Clinical Oncology (1996) 8:222-225 (~) 1996 The Royal College of Radiologists Clinical

Oncology

Original Article

Prophylactic Mastectomy for Genetic Predisposition to Breast Cancer: The Proband's Story J. W. 1, R. E e l e s 2, T. C o l e 3, R . T a y l o r 4, P. L u n t 5 a n d M. B a u m 6

1The Proband c/o 6, 2Royal Marsden NHS Trust and Institute of Cancer Research, Sutton, 3Birmingh.am Maternity Hospital, Birmingham, 4St George's Hospital, London, ~Bnstol Royal Hospital for Sick Chddren, Bristol and Royal Marsden Hospital, London UK

Abstract. The identification of the BRCA1 gene may prove a mixed blessing in the short term. First, the demand for testing might outstrip available resources, the ethics of testing are complex and the advice to give someone who tests positive is as yet unclear. Furthermore, the psychological dynamics within such families have not yet been considered seriously. As these families might be widespread, there will inevitably be problems involving clinical genetic centres in different parts of the country, or for that matter, in different areas of the world. In this paper we provide a case report, which might be considered an adumbration of things to come. The proband in this story (a coauthor) was known to have inherited a genetic predisposition to cancer. This was because her identical twin had already developed the disease and she came from a kindred with a very high probability for carrying a dominant breast cancer gene in the germ line. We describe the personal reactions of an individual woman faced with these difficult decisions, the impact on her family and the impact on the clinical genetic services in different parts of the country. Our experience could help to provide a template for the development of regional services once genetic testing for predisposition to breast cancer becomes widely available.

Keywords: Breast cancer; BRCA genes; Genetics; Prophylactic mastectomy

I N T R O D U C T I O N

The scientific and lay press are full of stories about the race to clone the BRCA1 gene. The interest for the lay public is based on a common misapprehension that the identification of this gene will allow the population at large to be tested for their susceptibility to breast cancer. This is clearly not the case because

Correspondence and offprint requests to: R. Eeles, Clinical Scient- ist and Honorary Consultant in Cancer Genetics and Oncology, Royal Marsden NHS Trust and Institute of Cancer Research, Downs Road, Sutton, Surry SM2 5PT, UK.

the BRCA1 gene is likely to be implicated in the genetic predisposition to breast cancer in only a limited number of familes world-wide. In addition to the significance for these families, the importance, as far as the scientific community is concerned, in cloning the genes that predispose to breast cancer and identifying their mutations, is that this may give an important insight into the biological mechanisms implicated in the genesis of breast cancer.

In the short term, after the cloning of a breast cancer predisposition gene, there will inevitably be a rush of worried women who judge themselves from their family history to be at an increased risk. The genetic services might become overloaded and there might be little time for mature contemplation on the practical and ethical issues surrounding the testing for the BRCA1 gene.

The case history reported in this paper may provide a helpful insight into many of the anticipated and unanticipated problems that can follow when an individual has been identified as being a carrier of a gene with a high penetrance, directly related to the development of breast cancer. The proband in this story might be the first ever case in the UK medical literature of an individual electing for prophylactic mastectomy who knew with confidence that she was indeed a carrier for a gene predisposing to breast cancer, in this case unlikely to be BRCA1, but probably, BRCA2. Such certainty arose because she was a member of a family with an undoubted genetic predisposition to breast cancer, with her identical twin developing the disease at an early age. Her story illustrates many of the personal problems that can arise in the difficult decision concerning prophylactic mastectomy and also the disturbance to the family dynamics resulting from her decision. Other, to some extent, unanticipated problems arose because other members of the family were under the care of various agencies in different regions and, because of our imperfect knowledge, received what appeared to be conflicting advice. This case report will be divided into two sections. The first is a description of the genetic aspects, together with the risk calculations for the unaffected female members (and male members) of the family, together with a description of the genetic fingerprinting process that confirmed that the

Prophylactic Mastectomy 223

proband was the identical twin of her sister who developed the disease. The second part of the story is written by the proband herself to provide a sensitive insight into the experiences of a woman identified as a gene carrier for breast cancer (this may also be the first report in the literature where one of the co- authors is the patient herself!). It is hoped that the experience of all the parties involved will allow the clinical genetic services in the United Kingdom to prepare themselves for the avalanche of activity that will follow the recent identification of the BRCA1 gene [1]. This should also be a valuable reminder to the purchasing authorities within the National Health Service to think hard about the funding of genetic testing for well women.

