflecting the difficulty of detection at an early stage. For a woman with BRCAl mutations who has had breast cancer, her risk of developing either a second primary in the contralateral breast or ovarian cancer appears to be similar to the risk of a first primary (shown in Figure l).' Mathematical modelling suggests that about 1 in 800 women have inherited a high-risk mutation.'" The true population frequency can be found, in principle, by screening a population-based sample of women, but this is impractical at present, except for particular mutations, such as the 185delAG in BRCAI which appears to be relatively common at about 1 per cent in Jews of Ashkenazi descent." Based on mathematical models, it has been. estimated that 5 per cent of cases diagnosed before the age of 40 years, 2 per cent of those diagnosed between the ages of 40 and 49 years, and 1 per cent of those diagnosed at or after the age of 50 years, s could be attributable to the high-risk genes.'" A most breast cancer occurs in postmenopausal women, about 1 per cent to 2 per cent of all breast cancers might be due to the high-risk mutations in BRCAI and BRCA2, and perhaps other yet-to-beidentified high-risk genes. The issue of how much breast cancer is due to particular genes can be resolved only by thorough mutation searches in population-based samples. Cancer genes are large and complex, however, and hundreds of different sequences, or variants, are possible. For some of these variants it can be inferred from the DNA sequence that they will lead to the formation of a truncated protein. These can be considered to be disease-causing muations, especially if they can be shown to run through families in tandem with affected individuals. For others, it may be clear from the sequence that they will not affect the gene's function, or they may be common among AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 vot. 20 NO 5 F GENETIC TESTING F R BREAST CANCER O people without the disease (these are called polymorphisms). For some variants, however, it is not clear what effect they will have, and it is difficult to determine whether they cause disease. Therefore, it is important that mutation searches involve both affected and unaffected individuals, and have the capacity to study DNA from family members. Such a study is being undertaken on material collected by the Australian Breast Cancer Family Study" (see pages 471-2, 'Progress'). as a80.7 Y a5- 0.4 0.3 - Other genes involved with breast cancer The autosonnal dominant Li-Fraumeni syndrome is the familial clustering of childhood bone and soft tissue sarcomas of an early onset, and breast cancer is sometimes observed in these very rare families, about half of which have mutations in the Tp53 gene." Perhaps 1 in 10 000 individuals in the population carry Tp53 mutations, and this gene may account for up to 1 per cent of breast cancer cases diagnosed before the age of 35 years, but a negligible amount iin older ages because few mutation carriers survive past middle age. The risk of breast cancer in women with Tp53 mutations is thought to be between 30 and 40 per cent by age 45 years. There is considerable uncertainty in the figures.I4 The ATM gene for the recessively inherited condition ataxia-telangiectasia on chromosome 11 was cloned recer1t1y.I~ Persons who inherit two defective copies, one from each parent, develop the disease, and sufferers of ataxia-telangiectasia are at high risk of breast cancer. Although it is far from well established, there is some evidence from families with ataxia-telangiectasia that individuals who carry one defective copy of the ATM gene may be at a threefold or more increased risk of breast cancer.'"' These carriers are relatively common. Perhaps 1 in 200 to 1 in LOO women have inherited this moderately increased genetic risk, and it may account for from 2 to 7 per cent of breast cancer in the population, although again there is much uncertainty about this.I4 Like BRCAl and BRCAZ, the ATM gene is very long and complex, and mutations can occur all along its length. The rare alleles at the HRASl locus are thought to be associated with about a 70 per cent increase in risk of breast cancer." Somewhere in the order of 1 in 10 women have these rare alleles, and a risk of about 20 to 30 per cent by age 70 years, so about 3 to 8 per cent of all breast cancer could be attributable to this gene.14 It is not clear whether the mismatch repair genes involved with nonpolyposis colorectal cancer syndromes increase the risk of breast cancer. The involvement in breast cancer of other genes, such as the androgen and oestrogen receptor genes and genes involwd in the metabolic detoxification of some environmental carcinogens and steroid hormones, is currently under investigation. Therefore, although the mutations in BRCAI and BRCAZ are associated with a high risk of breast cancer, and are more evident in cases with an earlier onset and consequently a greater loss of years of life, they are rare, and cause a very small proportion of Age (yean) Figure 2: The approximate age-specific cumulative risks of breast cancer for women who carry deleterious mutations in different genes, and the Australian population average. breast cancer overall. In contrast, more common mutations in a set of other genes, of which ATM and HRASl possibly