Journal of Public Health Medicine
Vol. 13, No. 1, pp. 2-12 Printed in Great Britain
Breast cancer: the decision to screen A. P. M. Forrest
On 25 February 1987, the Secretary of State for Health and Social Security, having considered a report by a working group, announced in the House of Commons that the Government was to implement a national breast screening service, with all necessary back-up assessment and diagnostic facilities, treatment facilities, counselling and after-care - and training for key groups of staff.1-2 The evidence supporting this decision was based on two controlled randomized trials in which population screening by mammography (and in one by clinical examination) had been offered on a random basis, and two case-control studies in which the screening history of women dying from breast cancer was compared with that of healthy controls.^ The results of all four studies were consistent with the conclusion that mammographic screening was 'good news'. The cost of providing the service had been assessed, and was reasonable compared with other essential health needs. As new funding had been provided to support this new service, it was not introduced at the cost of denying other health requirements. The proposed service was not only for the provision of screening mammography; it was comprehensive, covering all stages of the screening process: the screening test, assessment of a mammographic abnormality, a surgical biopsy when required, and the treatment of screen-detected cancers. It was considered on available evidence that the service should be offered only to women of 45-64 years of age, who would be invited for single oblique-view mammogram each three years. But these were initial recommendations, to be modified as new information arose.
gram was not a diagnostic investigation, but only determined whether a mammogram was normal or not, arrangements for the further investigations of abnormalities, and if necessary a surgical biopsy, needed to be made. This was best achieved by the formation of multidisciplinary 'teams' with the necessary skill and experience to apply the techniques used, i.e. additional mammographic and magnification views, ultrasonography, fine-needle aspiration and cytology, if necessary, under stereotaxic guidance. The provision of facilities for assessment has varied, and they may be provided in the screening clinic, in the hospital, or partly in both. An advantage in having the more sophisticated investigations hospital-based is that the services of the assessment team - surgeon, radiologist and cytologist - are available also to symptomatic patients. It must be emphasized that assessment is a multidisciplinary exercise, and that although a woman may well prefer the privacy of a doctor's consulting room, her interests are best served by the 'team' approach. And that a biopsy, should it be required, is performed by a surgeon and radiologist experienced in the technique of removing impalpable lesions, supported by a pathologist conversant with the difficulties of interpreting screen-detected particularly the borderline lesion and the specialized techniques required. Treatment also had to be considered. If screening is to appeal, a woman should expect that this should be less radical than had she found the lump herself. The safety of conservative treatment of small invasive and noninvasive cancers is not yet established, and a woman must also be aware of the need for clinical trials; one reason why counselling and frank discussion of available options is a critical part of all stages of the screening
The screening procedure The provision of facilities for basic mammographic screening was based on population needs, assuming that one mammography unit would examine 70 women a day, that 70 per cent of invited women would accept, that 10 per cent would be recalled for additional tests, and that provision would be made for self-referred women over 60 years of age. As a screening mammo-
Scottish Cancer Trials Office, Medical School, Teviot Place, Edinburgh EH8 9AG. A. P. M. FORREST, Professor Emeritus, University of Edinburgh •The HM Queen Elizabeth, the Queen Mother, Fellowship Lecture, given under the aegis of the Nuffield Provincial Hospitals Trust (delivered in Edinburgh on 19 June 1990).
© Oxford University Press 1991
BREAST CANCER: THE DECISION TO SCREEN programme. Considering the state of mammography in the United Kingdom, the introduction of a comprehensive screening service, including the training of personnel, was an enormous undertaking. That it has been accomplished is due to the enthusiasm and commitment of remarkable people involved in all stages of the programme.
