Download REPORT OF CONSENSUS MEETING ON THE MANAGEMENT OF

REPORT OF CONSENSUS MEETING ON
THE MANAGEMENT OF WOMEN WITH A
FAMILY HISTORY OF BREAST CANCER
Monday 12 January 1998 at the Wellcome Trust,
183 Euston Road, London NW1
Sponsored and organised by the R&D Office of the Anglia & Oxford NHS Executive
and the Unit for Public Health Genetics, Cambridge
Session 1
A.
Chairman; Dr Ron Zimmern (Cambridge)
Introduction
Dr Ron Zimmern (Cambridge) introduced the meeting by welcoming those attending, thanking them for their
support and hoping that the day’s proceedings would help in the search for a national consensus on the management
of women with an increased risk of breast cancer.
He raised five issues which he thought would be particularly relevant to the discussions.
1.
The meeting was to be about women who present with symptoms or signs of breast cancer or are anxious about
their own risk of breast cancer because they have relatives with the disease. The main focus was to be on the
management of clinical risk, and not on genetic testing or population screening.
2.
The management of those at increased risk would involve their categorisation into low, moderate and high risk
groups, based on family history. But there was no formal scientific evidence to suggest how best to manage
these women. The use of current interventions such as regular mammography was largely unproved. It was
essential for there to be well planned and co-ordinated research to determine the effectiveness of such
interventions.
3.
It was particularly necessary to raise awareness, in both clinicians and the general public, about the true risks of
breast cancer, and especially to convey the message that in spite of a familial predisposition, the genetics of
BRCA1 and BRCA2 would only play a small part in the overall management of the at risk population. Most
familial cases were due to as yet unidentified environmental-genetic interactions, associated with mutations or
polymorphisms of low penetrance, for which no advantage would be gained from specialist genetic referrals or
genetic testing. An important objective must be to provide consistent information about the genetics of breast
cancer for both the public and the profession in order to reduce ignorance, misunderstanding, and anxiety.
4
It was also necessary to emphasise that the interventions that were to be the subject of the day’s discussions,
such as regular mammography, tamoxifen or mastectomy, did not reduce the risk of developing cancer but the
risk of dying from the disease.
5
The profoundly difficult ethical problems that the rapid progress in genetics has posed should not be
underestimated. These issues would not be addressed in detail at the meeting but their implications had to be
considered in coming to a conclusion about the management of these women.
B. Proposals from the Anglia & Oxford Region
Dr Paul Pharoah (Cambridge) presented a review of the currently available epidemiological evidence, detailed in
Appendix A.
He noted that breast cancer could be either genetic or sporadic. Familial cancer included both sporadic cases and
cases in which there was a genetic predisposition. The cases of genetic breast cancer in which the family carried a
gene such as BRCA1 or BRCA2 were small. Many familial cases did not. Some would be the consequence of
common environmental influences; others of genetic susceptibility, probably due to a number of as yet unidentified
genetic mutations of low penetrance. Not surprisingly this complex interaction of specific genes, non- specific
genetic factors and environmental influences has led to much misunderstanding and confusion.
Risk was usually reported as either ‘relative’ or ‘absolute’. Relative risk described the ratio of the incidence in the
diseased or susceptible population to a control or normal population. Absolute risk took into account the baseline
risk of the control population. The absolute risk attributable to a person could be calculated by subtracting the
baseline risk from the risk in the susceptible group. The relative risk of a woman with a family history could be
calculated but a high relative risk did not necessarily imply a high absolute risk; the level of baseline risk was the
determining factor. The risk to an individual in a ‘breast cancer family’ depended on several factors. These included
the age of the subject, the number of family members with the disease,and the age at onset of menarche. Not all these
factors were recorded in the published epidemiological studies.
1
The genes so far implicated in inherited breast cancers were BRCA1, BRCA 2 and, rarely, p53. Individual women in
families who carried the mutation were only at 50 percent risk themselves. Even when mutations in these genes were
present, environmental factors were still important. The likelihood of a mutation being found in a family depended
on whether the family history was confined to breast cancer or whether individuals in the family also had ovarian
cancer or both breast and ovarian cancer; on the number of relatives with cancer; and probably most importantly, the
age of onset of the cancer in family members.
Dr Pharoah then considered the options for risk reduction:

Early detection - mammography.
The evidence for the effectiveness of mammography in the over 50s was now established and formed the basis
for the establishment of the National Breast Cancer Screening Programme. The evidence for effectiveness in
those aged 40 - 49 was growing but not yet wholly persuasive. There was no evidence to suggest that a
programme of regular mammography for those women at increased risk because of family history would prolong
survival. Nor, because of the emerging evidence that tumours in women who had a strong family history of
breast cancer might be more aggressive, was it known how often mammography should be recommended.
Moreover, the concern about the possible harm of early mammography on these subjects who may be more
sensitive than normal to radiation had not yet been answered.

Prophylactic surgery
A number of trials had given failure rates of 1% to 19% but these have all had relatively short follow-up periods.
Prophylactic mastectomy was probably effective at reducing the risk in very high risk women, but it was by no
means clear that, following the procedure, risk was reduced to zero.

Chemoprophylaxis
The results of several prophylactic tamoxifen trials were awaited.
Dr Pharoah put forward suggested criteria for categorising women into high, medium or low risk and outlined the
calculations which derived the numbers expected in each group within a population.
Dr James Mackay (Cambridge) outlined a management strategy for women. The details are presented in Appendix
B.
The need for a consensus derived in part from the confusion caused by the responses of the public, the press and the
profession to the recent identification of the two BRCA genes. Unrealistic expectations had been created which had
led to rapidly increasing demands on primary care and on breast units and regional clinical genetic centres. There
was a great deal of variation in practice throughout the UK. Many referrals were inappropriate and there was no
agreed strategy for dealing with the situation. Messages that were important to convey to patients included:

no matter how bad the family history, each individual patient seeking reassurance because of concern was only at
a 50 percent risk of inheriting a mutated gene

mutations in the BRCA genes were numerous, spread throughout the gene and technically difficult to detect. A
direct gene test carried out on an at risk patient in a clinical setting would only be feasible and informative if the
exact nature and site of the mutation in the family was known. Gene testing therefore required the patient to
have a living relative with breast cancer to be screened for the familial mutation

it was feasible to categorise patients into high, medium and low risk groups on the basis of their family history.
Although this was necessarily an arbitrary stratification, it did allow rational management strategies to develop
from it
 the effectiveness of strategies to reduce the risk of dying by a programme of regular mammography, prophylactic
mastectomy or tamoxifen was not yet determined. It was essential to establish a national study to determine the
effectiveness of mammographic screening in this group of women.
2
Dr Mackay proposed that the high risk group might be defined by one of the following family histories.
1.
2.
3.
4.
Breast / breast ovarian cancer families with 4 or more relatives on the same side of the family
affected at any age
Breast cancer (only) families with 3 affected relatives with an average age of diagnosis <40
Breast / ovarian cancer families with 3 affected relatives with an average age of diagnosis of
breast cancer <60
Families with one member with both breast and ovarian cancer
and that these patients, and only these, should be referred for specialist cancer genetic consultation at a regional
genetic centre. Within the genetic centre, a more detailed risk assessment and a consideration of genetic testing
could be undertaken. It would also, in appropriate cases, be right to discuss the possibility of prophylactic
mastectomy. In spite of the lack of detailed evidence regarding management, because of the very high lifetime risk of
breast cancer women in this group, it was probably appropriate to discuss and offer one of the three management
interventions
The moderate risk group was to be defined by one of the following family histories.
1.
2.
3.
4.