belong, which confer a more modest increase in risk could account for a greater proportion of breast cancer, especially among older cases (Figure 2). Risks associated with a family history Family history is not a well-defined term (just which family members are considered, and how strong is the history?) and cannot be used alone to identify unambiguously families in which the high-risk genes are causing cancer. There is imprecision in the risks associated with a family history of cancer. They do not take into account how far back people know their family history, or the number of sisters and aunts a woman may have, let alone whether their true cancer status is known. Genetic susceptibility can be passed down through the father's side as well as the mother's, but it is only rarely evident in terms of cancer in male relatives. Family history does not imply a genetic cause; it can also be a consequence of nongenetic risk factors shared by relatives, and chance alone will produce a large proportion of family clusters. To assess a familial risk properly, it is necessary to know about any cancer in all first- and seconddegree male or female relatives on both sides of the family. Every report of cancer in a relative should be confirmed, if possible. Family history needs to be updated on a regular basis, as it can change with time as relatives age, and as more information comes to light about relatives. Historically, risk estimates from case-control studies have been open to recall bias because reports of cancer in relatives were not verified." Cohort studies, such as the Nurses' Health Studylgand the Iowa Women's Health Study,2"population-based studies using cancer registries," and case-control studies in which reports of cancer in relatives were validated,22 have indicated that the earlier studies may have overestimated familial risks. That is, whereas it had been thought that in general an average woman's risk was doubled or more by having an affected mother (relative risk (RR)22.0), it is now more probable that this increase is closer to 50 per cent (RR-1.5). The increased risk associated with an VOL. AUSTRALIAN AND NEW ZEALAND JOURNAL O PUBLIC HEALTH 1996 F NO. HOPPER affected mother was thought to be threefold or more (RR23.0) or more if the mother had been diagnosed at a young age (for example, before the age of 45 years), but it may be closer to twofold (RR=2.0). In Australia, breast cancer develops in about 7.5 per cent of women who reach the age of 75 years; that is 1 in 13 women.23In the United States (US) this figure is closer to 10 per cent; that is, one-third higher. Therefore, risk estimates based on baseline rates in the US and the case-control studies in which cancer in relatives was not verified could be giving up to double the absolute risk of breast cancer that would be appropriate for Australian women with a family history.24 Moreover, tables based on the Gail model, derived for selecting eligible women for the Tamoxifen Prevention Trial, possibly overestimate absolute risk for Australian women because the data are from a study of white women in the US willing to have annual examination^.^^ It is therefore suggested that, in advising Australian women about their familial risk using tables based on data from the US, risk should be quoted as lying within a range that goes from 50 to 75 per cent of the published risk. This will help adjust for the above issues, while conveying the approximate nature of all familial risk estimates. Issues in genetic testing At this relatively early stage of breast cancer genetics, some issues about genetic testing are as yet unresolved. Although it is now technically possible to determine whether a person has inherited high-risk mutations, genetic testing requires specialised laboratory techniques, and is expensive and timeconsuming, especially if it is to cover all possible genetic errors. Currently, only a few Australian laboratories can conduct such specialised testing, and even then 100 per cent mutation detection is not yet available. It is not known just how many genes confer a high risk. Therefore, a woman with a strong family history, yet for whom no mutations of any of the known breast cancer genes can be found, cannot be assured that she has not inherited an increased risk. Even within a cancer family in which the causative mutation has been identified, women shown not to carry that mutation can still develop breast cancer-they will be at about the average population risk, depending on their life-style risk profile. It is not known whether different mutations confer different risks of breast cancer, or different prognoses in affected women. There is a suggestion yet to be confirmed that mutations at the 5-prime end of the BRCAI gene may be more likely to lead to ovarian cancer than those at the 3-prime end.26 It is not clear that there are proven and acceptable established strategies to inform women with an inherited susceptibility of what to do to ameliorate the risk of breast cancer. One strategy is a radical double mastectomy, but this is not a 100 per cent guarantee, owing to the possibility that cancer may develop in residual breast tissue, or that undetected cancer may have already spread into the lymph sys470 tem. More frequent screening starting at a young age would appear