Why screen? In the western world, breast cancer is a disease of substantial proportions. In the United Kingdom there are 25 000 new cases each year; some 150 000 women live with the disease, and one dies each 30 minutes.7 In the United States, during the 10 years of the Vietnam war, 57000 died from combat, while 330000 women died at home from breast cancer.' England and Wales head the international league for deaths from breast cancer;9 and in all developed countries the incidence of the disease in older women is on the increase, even when earlier diagnosis and better cancer registration are discounted.10 Were breast cancer infectious it would be registrable by law; a step that would allow its true incidence in Britain to be identified and monitored. During this century, our understanding of breast cancer was retarded by the concept that is was primarily a loco-regional disease, spreading by wave-like permeation along lymphatic pathways to be contained by the regional lymph nodes for a considerable time. Embolization of blood vessels was largely discounted; spread to distant sites believed to be a late phenomenon. Eradication of the disease was by radical surgery; hoping that one was in time to remove every cancerous cell. With realization that surgery might fail, the area of local treatment was extended by postoperative radical radiotherapy (for references see ref. 11). Not all agreed with this dogma, but the heated controversy that ensued concentrated on technical detail, disregarding the fact that the big step had already been taken in 1923, when, at the instigation of Professor George Gask, Geoffrey Keynes introduced treatment by intense irradiation alone, later to become, with local excision of the tumour, a viable alternative to mastectomy, allowing preservation of the breast.12 Keynes also recognized the illogicality of radical surgery, knowing that it was early dissemination of the disease that accounted for its fatal consequences. He suggested, rightly, that unless repelled by some other form of treatment the invaders were bound to gain the upper hand in the end - a statement as true today as in his time.13 Current understanding For screening to succeed it must be able to detect breast
cancer before dissemination with the formation of micrometastases has occurred. Originating in the epithelium of the secreting lobule of the breast, and preceded by a series of atypical proliferative changes, a cancer is initially non-invasive and confined by the basement membrane. 1413 But should a further series of fundamental changes in the genetic structure of the malignant cells allow them to degrade the basement membrane, to migrate into lymphatic and vascular capillaries and to circulate," the scene is set for the formation of micrometastases as forerunners of clinical relapse and death. This is not a rapid process, for breast cancer can be slowgrowing; a disease that 'disseminates early but may recur late'.17 Supporting evidence Two facts support this concept of the natural history of breast cancer. First, statistical cure of symptomatic invasive breast cancer has not been demonstrated; thus long-term follow-up studies have failed to uncover a group of disease-free survivors whose 'annual death rate from all causes is similar to that of a normal population group of similar age and sex'.18 Even 30-40 years after the local treatment of invasive breast cancer, excess deaths still occur from metastatic disease."-20 This does not imply that all women who develop breast cancer die from it. Some 30 per cent have no further evidence of the disease during their lifetime and therefore are personally cured. But this definition of cure includes the woman who, within a month of her mastectomy, is run over by a bus.21 Second, systemic treatment either by chemotherapy or the antioestrogen tamoxifen administered at the time of local treatment postpones relapse and prolongs life, confirmed by a recent meta-analysis of 61 randomized trials including over 28000 women.22 The effect, although modest, is real; and new trials of more potent chemotherapeutic compounds and longer-term tamoxifen therapy are beginning to show greater benefit. A threshold But is there an early stage of breast cancer at which treatment confers greater benefit? By definition, noninvasive cancer is at such an early stage, and, provided no areas of microinvasion are present, is curable by local surgery. However, the timespan of non-invasive cancer is long, and its earlier detection by screening cannot be expected to have an immediate effect on mortality. This depends upon whether there is an early stage of invasive cancer during which it can be detected before dissemination. Evidence in support is available from studies in which the size of the primary tumour at the time of local treatment has been related to the state of the axillary lymph nodes. A recent analysis of 25000 women with
JOURNAL OF PUBLIC HEALTH MEDICINE breast cancer included in the SEER programme of the National Cancer Institute has indicated that for invasive cancers of less than 1 cm in diameter the incidence of axillary-node involvement was less than 20 per cent and five-year survival over 95 per cent, comparing favourably with approximate figures of 50-60 per cent for all cancers.23 Small cancers without axillary-node involvement may still be aggressive, and the study from France, in which the parameter for early dissemination was the development of metastatic disease over a follow-up period of 25 years, is relevant. For those with a tumour of 1 cm or less in diameter at the time of primary treatment, this number did not exceed 20 per cent. These studies do not indicate that all small invasive cancers are non-aggressive, but that the treatment of invasive breast cancers when of small size is more likely to have a favourable outlook. A 1-cm tumour contains 1 billion cells. With an estimated doubling time of 2-5 months it would take 15 years for such a tumour to replicate from a single cell.23 There is no certainty of monoclonal origin; but equally no doubt that all breast cancers 'sojourn' for variable periods of time in a preclinical asymptomatic phase during which they are not palpable on clinical examination. However, they can be detected by mammographic imaging. Further, there is unequivocal evidence that the treatment of breast cancer at this early stage confers a mortality advantage that is greater than that observed by any other means.