Three first or second degree relatives with breast or ovarian cancer diagnosed at any age on the
same side of the family, or
Two first or second degree relatives with breast cancer diagnosed under 60, or ovarian cancer
at any age, on the same side of the family, or
One first degree female relative with breast cancer diagnosed under 40 or 1 first degree male
relative with breast cancer diagnosed at any age, or
A first degree relative with bilateral breast cancer
This definition would include women with relative risk of breast cancer of at least three times that of the general
population. In contrast to high risk women, and given the lack of evidence of benefit for any intervention for women
in this group, he suggested that an intervention should only be offered to moderate risk women in the context of a
national research study. A suggested protocol for such a research study is shown below:
< 30
No mammography
30-34
(a)
Youngest affected first degree relative diagnosed age 40+
No mammography.
(b)
Youngest affected first degree relative diagnosed age 39 or below
Annual mammographic screening starts 5 years below the age of diagnosis of the youngest
affected relative.
35-49
Annual mammography
50+
Mammography every 18 months with clinical examination around time of mammography.
Half of these mammograms will be performed within the National Breast Screening Programme
The patients in this group are at higher risk of breast cancer than the general population, but are less likely to be
carrying a mutation in one of the known BRCA genes. The purpose of the management strategy was to modify the
risk of dying from or to reduce morbidity from breast cancer. At present, genetic diagnosis and testing should play
no part in the management of these women.
The low risk group was to be defined as those whose family histories did not fall into those with high or moderate
risk
The strategy would be to discuss the difference between inherited and sporadic cancer and to explain that their
histories did not suggest that they had a genetic risk for which an effective intervention was available. They were to
be informed that the risk of sporadic breast cancer (the most common type) remained and encouraged to participate
in the National Breast Cancer Screening Programme at the appropriate age. Those at low risk were not to be referred
to the regional genetics centre, nor, to be referred for regular mammography.
3
Dr Mackay concluded with a few observations. The strategy outlined above would allow either the primary health
care team or the multidisciplinary breast care team at district level to stratify individuals with reasonable confidence.
It would be open to the primary health care team to identify those at low risk, and, following reassurance, to
discharge some of them, referring on to the breast unit those with a family history suggesting moderate or high risk.
Some patients in this low risk group would wish to seek the opinion of a breast specialist, and would also require
referral to the breast care team. Adopting the same strategy, the advice from the breast team should be similar to the
advice already received from the primary care team. This internal consistency would increase reassurance. Different
advice from different health professionals damaged patient confidence.
Individuals from high risk families would be ascertained in the breast unit and offered referral to the regional cancer
genetics clinic. Some individuals would not wish to be referred. Close collaboration, with rapid flow of accurate
information, between primary care, the district breast unit and the regional genetics centre, working to a single
management stratagem was essential.
Numbers at risk
It is estimated that for a total population of 1 million with an age and sex structure similar to that of England and
Wales there would be:
20-40
4,450
47,000
high risk families
women aged 35-49 at moderate risk
total women at moderate risk
Around 20 - 40 high risk families would be eligible for mutation testing. A mutation would have to be identified in
an affected individual in a family before a direct gene test could be offered to an unaffected individual in that family.
Techniques used in NHS clinical genetics laboratories detected fewer mutations than might be expected on the basis
of research studies. Optimistically, if mutations were to be identified in 20% of families, then gene testing would be
available for unaffected individuals in 4 - 8 families, likely to amount to 12 - 40 individuals. Half would not have the
mutation and therefore 6 - 20 individuals would be at very high risk (around 85% lifetime risk) of developing breast
cancer. Some of these individuals would not wish prophylactic surgery, and would continue with a programme of
regular mammography. Applying the 'new genetics' in this way might therefore prevent breast cancer in around 6 20 individuals per million of population, depending on the uptake of genetic testing and prophylactic mastectomy.
In those women aged 35-49 in the moderate risk group, up to 4,450 mammograms would be needed annually. It was
not known what proportion of women in this group would elect to be referred. Theoretical considerations suggested
that for every 1,000 women aged 35 who had an annual mammogram for 15 years, 6 deaths from breast cancer might
be prevented. This was based on the assumption that the relative risk of breast cancer in this group was 5 and that
annual mammography reduced mortality by 20 percent. The effectiveness of this strategy could only be assessed if
an appropriate trial was undertaken. A trial would require the recruitment of 20,000 women and their study for 5
years. To achieve this would require the enrolment of 10 percent of the nation’s 30 - 49 year old women at moderate
risk of breast cancer.
Discussion
Prof Michael Baum (London) raised two major concerns:
He was happy to accept the definition of the moderate risk group and that research was required to determine their
best management. He was concerned that the proposed national study did not address any specific hypothesis, and
was sceptical that an observational study would answer the question of whether regular mammography did or did not
enhance survival, favouring in its stead a randomised control trial. There were also concerns about how DCIS was to
be managed if detected in these circumstances.
He regretted that the proposed consensus statements were not issued in advance of today’s meeting and thought it
unreasonable to expect participants to reach a consensus.
Dr Ros Eeles (London) advised caution in using some of the recent BRCA analysis data from samples from high
risk families as some of these might be subject to biased ascertainment. It would be better to base risk stratification
on calculations from modelled epidemiological data such as those from Claus and the BCLC. The use of fixed
criteria based only on family history to categorise the three risk groups would include women of high risk in those
categorised as moderate risk. It would be better to stratify upon the posterior possibility of having a high risk gene.
4
Prof Rodney Harris (Manchester) emphasised the inevitable tension between those demanding high quality
evidence from RCTs and those responsible for providing an efficient and caring service. The objectives of those
providing a clinical service were necessarily different to those of colleagues who carried out research. He was
anxious that plans to establish and maintain family registers should be made as these facilitated future developments.
The principles considered today for breast cancer might also apply to the management of other cancers.
C.
Responses from the perspective of the surgeon, the radiologist and the GP.
Mr Douglas McMillan (Nottingham) first described a national audit of Family History Screening Clinics, which, at
present, included data from around 20 centres. The target population was asymptomatic women under 50 with at
least one first degree relative with breast cancer diagnosed before age 50. Questionnaires sought information on the
screening criteria used by the clinics and on the data obtained in the prevalent and incident screens and on interval
cancers detected in the programmes.
Women
Prevalence screen
Incident screen
Interval
6968
Cancers
36
6222
4372
Rates
5.2/1000
21
13
3.3/1000
3.0/1000
Prof Roger Blamey (Nottingham) agreed that the number of worried women was increasing and that we had no
proven strategy to deal with this. It was essential that we did not increase anxiety in women who were not themselves
alarmed. Most women who were referred because of anxiety could be effectively reassured, including those at
increased risk, but reassurance itself was not enough to quell the anxieties of all subjects. It was necessary to offer
something in the meantime, even by way of a less than perfect study based on the results of existing imperfect
evidence. It was not acceptable to wait for the results of a proposed national trial. The IBIS (Tamoxifen) Trial
which demonstrated the effectiveness of tamoxifen at preventing the development of cancer in the contralateral breast
of patients with the disease did not necessarily prevent the development of a second cancer; it was possible that the
drug was slowing the spread of tumour cells rather than preventing their growth. The results of studies on
mammographic screening for those women aged less the 50 appeared to give qualified support to the programme.
However interventions had to be cost effective as well as effective. In his view annual mammography, even in
patients at moderate or high risk were unlikely to be.
He agreed that gene testing should only be done when the result could change the management of the individual, and
that there had to be a known mutation in the family. He had problems accepting the proposed criteria for high risk
families since most families in the UK were rather small and many patients did not have enough relatives to meet the
suggested criteria. He was also concerned with the suggestion that clinical geneticists should only operate as a
tertiary service. He believed their involvement would be required at the level of the cancer unit.