prudent, but mammography is less effective in younger (premenopausal) women when their breasts are more dense (less fatty and translucent). Furthermore, it is possible that increased radiation may pose risks in women with genetic instability, such as those with mutations at either ATM or Tp53.I7It is not known if women with BRCAI or BRCA2 mutations are at an increased risk owing to radiation. Breast self-examination is of unproven benefit in this context. Other nonionising screening modalities, such as ultrasound and magnetic resonance imaging, are being investigated. Ultrasound does not have sufficient sensitivity and specificity to warrant use as a screening technique. Magnetic resonance imaging is expensive, and there are no clinical data to assess its long-term efficiency. It cannot be used to detect microcalcification, and its future use is likely to be in cancer staging, the assessment of treatments, and as a supplement for detecting cancer in women with dense breasts. Although life-style strategies based on putative risk factors for breast cancer, such as not delaying first childbirth, limiting use of oral contraceptives, and breast-feeding, may seem prudent, there are no data (yet) to support such advice for women with an inherited susceptibility. Some of these factors may have no effect, or even a reverse effect, in women with an inherited susceptibility. For example, there is evidence that the effects of some reproductive factors are different among women with a family history of breast cancer from among women without a family h i s t ~ r y . ~International collaborative efforts ’,~~ will be needed to clarify these issues. There are no prospective data on which to inform affected women with an inherited susceptibility of what to do to improve prognosis. Prospective studies are being initiated in the US and elsewhere, and Australian groups are planning to collaborate. Finally, only cancers in families with four or more cases of breast or ovarian cancer are more likely than not to be due to the rare high-penetrance genes.’O This is important for deciding which families should be referred to cancer family clinics for counselling and possibly genetic testing. Currently, only a very small proportion of women may be appropriate for genetic testing. Furthermore, genetic testing should be offered only with pre- and post-test counselling. This is to inform potential participants, prior to making an informed decision to go through with testing, about the limitations of testing and the consequences of being found to carry, or not carry, a high-risk mutation, taking into account the family’s cancer history. It is also essential in order to help individuals cope with the results of their tests, even if they are found not to carry a high-risk mutation. Recommendations for developing a systematic, research-oriented,evidence-basedapproach to genetic testing Recommendations for a coordinated Australian approach (Figure 3) were detailed in a report to the National Health and Medical Research Council VOL. AUSTRALIAN AND NEW ZEAIAND JOURNAL O PUBLIC HEALTH 1996 F 20 NO 5 GENETIC TESTING F R BREAST CANCER O 1 . To identify Australian public and private groups which are, or are planning to become, active in relation to breast cancer family clinics, genetic testing, genetic counselling, and associated reseo rc h. 2. To en:iure the above groups establish common information, ethical procedures and guidelines in order to advise, counsel and test appropriate women and families. 3. To establish and monitor standards for the quality ond accreditation of genetic counselling and testingi. 4. To establish means to update the knowledge and membership of the above groups, and to monitor ond evaluate their conduct. 5 . To prepare appropriate educational information to be distributed to women and professional carers and piactitioners, taking into account the availability and capacity of the groups and the limitations of current knowledge. 6. To ensure that relevant Australian data are collected, maintained and updated, in order to map the demand for genetic testing. 7. To develop a network of breast cancer family clinics and genetic testing laboratories, linked to nationcolly coordinated research groups. breast cancer families, based on a common protocol for collecting genetic and epidemiological information, to facilitate clinical treatment, counselling and research, in accordance with the NHMRC Guidelines for Genetic Registers, and for epidemiological research. Not to make any broad public announcements without first establishing the facilities to cope with the consequences of such pronouncements! 