Dissent Not all agreed that the decision to implement screening for breast cancer was correct.26"31 The main points of dissent were (1) the working group was biased; experts who acted with undue haste so that their conclusions were premature; (2) mortality benefit was overemphasized; women 'hoodwinked' into believing treatment was effective for screen-detected disease; (3) risks from radiation, psychological effects, unnecessary biopsies and overtreatment outweighed potential benefits; (4) there were faults in the suggested programme; selective screening had not been considered; (5) resources would have been better spent on other aspects of health care or on scientific research into cause and prevention. The working group and its conclusions The working group neither was biased nor acted with
undue haste. It was well balanced between specialties, interests, sex and countries. It had available to it updates of the HIP (Health Insurance Plan, New York) and Two-Counties (Sweden) randomized trials, now published, which strongly support the initial conclusions.32" 34 Re-examination of the HIP statistical tapes by other authorities had confirmed that the mortality advantage in that trial was beyond doubt, and the power and design of the Two-Counties trial could not be questioned.33-36 Since then, three additional case-control studies comparing- breast cancer mortality in 'ever-screened' and 'never-screened' women have been reported, all indicating significant benefit.37"39 When only those women over 50 years of age are considered, the mortality advantage from screening is greater than that reported overall (Fig. 1), and this is further increased when the delay between the introduction of screening and first evidence of benefit, which depends on the efficiency of the screening process, is discounted. It is difficult to imagine that in the face of this evidence the working group would now change its views. But account must be taken of recent reports indicating that neither in the Malmo or Edinburgh randomized trials nor in the British Comparative Trial of Early Detection of Breast Cancer (TEDBC) has a significant mortality advantage overall been observed;40"42 although in the Malmo trial and the TEDBC this has now emerged in the sixth and seventh years. Admittedly, the results of the British and Malmo trials are disappointing, but before condemning screening on this account one must consider whether the design, response rates and efficiency of screening were less than ideal. Design
The statistical power of both the Malmo and Edinburgh trials has been questioned. However, a greater confounding influence in the Malmo trial was that 24 per cent of a sample of the control population had at least one mammogram. Twenty per cent of cancers in the control group were detected by mammography, of which 11 per cent were non-invasive. When compliance is taken into account, the trial compared screening mammography in 74 per cent of study women versus 24 per cent of controls.43 The UK. TEDBC was not a randomized trial, and it now appears that the adjustment for expected mortality, at least in Edinburgh, may have been faulty. Further, the 'cluster' randomization by general practice in the Edinburgh trial has not provided comparable groups. Unlike other randomized trials, all-cause mortality in study and control populations differs markedly, mainly on account of cardiovascular deaths.
BREAST CANCER: THE DECISION TO SCREEN
REDUCED
INCREASED adjusted for 70% compliance
HIP Two-Counties Molmo Edinburgh Nijmegen Utrecht Florence
00
0-5
10
1-5
20
relative risk FIGURE 1 Relative risk of death from breast cancer in over-55-year-olds. (| is adjustment for compliance in case-control studies). (Reproduced with permission of Nuffield Provincial Hospitals Trust.)