GENETIC ASPECTS

The genetic management of this family illustrates some of the issues that will have to be addressed as counselling of high risk cancer families becomes more common due to the identification of cancer predisposition genes (CPG). Our estimates of risk in this field are often based upon different evidence from that used in classical clinical genetics. The main differences are the incomplete penetrance of CPGs and the presence of modifying genes, which intro- duce uncertainty that gene carriers will develop the disease, and the fact that, although a family may be likely to carry a CPG as determined by the family structure, the gene may not yet have been located. Estimates of penetrance are therefore based upon epidemiological studies or studies of small numbers of families with the same structure. All these esti- mates therefore have some uncertainty, and the slightly different figures between studies, which can be quoted either in one consultation or by different clinicians, can make patients feel insecure. This will be further complicated when counselling families in future when BRCA1 and BRCA2 have been excluded. The effect will be to invalidate previously collected data from epidemiological series of familial breast cancer, which will include significant numbers of BRCA1 and BRCA2 families. There are some data suggesting that patients do not wish to receive precise numerical information [2]. In the future, cancer genetics counselling may involve a risk level 'con- cept', such as high risk, but no precise figures. The patient would then be conveyed a perception of the degree of risk and would make a value judgement about future management options. The challenge is how to present this risk.

This family was managed by two clinical geneticists and a clinical oncologist with a genetic interest, who were situated in three different health regions. This occurred because the family lived in different parts of the country. Communication between clinicians managing different branches of a family is of utmost importance.

The proband in this case report is a member of a breast cancer family, which has a history of both female and male breast cancer. There are four cases

of breast cancer out of 13 female relatives who could be potential gene carriers. Two occurred at less than 50 years of age and one was bilateral. From epi- demiological studies of breast cancer [3], these features indicate a 94% chance that a breast CPG is segregating in this family. The family tree has not been shown for reasons of confidentiality. However, the pattern of cancers in the family suggests the presence of an autosomal dominant CPG.

One of the cases was breast cancer in a male and therefore it is unlikely that the gene responsible is BRCA1 [4], a high risk dominant CPG on chromo- some 17q [5]. However, the pattern of cancers in this family is similar to other families due to the CPG named BRCA2, recently localized to 13q12-1316].

When counselling the proband about her risks of developing breast cancer to help her in her decision- making process prior to prophylactic mastectomy, the first consideration was whether a CPG was present in this family. This is highly probable as described above. The second factor was, had she inherited the gene? She has an identical twin sister who was affected with breast cancer at the age of 38, and who was very likely be a gene carrier. From studies of the phenotypic/genotypic correlations of twins, 1%-5% of those who are phenotypically identical are not genetically identical [7,8]. Although the location of the CPG in this family is unknown, determining whether the twin sisters were indeed genetically identical would indicate whether the pro- band had inherited the same genes as her twin and therefore if she also carried the predisposition gene. Genetic fingerprinting was therefore performed on the proband and her twin sister by Southern analysis of lymphocyte DNA using Hinfl digests and the multilocus repeat probes 33.6 and 33.15 [9]. The former showed at least 20 and the latter at least 14 identical bands. This result implies that these twin sisters are genetically identical with an extremely high probability.

The chance that the proband had inherited a breast CPG therefore was the chance that there is a gene at all in this family(94%). However, the problem with CPGs is that they do not have 100% penetrance (i.e. not all gene carriers manifest the disease). There were two choices for the penetrance figures used in councelling the proband. The first was for those for BRCA2, which have been determined from segre- gation analyses based on the Utah kindred K107 [10], and the second was for those from large epidemiolo- gical series, such as the Cancer and Steroid Hormone (CASH) Study [3]. The former give a risk of breast cancer of 63% by age 70 and the latter 67% by age 70. The risk figures if the proband had not been geneti- cally identical were a 47% risk of being a gene carrier and a 28% risk of breast cancer by age 70. This illustrates the importance of determining if the twins were genetically identical. The fact that the proband was a monozygotic twin means that her risk is almost certainly higher than that predicted by the CASH model, as the sisters are identical at all loci and probably possess other modifying genes. However, we counselled the proband on the lower risk figure (approximately 60% by age 70) since we felt that it was important that she made a decision about pro- phylactic mastectomy on the lowest possible breast

224 J.W., et al.

cancer risk figure. This was reiterated in writing to the proband.