8. To establish a database of persons who are trained and proficient in these specialised activities, operating out of nationally accredited centres. There is a need to accumulate appropriate local data, in terms of the epidemiology, the genetic capabilities, and the psychosocial aspects of genetic testing. Studies of psychosocial factors in relation to genetic screening for cancer families have commenced overseas, and some collaborations with a few Australian groups have been established. Studies examining clinical aspects of the treatment of women with breast cancer who have an inherited susceptibility are being established to consider issues such as sensitivity to radiation and the use of Tamoxifen. The results of the majority of these clinical studies should be directly translatable to Australian women. Ethical and legal issues need to be considered at all levels and continually reconsidered in the light of changing evidence, practice, and public and professional opinion. A major problem in predicting future demands, and in determining what is appropriate testing and counselling policy, is the inability at present to define clearly a ‘high-risk’family based alone on the cancer history of relatives. It is possible that this may become clearer when mutation searches are carried out on population-based samples, and when more breast cancer genes are cloned. In the meantime, the vagueness of the term ‘family history’ is likely to cause unnecessary distress and anxiety to many women and their families. A nationally coordinated approach to breast cancer family clinics is important to ensure that counselling is properly informed, that high standards are achieved, and that uniform information is given, not least because some families will be spread across different centres and different states. Without this, it is likely that demand, fuelled by groups with a financial or other motivation, will lead to piecemeal setting up of clinics without infrastructure or evaluation. The cost to health services and the community may be unnecessarily high, with little public health benefit. Progress Since the recommendations shown in Figure 3 were written substantial progress has been made. The National Breast Cancer Centre and the Australian Cancer Network have been bringing together cancer family clinics, researchers, clinicians, and other groups to establish common guidelines covering consent procedures, risk assessment, clinical management and counselling. These initiatives cover recommendations 1 to 4. With respect to recommendation 5, educational material for health professionals, which identifies three groups of women with respect to familial risk has been developed by the and National Breast Cancer Centre and the Australian Cancer Network, and was distributed in September 1996. Educational material for women is also being developed. The Australian Breast Cancer Family Study, a Figure 3: Recommendations for developing a systematic, evidencebased approach to genetic testing for breast cancer (NHMRC) National Breast Cancer Centre in July 1995,and are in the process of being acted on in collaboration with the Australian Cancer Network. At present, there are only a few genetics services in Australia with experience in breast cancer. The early experience of such clinics, in Australia and overseas, is that the great majority of women seeking genetic testing are not at high risk, and therefore constitute a considerable cost in terms of inappropriate utilisation of scarce professional expertise. The facilities for genetic testing in Australia are at present limited. Laboratories need to conform to high standards using the best possible technologies. The transfer of genetic information to families must be undertaken in an ethically approved manner by AUSTRALIAN AND NEW ZEALAND JOURNAL O PUBLIC HEALTH 1996 VOL. 20 NO 5 F HOPPER large locally funded population-based case-control family study of early-onset breast cancer being conducted in Melbourne and Sydney, has been s u p ported and extended in part by a new grant from the National Institutes of Health (US) to establish an international Cooperative Family Registry for Breast Cancer Studies." With respect to recommendation 6, the study should provide accurate and precise estimates of familial risk, and mutation analyses should answer questions about the population characteristics of the cloned genes, BRCA1 and BRCA2. A consortium of Australian groups and family cancer clinics involved in breast cancer genetic research, CONFAB, is being formed to facilitate studies into the genetic epidemiology, biology and aetiology of inherited forms of breast cancer, to develop effective regimens for prevention, surveillance and treatment, and to enable cost-effective genetic testing and counselling to be undertaken in a coordinated way across the country. This will help cover recommendations 6 to 8. Therefore, substantial progress has been made, and given the continuing goodwill and cooperation evident to date, cost-effective and appropriate genetic testing for breast cancer could become a reality. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database. Recommendation 9 relies on the common sense of all individuals and groups involved. Acknowledgments This is an updated, revised, and shortened version of Genetic testing: review of the scientzjic literature, a report commissioned by the NHMRC National Breast Cancer Centre. This work was supported by the National Health and Medical Research Council, the NHMRC National Breast Cancer Centre, and the Victorian Health Promotion Foundation. I would like to thank Dr Douglas Easton, Dr David Goldgar, Dr Richard Cotton, Dr Deon Venter, Dr Margaret McCredie, Dr Graham Giles and Professor Peter Boyle for their assistance, advice and support, and take full responsibility for the information and opinions expressed.

Journal

Australian and New Zealand Journal of Public Health – Wiley

Published: Oct 1, 1996

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