Response
Extent of benefit
Compared with compliance in Sweden, that in the British studies was poor. In Edinburgh, only 60 per cent of invited women attended for the first screen; many did not return. In the TEDBC, 51 per cent of cancers were detected in 28 per cent who did not attend for screening, compared with 30 in 10 per cent in the Two-Counties trial.
Concern that the mortality benefit of breast screening is not reflected in a reduction of total all-cause mortality has no substance. In the age group that benefits, breast cancer accounts for a relatively small proportion of all deaths. Even in the Two-Counties trial, the expected reduction in all-cause mortality could not exceed 1 per cent.34 Numerically, the number of lives 'saved' in these trials is small, but if extrapolated to all women with the disease becomes substantial. Were a 30 per cent reduction in mortality achievable in the United Kingdom, over 1500 deaths would be prevented in women of 50-64 years. Only women with breast cancer can benefit from breast cancer screening, and for them the potential gain is substantial.
Efficiency Estimates of efficiency suggest that performance in Edinburgh was not comparable to that of Swedish or Dutch centres. The sensitivity of mammography, determined by the rates at which cancers surfacing after a negative screen (interval cancer rates), were higher than in these centres, particularly when those detected at the intervening 'clinical-only' examinations were taken into account. Further, the stage of cancers detected was less favourable in Edinburgh than in Sweden.42 In neither British study was the certified cause of death verified, which, considering likely errors, is a necessary precaution.44 More detailed analyses are clearly required.
Risks Radiation In a recent survey of the 15 Canadian trial centres, the dose to breast from two-view mammography ranged
JOURNAL OF PUBLIC HEALTH MEDICINE 43
from 1-3 to 2-6 mGy. Considering the small dose of radiation received from modern mammographic equipment, fears of radiation risk are unfounded. The doses of radiation given for diagnosis or therapy or on account of atomic warfare were far in excess. It has been calculated that exposure of the adult breast to 1 -5 mGy would cause only one extra case of breast cancer per 2 million women per year,** and then only after a latent period of 10 years. A large case-controlled study from Israel suggests that small doses of radiation can increase breast cancer risk, but only when exposure occurs at an age of 5-9 years, during the early active stages of breast development.47 The breast of a 50-year-old woman is involuting; its epithelium atrophic. Psychiatric morbidity Studies now reported from Edinburgh and Guildford suggest that risks of psychiatric morbidity from screening have also been overstated.48*' One study investigated only the effect of attending for screening; the other also that of recall following the detection of a mammographic abnormality. Both used the General Health Questionnaire to assess psychiatric morbidity before and at 3-6 months after screening. In Edinburgh this was supplemented by interview. Neither study showed excess morbidity as a result of screening. Women recalled for review did have significantly increased morbidity from anxiety, but, provided the diagnosis was benign, this did not last; nor was it any greater than that observed in women attending a symptomatic hospital clinic. Serious and lasting morbidity was observed only in women proven to have cancer; again, similar to that in symptomatic cases. This is not to say that women are not anxious, even if not morbidly so, but anxiety can be reduced by short waiting times and good communications. Recall To allay anxiety, recall rates must be kept to a minimum. These depend on the quality of the screening mammogram, and of its interpretation. In Sweden, 5 per cent of women are recalled for additional mammography and just over 1 per cent for full examination.50 In Britain, initial recall rates have averaged 7-4 per cent; in some centres they are much greater.31 With the incorporation of moving grids in mammographic units, dense films from so-called dysplastic breasts are not now common.52 Poor-qualityfilmsare a rare cause of recall. In the Lothian mobile mammography study, only 1 per cent of women were recalled for this reason, faulty packing being the main cause.53 Mandatory training and accreditation of radiographers by their college is ensuring high standards of practice. Radiologists interpreting screening films must also