Another important counselling issue was the risk of other cancers. BRCA1 mutations are known to confer an increased risk of ovarian cancer as well as breast cancer in some families [11]. Due to the presence of the male breast cancer case in this family, it is unlikely that a mutation in BRCA1 is present. However, this will only be conclusively proved when direct mutational analysis of BRCA1 approaches 100% detection. The risk of ovarian cancer was estimated from the CASH study, which gives an ovarian cancer risk in a gene carrier of 10% by age 60. This is almost certainly an overestimate of the ovarian cancer risk to carriers of genes other than BRCA1, since much, perhaps the majority, of the ovarian cancer risk is due to BRCA1 in the CASH estimates.

Ovarian cancer screening, even in high risk groups, is unproven [12] and no randomized studies have been performed in this population. Ovarian cancer screening is therefore recommended empirically, and most geneticists and oncologists would recommend it in families with two or more cases of ovarian cancer at any age (who are at 30 times the population risk of ovarian cancer), or in families in which it is likely to be due to the BRCA1 gene, when the risk of ovarian cancer in a gene carrier is 30% by age 60 [13]. One member of this family was very anxious about her ovarian cancer risk; she had already had breast cancer at a young age and was likely to be a gene carrier. In order to allay anxiety, ovarian screening could in theory be offered in this situation, but after discussion between the three geneticists involved, and in the light of the evidence above, ovarian screening was not actively promoted. The penetrance curves for the ovarian cancer risk from BRCA2 are not yet determined. This advice may alter once the risk of ovarian cancer due to BRCA2 is quantified.

This case illustrates the complicated assessments of different cancer risks that have to be made in certain families when considering if unaffected members are at risk of cancer. The ability to make more accurate estimates will improve as further CPGs are cloned and mutations are identified in studies of defined cancer populations. However, this will not solve the problem of incomplete penetrance, with the uncer- tainty that cancer will definitely develop, and pre- viously compiled risk estimates will be less reliable since they include cases due to BRCA 1 and the family may not be due to this gene. Furthermore, the preventative and early detection options need to be improved so that less drastic measures are available to women at high risk of breast cancer due to a genetic predisposition.

The procedure for the management of cancer gene carriers and their families needs to be defined before many of the CPGs are cloned. The recent cloning of BRCA1 has increased this urgency [1]. Although BRCA1 probably only accounts for about 2.5% of breast cancers, as further breast CPGs are cloned, the number of women requiring counselling could be enormous and will swamp the currently available genetics services.

THE PROBAND'S STORY

I have lived with the idea of breast cancer and its familial link for several years and experienced the anxiety and fears connected with this. However, the discovery of breast cancer in my identical twin and the resulting genetic consultant's report made the situation feel more critical.

The most important aspect of my first hospital appointment was the need to feel heard and to have my feelings understood. I was given time to express my feelings and spoke of how scary it felt to have so little control over this issue. The surgeon outlined in a clear and informative manner the choices that I had. I left the appointment feeling I did have some choices and would be supported in whatever decision I made. I feel that communication between genetic consultant, surgeon and patient is important. In my case, I was made to feel part of a team in the decision- making process.,

Having decided to proceed with a bilateral prophy- lactic mastectomy, I was given an operation date for the following month. My partner was included in the preoperative counselling, which involved talking over the practical aspects of the operation and an opportunity to view photographs of the reconstruc- tive surgery of other women. In hindsight, it would have been very useful to have had the chance to speak to a 'real life' patient who had undergone such surgery and it may have helped to alleviate some of the pre- and postoperative anxieties I experienced.

On admission to hospital I found the staff on the breast unit ward very approachable and a consider- able amount of time was spent on clear explanations and checking out my knowledge of the forthcoming operation. My own feelings were ambivalent; I felt strangely euphoric. I feel that it was the approach- ability of the nursing staff that eventually enabled me to discuss my fears on that day.