Dr Rob Wilson (Nottingham) reported that the Royal College of Radiologists had been developing a set of
guidelines on breast imaging. These were, by and large, consistent with the consensus proposals offered to this
meeting. Two-view mammography (medio-lateral oblique and cranio-caudal) produced better results and were
recommended, but the question of optimal frequency has not yet been settled. The shortage of radiologists was a
cause for concern.
Dr Nadeem Qureshi (Nottingham) considered the potential attributes of general practice that would facilitate the
incorporation of familial cancer genetics into primary care. Knowledge of the patient and their family facilitated the
task of knowing how, when and where to discuss sensitive genetic risk information. The taking of a family history
was also an integral part of a GP’s function, but there was scope for error in risk stratification in a primary care
setting. GPs were gatekeepers to secondary and tertiary care and would be able to support appropriate referrals to
hospital for those at moderate or high risk. Their major workload would be to support and reassure patients defined
as low risk. Education was an important component: to provide accurate information on breast cancer risk to the
general population, to “at risk” women and to health professionals. A national consensus on the management of
these women would do much to enhance this task. Different management strategies across the country could result in
confusion and increased anxiety among those women who perceived themselves to be at increased risk. Both the
public and health professionals had to understand that despite research evidence, much uncertainty often remained.
5
Discussion
Prof Tony Howell (Manchester) asked how the proposed extra screening for the moderate risk group would
compare with the current workload of the NHSBSP. A rough calculation from the Nottingham figures suggested it
would add about 10 percent.
Prof Sandy Raeburn (Nottingham) thought that it was unwise to think that low risk women required no action.
Reassurance was essential, particularly in respect of the possible insurance consequences.
Prof Theresa Marteau (London) emphasised that research was equally important in the low risk group. It was
necessary to determine the best ways of providing reassurance and the best people to do it. She also suggested that
consumers should be consulted about trial design and informed consent
Prof Michael Baum (London) felt strongly that, having failed to do a randomised control trial 10 years ago when
the time would have been more opportune, didn’t mean that we shouldn’t do one now. He was worried by the
profession’s generally patronising attitude to patients and especially their double standards towards informed consent.
Dr James Mackay (Cambridge) said that irrespective of whether the proposed study design was a RCT or a well
designed observational study the need to obtain fully informed consent would be present.
Dr Ron Zimmern (Cambridge) asked that the groups in the afternoon should address the question of whether an
observational study would be adequate or if an RCT was essential.
A number of speakers were worried about the resource implications of the proposed management strategy and the
training that would be needed. Many existing family cancer clinics were funded largely on research grants.
Concern was expressed that some women in the moderate risk group might decline to enter a controlled trial and then
be refused early mammography. This was seen by patient groups to be undesirable, but the public health view was
that as there was genuine uncertainty about the benefits of these intervention, the failure to provide it on demand or as
a matter of right was not only desirable but ethical. Alistair Kent (GIG) noted that the best way to manage such a
situation was for GPs to have a confident strategy that allowed them to convince patients that entry into a trial was in
their best interests.
Dr Hilary Harris (Manchester) accepted that primary care would inevitably be involved in the risk stratification
and management of all groups. If well organised and provided with appropriate computerised information and
programmes, GPs and their staff should be able to cope with all conditions with a family history, not just cancer.
Dr Gareth Evans (Manchester) described how the service in Manchester, covering a population of about 4 million,
had been developing since 1987 and had now accumulated over 200 high risk families. To date 42 mutations had
been found, although not all families had yet been tested. He suggested that the proposal that there were only 20 - 40
families per million total population in the high risk group to be an underestimate. He also made the point that
present management was probably also unethical because of a lack of evidence to support their effectiveness.
Dr Ron Zimmern (Cambridge) replied that this was precisely the concern driving today’s meeting. An important
question for health authorities to consider was whether they should only purchase mammography for the moderate
risk group in the context of national studies and decline to make mammography available to those in the low risk
group.
Dr Mike Gill (London) thought that savings might be made from within existing breast cancer budgets, for example,
from the inappropriate use of chemotherapeutic agents, if research eventually showed that regular mammography was
effective in the moderate risk group. Several speakers had thought that too many women at only slightly increased
risk, were already inappropriately managed with regular mammography.
Dr Joan Patterson (London) took issue with what she felt to be rather rigid referral criteria. She thought that to
restrict moderate risk women to breast units and high risk ones to regional genetic centres was not appropriate. It
could be argued that family histories of moderate risk women were more difficult to assess than those of high risk
women and that many breast units did not have the staff or expertise to deal with them.
6
Ms Anne Andermann (Oxford) thought that there was a real need for better quality evidence and that this was best
obtained via RCTs. It was necessary to try harder to convince women of the rationale and value of RCTs. Prof
Roger Blamey (Nottingham) put delegates on the spot by challenging them to say whether they would advise their
wives or daughters or themselves to enter an RCT. A rough count of hands suggested a response of about 50/50.
Session 2
A.
Chairman; Dr Lindsay Davies (Trent)
Consensus Statements
Delegates split into 4 groups to consider the Consensus Statements (Appendix C). The results for each of the
questions in the statements are shown in the Appendix.
The chairmen reported back on the most difficult areas for their discussion groups
Group A: Dr Henrietta Ewart
Although there was broad agreement that the concept of trying to get a consensus was a good one, in practice it
turned out to be a difficult exercise since there was a resistance to accepting the rather dogmatic statements and the
specific definitions offered.
Group B: Dr Penny Bridger
The most controversial issue was the type of study that should or could be undertaken. There was a tendency to
qualify statements with “generally” or “normally’. Overall a reasonable consensus was obtained on most questions.
Group C: Dr Clive Buxton
The group considered that since many of its members were not experts, they was not really competent to make the
requested judgements. There was a reluctance to accept the specificity of some of the statements. There was a
particular concern about the proposal to exclude the moderate group women from clinical genetics centres.
Group D: Dr Richard Richards
The group was troubled by thresholds, whilst accepting the principle behind some of the statements. The details were
sometimes not acceptable. There was also a dispute about whether a RCT was needed or whether an observational
study sufficed.
Dr Lindsey Davies (Trent) summarised the discussions as useful and lively. It was unsurprising that there was a
tension between ideals and reality.
There appeared to be a consensus, defined as agreement of 90 percent or greater for the following statements:
1.
2.
3.
4.
5.
There should be no population based or opportunistic screening of women for a family history of breast cancer
Patients seeking medical attention because of breast symptoms, or anxious that they might be of higher risk
because of family history, should have a family history taken
It was appropriate to categorise risk into three groups - low, moderate and high - based on family history
Genetic testing should only be offered in the high risk group under the guidance of a cancer geneticist in a
regional genetics centre
Women categorised to be at low risk should generally be managed within the primary care setting and not be
referred for specialist consultation
The original Q9 - Statement 5 above - was drafted without the word “generally”. One group would only agree with
the statement if the extra word were included. Without its inclusion, the score would have been 72 percent.
There was no agreement, defined as agreement of 40 to 60 percent, for:
1.
2.
The criteria presented in this meeting for separating women into the low, moderate and high risk groups
The suggestion that referrals to the regional genetics centre should be confined only to women in the high risk
group
7
There was a moderate agreement, defined as agreement between 70 and 90 percent, for the views that:
1.
3.
4.
5.
B.
Genetic testing should only be offered if a living relative was available to provide tissue for a mutation screen
Women in the moderate risk group should be offered an intervention only in the context of a national study
It was acceptable for this to be a well designed observational study as opposed to a randomised controlled trial
Purchasers should not commission mammographic services except in the context of a national study.
Summing Up
Dr Muir Gray.
The R&D Perspective
Dr Muir Gray noted that this was effectively the third meeting in a series whose original objective was to bring public
health physicians together with clinical geneticists to examine the impact of the rapid progress in genetics on the
NHS. As joint chairman of the National Screening Committee (NSC) he emphasised the need for a simple approach
to screening, which he defined as the systematic application of a test or enquiry to a non-symptomatic population. It
could be pro-active, as in the NHSBSP, or reactive. The taking of a family history should be thought of as a
screening test. The concept of opportunistic screening caused confusion and was best avoided. We should aim to
“stop procedures not proven from starting; start to stop procedures not proven, and start proven procedures”. To
obtain the necessary proof would often require new research and one of the purposes of the day was to argue the case
for an urgent need to undertake research into the most effective management of women at increased risk of breast
cancer. There were important consequences for the service, both in terms of clinical quality and of resource usage,
in not having good evidence. He welcomed the debate on the type of study that should be undertaken on the
management of these women and asked for the report of the day to be sent to the National Screening Committee.
Dr Penny Bevan.
The Health Authority Perspective.
Dr Bevan admitted starting from a position of thinking a consensus was impossible since there wasn’t sufficient
evidence. There was clearly disparate service provision around the country and no agreed best practice. The issue of
patient demand further complicated the situation. She was able to accept, at the end of the day, that there was good
agreement on the management of high risk women and on the need for further research on the moderate risk group,
notwithstanding the debate on the form of such research. She wondered whether an RCT, although ideally desirable,
was in practice feasible. In the meantime it might not be acceptable to offer no interventions for women who are
assessed to be at greater than three times the risk of the general population. There was a danger that the NHS might
be seen to have ‘failed’ if, by refusing to offer the intervention, these women were driven into the private sector.
There was a clear need for education and training for health care professionals and for clear and consistent
information for all sectors of the NHS and for the public.
Prof Tony Howell.
Perspective of the Oncologist
(Chairman of the UKCCCR Breast Cancer Sub-Committee)
Not all was bleak. Survival data had improved significantly. Studies to date had suggested that adjuvant therapy and
mammography screening conferred some benefits. However it was not yet known whether cancer family clinics,
genetic tests or chemoprevention would benefit women at increased risk of breast cancer. But the potential offered
8
by them would not go away and it would be unethical to ignore them. Our alternatives were:

to muddle on as at present and to make ad hoc plans (the usual British solution)

to apply clinical science and organise well planned and co-ordinated trials to measure the effectiveness of our
interventions.
He believed that it was necessary to do the latter, and to do so quickly, as the opportunity would soon be lost.
Dr Lindsey Davies
Regional Director of Public Health, Trent RO
Dr Davies thought that, although there was a lack of clarity about best management in some areas, we were close to a
consensus view in many others.
She proposed that:
1.
A nationally co-ordinated research programme should be planned. This could emerge from the report of this
meeting, possibly followed by more detailed discussion between some of the participants. The report should be
presented to the National R&D Committee by Dr Muir Gray.
2.
The agreed proposals should be developed into a set of national guidelines. The Public Health Genetic Unit in
Cambridge should act as catalyst for ensuring that this happened. Perhaps a group from among the participants
could take this forward. The work might also link eventually with the new National Institute for Clinical
Excellence (NICE).
3.
A consensus meeting should be convened in about a year to review progress and to take any actions necessary to
consolidate this.
Discussion
Dr Muir Gray supported these proposals and advised that the research plan should concentrate on principles rather
than a mass of details. However Dr Ros Eeles urged that an agreed protocol must be developed if any study was to
be widely supported. Prof Blamey hoped that those groups which were currently undertaking related studies would
be encouraged to complete these and to publish their results.
Epilogue
After the meeting it was agreed that a Working Group, chaired by Dr Ron Zimmern, should be convened to take
these matters forward, in particular to see if a greater consensus might be attained and to make recommendations for
a national study or trial of mammography for moderate and high risk women. The results of their deliberations will
be brought back to a Consensus Meeting in January 1999. The following people have been asked to join the
Working Party:
Dr Ron Zimmern
Dr Ros Eeles
Director of the Unit for Public Health Genetics, Cambridge
Clinical Senior Lecturer & Honorary Consultant in Cancer Genetics & Clinical
Oncology, Cancer Genetics Group, Royal Marsden Hospital, Sutton
Dr Gareth Evans
Consultant in Clinical Genetics, Christie Hospital NHS Trust, Manchester
Dr James Mackay
Consultant in Cancer Genetics, Addenbrooke’s NHS Trust, Cambridge
Professor Tony Howell
Professor of Medical Oncology, Christie Hospital NHS Trust, Manchester
Professor Roger Blamey
Consultant Surgeon, Nottingham City Hospital, Nottingham
Professor Michael Baum
Professor of Surgery, Institute of Surgical Studies, London
Dr Rob Wilson
Consultant Radiologist, Nottingham City Hospital, Nottingham
Dr Hilary Harris
General Practitioner, Manchester
Professor Nick Day
Honorary Director & Professor of Community Medicine, Institute of Public Health,
Cambridge
Dr Paul Pharoah
CRC Clinical Research Fellow, Strangeways Laboratories, Cambridge
Professor Theresa Marteau Director, UMDS, Guy’s & St Thomas’ Medical & Dental School, London
9
Appendix A
CONSENSUS CONFERENCE
MANAGING WOMEN AT HIGH RISK OF BREAST CANCER
BECAUSE OF A FAMILY HISTORY
ASSESSING THE EVIDENCE
PRODUCED BY DR PAUL PHAROAH, DR JAMES MACKAY AND DR RON ZIMMERN
10
SUMMARY
1. Two of the genes involved in familial breast cancer, BRCA1 and BRCA2 have recently been
identified.
2. Widespread professional and public misunderstanding of the likely impact of these advances.
3. Majority of breast cancer is not genetic.
4. The increased risk associated with a family history of breast cancer is usually small.
5. In women at increased risk of breast cancer there are three major approaches to risk reduction;
early detection (ie mammographic screening), surgery (prophylactic mastectomy) and
chemoprevention. Good research evidence for the effectiveness of any of them is lacking.
6. A direct gene test is a relatively simple test which can detect the presence or absence of a
single specific mutation in an individual. This is used when a specific mutation is known to be
segregating in a family in order to test unaffected members of that family for that mutation.
7. A mutation search is carried out if the mutation causing breast cancer in a particular family is
not known. This is a technically demanding and laborious procedure.
8. A negative mutation search is not a guarantee that no mutation is present. Perhaps 20% of
mutations in BRCA1 and BRCA2 are missed with current techniques.
11
BACKGROUND
The recent identification of one of the genes involved in familial breast cancer has been followed
by the identification of other genes involved in the familial forms of cancer of the breast, ovary
and colon. There is widespread professional and public misunderstanding of likely impact of
these recent advances, particularly in breast cancer, which has attracted great media attention.
There is an unrealistic expectation that genetic tests will become readily available and there
appears to have been an almost automatic acceptance of the assumption that identification of
individuals carrying a mutation in one of these cancer susceptibility genes will be beneficial to
that individual and will result in a reduction in mortality. In addition, the important fact that the
majority of breast cancer is not genetic has been obscured and the importance of genetic factors
has been overemphasised. Pre-symptomatic screening programmes (mammography) in at risk
women are perceived as highly advantageous and the disadvantages have been minimised. This
has resulted in a large number of anxious individuals who have a relative with breast cancer
approaching the primary care team seeking advice on and access to genetic testing, or at the very
least mammographic screening. Without adequate guidance or support the primary care team is
ill equipped to deal with this demand.
OBJECTIVES
The purpose of this paper is to summarise the recent literature on familial and genetic breast
cancer risk and to discuss the available evidence on the effectiveness of risk modification. Based
on this evidence we describe criteria which enable us to
1. Categorise women with a familial predisposition into a moderate risk group and a low risk
group
2. Determine a high risk subset of those in the moderate risk group who are suitable for
specialist cancer genetic consultation
Women in the high risk subset would have a significant probability (c.20%) of
coming from a family with an identifiable genetic alteration such as a mutation
in BRCA1 or BRCA2.