The preoperative day also involved a visit to the medical photographer. I feel that the timing of this visit is extremely important. It is a sensitive, emotional experience, which may be more suited to a previous outpatient appointment. For myself, it involved a lonely visit to a dark hospital basement, where I was acutely aware that the male photo- grapher was going to be the last person to see my breasts as they then were and this made the pro- cedure extremely traumatic. Therefore, I feel the emotional importance of this needs to berecognized and the patient accompanied and supported through- out it.

My initial recovery after surgery required a stay in hospital for a week. (Surgeon's note: Surgery involved bilateral subcutaneous mastectomies with subpectoral 'Becker' tissue expanders.) During this time the physical pain was manageable with analge- sics. There was some relief that I was now post- operative, but I had a reluctance to view my breasts, which were well protected with dressings and a Friedrich's bra. From this reluctance developed a need for the initial removal of the dressings to be experienced in privacy, accompanied by a nurse. I was respected and supported in this and found it helpful to have time to look, ask questions and take it

Prophylactic Mastectomy

in. One of the most difficult experiences to cope with was the lack of sensation in my breasts; it was something I had been informed about, but was and is still now a traumatic aspect of this surgery. Personally, it made the adjustment to the acceptance of the implants as part of my body more difficult.

The experience of being a 'non-cancer' patient in a cancer ward created a range of emotions from relief to guilt about my differentness. However, in many ways it helped as an affirmation of a difficult decision.

My recovery from the operation was a long, slow process. Pain and discomfort remained a feature of my life for a long time: a sensation of 'cut glass' under the skin plus extreme tightness across the pectoral muscles. The valves were often uncomfortable, making it difficult to lie on either side. The inflation process was a strange sensation but not painful; with each addition of saline, my breasts became more 'normal' in appearance, although they were still very hard and there remained a lot of discoloration. I was physically exhausted and I felt apprehensive and vulnerable in a crowd.

Emotionally, the operation invoked an extreme sense of loss in terms of sexuality and feminity. This sense of loss was linked to the lack of sensation in my breasts and the practical difficulty in obtaining suitable bras. The acceptance of a 'foreign body' within yourself is a lengthy process, both physically and emotionally. For myself the first sign of a 'real' recovery was an acceptance of the new breasts not being as before. However, I could never have envisaged how long this would take and therefore feel that clear information about the length of the procedure is of vital importance and would assist in the healing process.

The follow-up care involved monthly visits to the hospital plus regular contact with my own GP. The visits to my GP were invaluable, providing an opportunity to talk through fears, and to receive help with infections and reassurance about any 'changes' that may have occurred. This link was invaluable in monitoring each saline addition and in offering me encouragement when positive input was important.

For myself, a supportive relationship with my GP provided a 'refuge' at times when it was too difficult to share my feelings within my own family. It also helped in communicating my needs to the hospital between visits. I feel there should be a strong emphasis on caring for the 'whole person' during follow-up; the availability of my GP in terms of time and acceptance of my feelings enabled this to happen. The support of one's GP at the start of the decision-making process is also essential. In my case, a strong link was forged between myself, my GP and the hospital. I also feel that a network of support, provided through a link-up with other women who have experienced this operation, would be invalu- able.

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Ideally, given time and the facilities, I feel more emphasis could be placed on genetic screening being seen as a whole family dilemma. An opportunity should be given to all interested family members to discuss its implications.

In conclusion, I have no regrets and I feel I am now at a stage where I can truly celebrate my good fortune and feel happy about what I am and have. I am grateful to the hospital, my surgeon and my own GP, for the medical expertise and support given to me, which has know enabled me once again to feel in control of my life.

Note added in proof: since the writing of this paper, the BRCA2 gene has been cloned (Wooster et al. 1995:Nature 378,789.

Acknowledgements. We should like to thank Dr V. Murday for arranging the genetic fingerprinting tests, Dr D. Easton for statistical and genetic epidemiologi- cal advice and Dr M. Stratton for helpful comments. The fingerprinting probes were a kind gift from Professor Alec Jeffreys.

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Received for publication January 1996 Accepted February 1996