12
BREAST CANCER RISK
A variety of terms have been used to describe the different types of breast cancer. In particular
breast cancer may variously be described as sporadic, familial, inherited/hereditary, or genetic.
For the purpose of this paper, we consider breast cancer can be divided into two main types:

Genetic breast cancer occurs in women with an alteration in a breast cancer
susceptibility gene which has been inherited through the germline, and is synonymous
with inherited breast cancer.

Sporadic breast cancer occurs in women with no such predisposition.
Familial breast cancer occurs in women with a relative with breast cancer and includes those with
both sporadic and genetic breast cancer. This is because familial clustering of breast cancer may
be due to chance, increased genetic susceptibility, or shared environmental/lifestyle risk factors.
All individuals who have a relative with breast cancer are at slightly increased risk of developing
sporadic breast cancer themselves, but the risk is moderately increased (say more that three times
the population risk) in only a small minority of these individuals. In that minority, there are a
small number of individuals who are at very high risk of developing inherited breast cancer and
who may benefit from the recent genetic advances either now or in the foreseeable future. This is
diagrammatically represented in figure 1.
Figure 1
breast cancer cases
relatives of those with
breast cancer
women at moderately increased
risk of breast cancer
women at high risk of developing
inherited breast cancer
QUANTIFYING BREAST CANCER RISK
Helping the public to understand breast cancer risk is a difficult task for professionals. There a
several ways of presenting the same risk data, but the two most common are relative risk and
absolute risk.
Relative risk is defined as the incidence of breast cancer in a defined “at risk” group divided by the
incidence in women without that risk factor.
An absolute risk is the probability of developing breast cancer at some point in a
defined time period. These are often presented as the lifetime risks, which is the
risk of developing cancer at some time in life. This depends on both the age
specific incidence of breast cancer and all cause mortality rates.
For example in the British female population as a whole, the lifetime risk of developing breast
cancer is about 8%. In other words, 1 in 12 women will develop breast cancer at some point
during her life. These general public estimates do not take into account the presence or absence
of known risk factors (such as family history). Absolute risks can however be calculated from
relative risk, population age-specific incidence, and mortality1. Table 1 shows several measures
of absolute risk (%) of breast cancer for women of different ages and at various levels of relative
risk. For example a 40 year old woman with a history of breast cancer in a first degree relative
has a 2.6% chance of developing breast cancer in the next ten years and a 14.7% chance of breast
cancer by age 85.
13
Table 1: Absolute risks (%) of breast cancer by age and relative risk
Age
20
30
40
50
60
70
Risk of breast cancer by age 50
1.7
1.7
1.3
Risk of breast cancer by age 85
8.0
8.0
7.7
6.5
4.9
3.0
Risk of breast cancer in next ten
years
0.0
0.4
1.3
1.9
2.4
2.2
Risk of breast cancer in next 20
years
0.5
1.7
3.2
4.1
4.3
Risk of breast cancer by age 50
3.4
3.4
2.6
Risk of breast cancer by age 85
15.3
15.2
14.7
12.6
9.6
5.8
Risk of breast cancer in next ten
years
0.1
0.8
2.6
3.8
4.7
4.3
Risk of breast cancer in next 20
years
0.9
3.4
6.2
8.1
8.3
Risk of breast cancer by age 50
8.4
8.2
6.3
Risk of breast cancer by age 85
33.5
33.4
32.3
28.2
22.0
13.8
Risk of breast cancer in next ten
years
0.2
2.0
6.3
9.2
11.2
10.4
Risk of breast cancer in next 20
years
2.2
8.2
14.8
18.9
19.3
Risk of breast cancer by age 50
16.0
15.7
12.3
Risk of breast cancer by age 85
54.6
54.6
53.0
47.4
38.3
25.2
Risk of breast cancer in next ten
years
0.4
4.0
12.3
17.4
21.0
19.5
Risk of breast cancer in next 20
4.4
years
Adapted from Pharoah and Mackay2
15.7
27.2
33.9
34.3
Relative risk 1
Relative risk 2
Relative risk 5
Relative risk 10
FAMILIAL RISK
All women with a family history of breast cancer are at increased risk of breast cancer
themselves, but the extent of this risk varies according to the nature of the family history, that is
14
the type of relative affected, the age at which the relative developed breast cancer and number of
relatives affected, and it also varies according to age of the individual. There is a large body of
epidemiological data on the risks associated with different family histories which has been
summarised in a recent systematic review and meta-analysis3. The results of this meta-analysis
are summarised in Table 2. The risk categories described in most studies are however simple,
and the risks associated with more complex histories are difficult to estimate. For example, the
risk to a 40 year old woman whose mother developed breast cancer age 65 and whose oldest
sister (of 3) developed breast cancer aged 51 is difficult to estimate with any precision.
Table 2: Relative risk (95% CI) of breast cancer by age of subject and age of affected relative
Subject age
Relative age
50 years
<50 years
All ages
Any first degree relative
<50 years
3.3 (2.8,3.9)
1.8 (1.6,2.0)
2.3 (2.2,2.5)
50 years
1.8 (1.5,2.2)
1.7 (1.5,2.0)
1.8 (1.6,2.0)
All ages
2.4 (2.2,2.7)
1.9 (1.8,2.0)
2.1 (2.0,2.2)
Mother
<50 years
2.5 (1.6,3.8)
1.7 (1.1,2.6)
2.0 (1.7,2.4)
50 years
1.6 (1.1,2.3)
1.7 (1.2,2.4)
1.7 (1.5,2.0)
All ages
2.2 (1.9,2.6)
1.8 (1.6,2.1)
2.0 (1.8,2.1)
Sister
<50 years
3.3 (2.1,4.5
1.8 (1.2,2.4)
2.7 (2.4,3.2)
50 years
3.0 (1.4,4.6)
1.9 (1.1,2.7)
2.0 (1.7,2.4)
All ages
3.0 (2.5,3.5)
2.0 (1.8,2.3)
2.3 (2.1,2.4)
Any second degree relative
All ages
1.7 (1.4,2.0)
1.6 (1.3,2.0)
1.5 (1.4,1.6)
GENETIC BREAST CANCER
Epidemiological studies suggest that much of the familial clustering of breast cancer is due to the
inheritance of dominant predisposing genes. These genes can be thought of in two classes: 1)
strongly predisposing genes which may confer a lifetime risk of 70% or more, and 2) weaker
genes, such as HRAS1, some alleles of which are associated with a roughly two fold increase in
risk. Three major breast cancer susceptibility genes have now been identified: BRCA1, BRCA2
and p53. BRCA1 (Breast Cancer 1), located on chromosome 17q12-21, was identified in 1994. It
is a large gene, with a coding sequence of 5,592 base pairs, encoding a protein of 1863 amino
acids. The second gene, BRCA2, is located on chromosome 13q12-13. It is even larger than
BRCA1, with a coding sequence of 10,254 base pairs, encoding 3,418 amino acids. BRCA1 and
BRCA2 are between them responsible for the majority of families with 4 or more individuals
affected with either breast cancer before 60 years of age or ovarian cancer. Numerous mutations
15
have been identified throughout the length of both BRCA1 and BRCA2. Germline mutations in
p53 are rare and account for a tiny proportion of breast cancer cases.
Breast and ovarian cancer risks
Indirect estimates of risk of breast cancer in women with mutations in BRCA1 have been made
based on data collected on linkage families4, and direct estimates of risk have been made for
women carrying one of the three Ashkenazim founder mutations5. These risks are given in table
3.
Table 3: Breast and ovarian cancer risks associated with mutations in BRCA1
Age
Cumulative breast
cancer risk % (95%
CI)
Cumulative ovarian
cancer risk % (95%
CI)
50
51 (25-67)
23 (5-38)
70
85 (51-95)
63 (25-82)
70
56 (40-73)
16 (6-28)
50
33 (23-44)
7 (2-14)
Reference
Ford et al4
Streuwing et al5
The risk of breast cancer conferred by BRCA2 seems to be similar6, but the risk of ovarian cancer
is much lower.
Gene frequency of BRCA1 and BRCA2
Again no direct measurements of gene frequency are available. The best estimate of the gene
frequency of BRCA1 is 0.0006, which corresponds to a carrier frequency of 1 in 800. The
frequency of BRCA2 is probably similar.
Other cancer predisposing genes
Several more common genes have been shown to have a moderately increased risk of breast
cancer. The so called 'rare' alleles of HRAS1, which are associated with increased risk of breast
cancer, are present in about 6% of the population. Because they are so common in comparison to
BRCA1, the attributable risk is estimated at 9%, over twice as much as for BRCA1. Other
candidate 'low risk' breast cancer genes for which there is already some evidence include the
ataxia-telangiectasia gene and the vitamin D receptor gene.
Genetic testing
It is now possible to institute a search for a faulty copy of BRCA1 or BRCA2 in a family. There
are two quite distinct stages in doing this - a mutation search and a direct gene test. A direct gene
test is a relatively simple test which can detect the presence or absence of a single specific
mutation in an individual. This is used when a specific mutation is known to be segregating in a
family in order to test unaffected members of that family for that mutation. If the mutation
causing breast cancer in a particular family is not known, a direct gene test cannot be carried out.
In such circumstances a mutation search may be carried out to look for any one of the many
mutations that might be responsible in the family. It is however important to realise that such a
search is technically demanding and may not produce a useful result. BRCA1 and BRCA2 are
large genes. The mutations tend to differ from family to family, and to occur at any point along
the length of the gene. Extensive analysis may therefore be needed before a mutation is found;
16
and even then, a negative result is not a guarantee that no mutation is present. Perhaps 20% of
mutations in BRCA1 and BRCA2 are missed with current techniques. In some families,
predisposition is not due to BRCA1 or 2 but to other genes as yet unidentified, which therefore
cannot be analysed.
Genetic prediction is therefore possible only in the case when a predisposing mutation has been
clearly identified in the family, and other family members can be tested to determine whether or
not they have inherited it. If a mutation is identified in the family a first degree relative (mother,
daughter, sister) of an affected member will have a 1 in 2 chance of having the mutation. Failure
to find a mutation in the family may mean that no mutation is present and the family history is not
due to inherited predisposition - but this is not a safe conclusion because it may also be that a
mutation is present but has not been found. If no mutation is found in the family, genetic
prediction is not possible.
17
RISK MODIFICATION
Given the possibility of identifying women at increased risk of breast cancer, serious consideration needs to be given
to the options available to prevent or reduce morbidity from breast cancer in these women. There are three major
approaches, which are currently feasible; early detection, surgery and chemoprevention. These are briefly described
below, but research evidence for the effectiveness of any of them is lacking.
Early detection
The mainstay of early detection is regular screening of the breasts by mammography. The
effectiveness of mammography for women of average (population) risk aged 50-69 is well
established. For them, mammography reduces breast cancer mortality by around 30%7. The
effectiveness of mammographic screening in younger women is controversial, though evidence of
benefit in women aged 40-49 is mounting8. However, the available evidence relates to women of
average risk and the situation may be different in a high risk group. Ionising radiation is a risk
factor for breast cancer and there is a potential increased risk of breast cancer when
mammography is started at an early age9. This risk may be potentiated by some genetic
alterations which increase susceptibility to ionising radiation, though many experts believe the
benefit of early detection will outweigh the risk10. In addition, the biology of familial breast
cancer may differ from that of non-familial disease, and factors such as screen interval may need
to differ in those with a family history . Data from the Two Counties study in Sweden suggests
that if mammographic screening is to be effective in women with a family history, high quality
mammography coupled with frequent screening will be required – eg annual screening in women
aged <50 and every 18 months in those aged 50+ (S. Duffy, personal communication).
Surgery
Prophylactic mastectomy is the most drastic form of breast cancer prevention, and is already
being offered to women at very high risk of developing breast cancer. This surgical procedure
reduces the risk of breast cancer, but does not eliminate it. Although mastectomy eliminates more
than 95% of epithelial cells, the few cells that remain are still susceptible to tumorigenesis. Also,
animal studies suggest that the risk reduction may not be proportional to the amount of tissue
removed. These observations are supported by the finding that cancer following prophylactic
mastectomy has been documented in case reports and observational series11-14. Failure rates from
1 to 19% have been recorded in “high risk” women, but these figures include those with nonfamilial risk factors, and duration of follow-up was variable.
Chemoprevention
A variety of agents, such as the anti-estrogen tamoxifen, have been suggested as candidate drugs
which might reduce the risk of breast cancer. However, their use remains experimental, and the
results of clinical trials to assess their effectiveness are awaited.
RISK STRATIFICATION
Individuals presenting with a family history of breast cancer can be stratified according to the
nature of that family history into various at risk groups. We have chosen to stratify into three
broad risk categories; greatly increased risk, moderately increased risk or slightly increased risk
18
compared to the general population. We have called these the high, moderate and low risk groups
respectively and they are defined below.
High Risk Group
Women in this category are those whose family history suggests they may be carrying a mutation
in one of the known breast cancer susceptibility genes; that is they are at substantial risk of
developing inherited breast cancer. The likelihood that a mutation in one of the major
susceptibility genes is segregating in a given family depends on the size of the family, the number
of individuals in the family who have developed cancer, the type of cancer, and the age at which
cancer occurred in family members. The best evidence published on probability of detecting a
mutation in BRCA1 comes from an analysis of high risk families in the United States15. The
families analysed had on average 4 affected members. Early age of diagnosis of breast cancer and
the presence of ovarian cancer in the family were both found to increase the probability of finding
a mutation in BRCA1. This data is summarised in Table 4. No such data is available for
BRCA2.
Table 4: Probability of detecting a BRCA1 mutation in families
Average age at
diagnosis of breast
cancer
Probability of BRCA1
mutation in affected
member
Breast cancer only
<40
40-49
50-59
>60
15
6
2.5
1.3
Breast and ovarian cancer
<40
40-49
50-59
>60
49
28
14
7
Breast and ovarian cancer in one member
<40
72
40-49
56
50-59
30
>60
17
Adapted from Crouch et al15
Based on this evidence we propose that the following criteria are used to identify families with a
20% or greater chance of being caused by a mutation in BRCA1:
.
1.
2.
3.
Breast/breast ovarian families with 4 or more relatives on the same side of
the family affected at any age
Breast cancer (only) families with 3 affected relatives with an average age
of diagnosis <40
Breast/ovarian cancer families with 3 affected relatives with an average age of diagnosis
of breast cancer <60
4.
Families with one member with both breast and ovarian cancer
19
The probability that any individual in the family has a mutation will depend on her relationship to affected family
members.
Moderate Risk Group
Women in this category are at substantially increased risk of breast cancer - at least three times
the population risk - because of a positive family history, but are less likely to be carrying a
mutation in one of the known breast cancer susceptibility genes.
As described above, limitations in epidemiological make precise estimation of risk for minor
degrees of family history difficult. Any categorisation of family history will therefore be crude
and some women falling outside the moderate risk criteria may still have a risk of breast cancer
greater than three times the population risk. However, the most appropriate intervention (if any)
for this group of women is not yet clear and any risk misclassification will be of limited clinical
significance.
1. 3 first or second degree relatives with breast or ovarian cancer diagnosed at
any age on the same side of the family, or
2. 2 first or second degree relatives with breast cancer diagnosed under 60, or
ovarian cancer at any age, on the same side of the family, or
3. 1 first degree female relative with breast cancer diagnosed under 40 or 1 first
degree male relative with breast cancer diagnosed at any age, or
4. A first degree relative with bilateral breast cancer
Low Risk Group
Women in this category are at increased risk of breast cancer because of a positive family history
which fall outside the criteria for the moderate risk group. Their relative risk is less than three
times that for the general population.
ESTIMATING NUMBERS OF WOMEN IN MODERATE RISK GROUP
METHODS
The probability that a particular woman has a family history of breast cancer depends on the
number of her female relatives and their ages, and the probability that each of those relatives has
developed breast cancer. This probability is approximated by the cumulative risk of breast cancer
to a given age, which depends on age specific incidence of breast cancer and the relative risk of
breast cancer associated with specific family histories.
Estimating number and ages of female relatives
The 1981 census provided data on family kinship size was used to enumerate women with
various numbers of first degree female relatives: Each woman has a mother, and assuming half
of all siblings are sisters, women can be stratified into those with 0, 1, 2, 3, or 4+ sisters. In order
to enumerate women with breast cancer in second-degree relatives, a woman was estimated to
have an average of 1.08 sisters. Thus, in the population, each woman is assumed to have a
mother, a maternal grandmother, a paternal grandmother, 1.08 maternal aunts and 1.08 paternal
aunts. Sisters were assumed to be the same age as at risk woman, mothers and aunts 25 years
older, and grandmothers 50 years older.
20
Estimating cumulative risk
The cumulative risk of breast cancer to age x (CRx) was estimated from the cumulative incidence
(CI) using the formula16
CRx = 1 – Exp(-CIx)
Age-specific breast cancer incidence for the general population were obtained from the OPCS
Cancer Registrations statistics for 1989. For women with an affected relative, the general
population incidence was multiplied by the appropriate relative risk of breast cancer for that risk
group as follows:Relative risk for women with a first degree family history (RR1) = 3
Relative risk for women with a second degree family history(RR2) = 1.5
Estimating probability of having a specific family history
The following examples show how the probability of having a specific family history was
calculated. This calculated probability was multiplied by the number of women in each age
group to derive the total number of women with the specified family history.
For woman aged 45 with one sister:
Risk that her mother but not her sister has had breast cancer = CR70.(1-CR45)
Risk that her sister but not her mother has breast cancer = CR45.(1- CR70)
Risk of sister and mother having breast cancer = CR45.CR70.RR1
Woman aged 60 with two sisters
Risk that both sisters (and not mother) affected by age 40 = CR40.(CR40.RR1).(1-CR40)
Risk that one sister, and mother and maternal aunt affected at any age
= [CR60.(1-CR60).RR1.RR2.2].[CR85].[CR85.RR1.1.08]
Similar formulae were used to estimate risks for all the following family histories
One affected first degree relative Sister or mother
Two affected first degree relatives
Three affected relatives
Sister and mother; Two sisters
Sister, sister and mother; Sister, sister and sister; Sister, sister & grandmother; sister,
sister & aunt; sister, mother & aunt; sister ,aunt & aunt; sister, mother & grandmother;
sister, aunt & grandmother; mother, aunt & aunt; mother ,aunt & grandmother; aunt, aunt
& grandmother
Results
The numbers of women per million total population in the following three categories were
estimated and are given in Table 5.
21
Group 1 – breast cancer in 3 first or second degree relatives on the same side of the family
Group 2 – breast cancer before age 60 in 2 first or second degree relatives on the same side of the family
Group 3 – breast cancer before 40 in 1 first degree female relative
Table 5: Number of women per million total population in moderate risk groups by age
Population
Group 1
Group 2
Group 3
Total
Women age 35- Women age 25- Women age
49
49
20+
97,000
165,000
365,000
2,100
2,200
32,400
2,000
2,500
13,200
350
480
1,100
4,450
5,180
46,700
REFERENCES
1 Dupont WD. Converting relative risks to absolute risks: a graphical approach. Statistics in
Medicine 1989;8:641-651.
2 Pharoah PDP, Mackay J. Absolute risk of breast cancer in women at increased risk: a more
useful clinical measure than relative risk? The Breast 1997.(submitted for publication)
3 Pharoah PDP, Day NE, Duffy S, Easton DF, Ponder BAJ. Family history and the risk of breast
cancer: a systematic review and meta-analysis. Int J Cancer 1997;71:800-809.
4 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, Breast Cancer Linkage Consortium.
Risks of Cancer in BRCA1 mutation carriers. Lancet 1994;343:692-695.
5 Streuwing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific
mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-1408.
6 Easton DF, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to
BRCA2 on chromosome 13q12-13. Am J Hum Genet 1997;61:120-128.
7 Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening
mammography: a meta-analysis. J A M A 1995;273:149-154.
8 Feig SA. Increased benefit from shorter screening mammography intervals for women ages 4049 years. Cancer 1997;80:2035-2039.
9 John EM, Kelsey JL. Radiation and other environmental exposures and breast cancer.
Epidemiol Rev 1993;1993:157-162.
10 Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an
inherited predisposition to cancer. II. BRCA1 and BRCA2. J A M A 1997;277:997-1003.
11 Goodnight JE, Quagliana JM, Morton DL. Failure of subcutaneous mastectomy to prevent the
development of breast cancer. J Surg Oncol 1984;26:198-201.
12 Kieback DG, Kieback CC. Advanced breast cancer after subcutaneous mastectomy and
immediate prothetic reconstruction for benign breast disease. Breast Cancer Res Treat
1986;7:119-120.
22
13 Mies C. Recurrent secretory carcinoma in residual mammary tissue after mastectomy. Am J
Surg Pathol 1993;17:715-721.
14 Eldar S, Meguid MM, Beatty JD. Cancer of the breast after prophylactic subcutaneous
mastectomy. Am J Surg 1984;148:692-693.
15 Couch FJ, Deshano ML, Blackwood MA, et al. BRCA1 mutations in women attending clinics
that evaluate the risk of breast cancer. N Engl J Med 1997;336:1409-1415.
16 Clayton D, Hills M. Statistical models in epidemiology. Oxford: Oxford University Press,
1993.
23
Appendix B
CONSENSUS CONFERENCE
MANAGING WOMEN AT HIGH RISK OF BREAST CANCER
BECAUSE OF A FAMILY HISTORY
PROPOSED STRATEGY FOR THE MANAGEMENT OF
FAMILIAL BREAST CANCER RISK
24
PRODUCED BY DR PAUL PHAROAH, DR JAMES MACKAY AND DR RON ZIMMERN
25
INTRODUCTION
The proposed strategy is concerned with the management of the patient who is at high risk of
breast cancer because of a family history. The patient seeks medical attention either because of
breast symptoms or because, knowing of a relative or relatives with breast cancer, she is anxious
that she might have an increased risk of developing the disease herself. The strategy is based on
categorising women with a familial predisposition into low and moderate risk groups on the basis
of a detailed family history, and on determining a high risk subset of those in the moderate risk
group who are suitable for specialist genetic consultation. The technical details supporting the
strategy is described in the accompanying document “Assessing the Evidence”. The strategy is
concerned essentially with clinical management. It does not recommend that women are
routinely screened for a positive family history of breast cancer, either through a population based
programme or opportunistically. It suggests a management strategy only for those women who
present with breast symptoms or because of concern about their family history.
MANAGEMENT
Management of high risk group
The high risk group is defined as those with the family history shown below.
1.
Breast/breast ovarian families with 4 or more relatives on the same side of
the family affected at any age
2.
Breast cancer (only) families with 3 affected relatives with an average age
of diagnosis <40
3.
Breast/ovarian cancer families with 3 affected relatives with an average age of diagnosis
of breast cancer <60
4.
Families with one member with both breast and ovarian cancer
These patients should be referred for specialist cancer genetic consultation at the regional genetic
centre. Gene testing may be appropriate for some of these patients.
Management of moderate risk group
The moderate risk group is defined as those with the family history shown below.
26
1.
3 first or second degree relatives with breast or ovarian cancer diagnosed
at any age on the same side of the family, or
2.
2 first or second degree relatives with breast cancer diagnosed under 60, or
ovarian cancer at any age, on the same side of the family, or
3.
1 first degree female relative with breast cancer diagnosed under 40 or 1
first degree male relative with breast cancer diagnosed at any age, or
4.
A first degree relative with bilateral breast cancer
Given the lack of evidence of benefit for any intervention for women in this group, we believe
that no intervention should be offered except in the context of a research study. The relative risk
of breast cancer for women in this group is at least three times that of the general population. An
age dependent screening protocol for a research study is suggested below.
Suggested Management of Moderate Risk Women
Below 30
No mammography
30-34
(a) Youngest affected first degree relative diagnosed age 40+
No mammography.
(b) Youngest affected first degree relative diagnosed age 39 or below
Annual mammographic screening starts 5 years below the age of
diagnosis of the youngest affected relative,
35-49
Annual mammography
50 and over
Mammography every 18 months with clinical examination around time of
mammography. Half of these mammograms will be performed within the National
Breast Screening Programme
The patients in this group are at higher risk of breast cancer than the general population, but are less likely to be
carrying a mutation in one of the known breast cancer susceptibility genes. The purpose of a management strategy
should be to modify the risk of reducing morbidity from breast cancer. It is our view that, at present, genetic
diagnosis and testing plays no part in the management of these women.
Management of low risk group
The strategy for these women should be to discuss the difference between familial and nonfamilial cancer and to explain that individual’s risk is not significantly elevated. They should be
27
informed that the risk of non-familial breast cancer (the most common type) remains and be
encouraged to participate in the National Breast Screening Programme at the appropriate age.
THE PATIENT JOURNEY
The strategy outlined above allows both the primary health care team and the multidisciplinary
breast care team to stratify individuals with reasonable confidence. The primary health care team
can identify those considered at low risk, and may be able to discharge some of them. Others
may wish to seek the opinion of a breast specialist, and will therefore require referral to the
breast care team. Assuming this team has adopted the same strategy and there have been no
errors in interpretation, then the advice from the breast team should be similar to the advice
already received from the primary care team. It is likely that this internal consistency will
increase reassurance. Different advice from different levels can be very damaging to patient
confidence. Individuals from high risk families will be ascertained in the breast unit and offered
referral to the cancer genetics clinic. Some individuals will not wish to be referred. Again, it is
hoped that internal consistency in the advice offered will strengthen patient confidence. Close
collaboration, with rapid flow of accurate information and easy access to advice between the
three different levels is essential.
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RESOURCE IMPLICATIONS
Numbers at risk
The following estimates are based on a population of 1 million with an age sex structure similar
to that of England and Wales.
High risk families
20-40
Women aged 35-49 at moderate risk
4,450
All women at moderate risk
Total population (men & women)
47,000
1,000,000
Costs and benefits
The potential impact of the proposed strategy is again based on a population of 1,000,000.
High Risk Group
Around 20 families will be eligible for mutation testing. Because BRCA1 is a long gene and
mutations are dotted all the way along the gene, a mutation must be identified in an affected
individual in a family before a gene test can be offered to an unaffected individual in that family.
The criteria outlined above are designed to maximise the chances of finding BRCA1 mutations.
However, using the techniques currently employed in the NHS Clinical Genetics laboratory, we
are picking up mutations less often than expected in comparison with the performance of research
laboratories throughout the world. Optimistically, if mutations are identified in 20% of families,
then gene testing will be available for unaffected individuals in 4 families. This is likely to be
around 12 - 20 individuals. Half will not have the mutation and therefore 6-10 individuals will be
classified at very high risk (around 85% lifetime risk) of developing breast cancer. Some of these
individuals will not wish prophylactic surgery, and will therefore continue with screening.
Applying the ‘new genetics’ in the way proposed may therefore prevent breast cancer in around 6
individuals per million of population, depending on the uptake of genetic testing and prophylactic
mastectomy.
Moderate Risk Group
We have estimated the potential costs and benefits of annual mammography in those women aged
35-49 in the moderate risk group. Up to 4,450 mammograms would be needed annually
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(depending on proportion of eligible women that are referred and uptake). We estimate that for
every 1,000 women aged 35 who have an annual mammogram for 15 years, 6 deaths from breast
cancer will be prevented. This is based on the assumptions that the relative risk of breast cancer
in this group is 5 and annual mammography reduces mortality by 20%.
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Appendix C
CONSENSUS CONFERENCE
MANAGING WOMEN AT HIGH RISK OF BREAST CANCER
BECAUSE OF A FAMILY HISTORY
CONSENSUS STATEMENTS
PRODUCED BY DR PAUL PHAROAH, DR JAMES MACKAY AND DR RON ZIMMERN
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Consensus Statements
The following consensus statements are for discussion. Each participant should take a view on
whether they agree or disagree with each of them
1.
A population based screening programme which seeks to determine the family history of
breast cancer in the general population cannot be justified on the basis of present evidence.
2.
Opportunistic screening which seeks to determine the family history of breast cancer in
patients who seek medical advice for non-breast related problems cannot be justified on the
basis of present evidence.
3.
Patients who seek medical attention because of breast symptoms should have their family
history taken as part of the clinical consultation.
4.
Patients who seek medical attention, anxious that they might be at higher risk because they
have a family history of breast cancer, should have their family history taken.
5.
It is clinically appropriate to categorise such patients into three risk groups, low, moderate
and high on the basis of their family history.
6.
Referrals to the regional genetic service should be confined to those in the high risk group,
and should not be offered to those in the moderate or low risk group.
7.
Genetic testing should only be considered in the high risk group under the guidance of a
cancer geneticist in the regional genetic centre.
8.
Genetic testing should normally only be offered if a living relative with breast cancer was
available to provide tissue for a mutation screen.
9.
Women categorised to be of low risk should be managed within the primary care setting and
should not be referred for specialist consultation, either with the local breast unit or to the
regional genetics centre.
10. The definition of the moderate risk group, as set out in Assessing the Evidence, is
acceptable
11. The definition of the high risk group, as set out in Assessing the Evidence, is acceptable
12. Women in the moderate group should only be offered an intervention, such as regular
mammography or tamoxifen, in the context of a national research study, because of the
absence of evidence regarding the effectiveness of such interventions in reducing morbidity
or mortality in this population of women.
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13.
A mammographic service for women in the moderate risk group should not be
commissioned within the NHS except in the context of a national research study, because of
the absence of evidence regarding the effectiveness of such interventions in reducing
morbidity or mortality in this population of women.
13a The national research study mentioned in 13 above should be in the form of a randomised
control trial rather than an observational study.
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Category
Public Health Physician ( ) Geneticist ( ) Surgeon ( ) GP ( ) Radiologist ( ) Nurse
- Primary Care ( )
Nurse - Breast Clinic ( ) Genetic Nurse or Associate ( ) Manager ( ) Other ( )
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
13a
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
Agree (
)
)
)
)
)
)
)
)
)
)
)
)
)
)
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree ( )
Disagree (
Disagree ( )
)
Region: ................................................................................................
Please return this sheet to the leader in your small groups.
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