work to a very high standard, and, as was suggested in the Pritchard report, should read thefilmsfrom at least 6000 women each year.54 This report provides comprehensive advice on all aspects of mammographic screening, including the evaluation of equipment, the performance of screening, and the identification of deficiencies. Endorsed by the Royal College of Radiologists, its recommendations are being applied. Considering lack and poor quality of mammography in the United Kingdom at the time of the working group report, the development of efficient mammographic screening has been a remarkable achievement. Biopsy A breast biopsy is bound to cause serious anxiety. It can also cause physical morbidity; and by distorting the breast it can compromise the interpretation of subsequent mammograms. Unnecessary biopsies must be avoided. This is particularly important for the nonpalpable lesion, removal of which in Britain usually involves a hospital stay and general anaesthetic. The assessment of a mammographic abnormality is initially the responsibility of the radiologist. It was considered that an additional mammographic view would be the likely first step in assessment, but with experience it has become apparent that all recalled women should have a clinical examination. Should the mammographic abnormality be palpable, its further investigation byfine-needleaspiration (FNA) cytology is straightforward and can provide a definitive diagnosis without the need for further X-rays. It is the impalpable abnormality that requires additional imaging - further views, magnification mammography and ultrasonography - and, if these are suspicious of cancer, a surgical biopsy. But, as in the palpable lesion, cytology is becoming an essential aid, although the need for stereotaxic radiological guidance increases its complexity. Should a diagnosis of cancer be confirmed by stereotaxic aspiration cytology, a biopsy is no longer appropriate. The further management of the patient, including the operation, is for cancer. Before stereotaxic FNA was available, we found that a 'diagnostic' operation for an impalpable cancer resulted in incomplete removal of half, necessitating the unpleasantness and risks of a second operation.35 Cytology also may confirm the simplicity of a mammographic abnormality which is not believed to be malignant, supporting a decision to observe rather than remove it. In Stockholm, 2005 women with nonpalpable mammographic lesions believed radiologically and cytologically to be benign have been observed over a period of 2-6 years.56 In only one case was cancer missed. From Italy it has been reported that the
BREAST CANCER: THE DECISION TO SCREEN introduction of stereotaxic aspiration cytology reduced benign biopsies by one-third.57 The rate of biopsies and the ratio of benign-tomalignant histology provide an indication of the quality of the assessment. Sweden and The Netherlands provide the standard, but British rates, although higher, are still reasonable;54-58 contrasting with those in countries where the multidisciplinary nature of assessment and the need for a team approach are not accepted.59 A review of our experience of over 350 localization biopsies for non-palpable lesions has confirmed the value of this team approach. 60 Rates of benign-tomalignant biopsies were greatly reduced in those women who had been referred through the screening service, with its system of a formal review, compared with those seen at a symptomatic breast clinic where the decision for biopsy was made on the basis of the radiological report. All women with suspected mammographic abnormalities, irrespective of their source of reference, should have the benefit of formal review before a decision to biopsy is advised. Overtreatment Successful screening detects a large number of invasive cancers when they are still of small size. In the Edinburgh trial, the proportion of cancers amenable to conservation therapy in the population invited for screening now far exceeds that in the control population, both being treated by the same surgical team. In Gavleborg, Sweden, where screening has been in operation for many years, 75 per cent of invasive cancers are less than 2 cm, and are treated by local excision alone.61 Trials are in progress to determine whether this is adequate treatment. A three-year follow-up report of that from Uppsala indicates a local relapse rate of 7-6 per cent; survival is not compromised.62 In Scotland, small invasive cancers are being included in a trial in which tumours of 4 cm and less are treated by local excision and systemic therapy (most often by tamoxifen) with subsequent randomization for radiation or no further local treatment. Mammographic screening also detects a larger number of tumours at a non-invasive stage; for these the risk of overtreatment is real. Admittedly, non-invasive cancer of ductal origin is cured by mastectomy, and some surgeons advise and women prefer this once-forall radical approach, particularly as there is doubt concerning the efficacy of radiation therapy in in situ disease.63 In Europe the consensus view is that the breast should be conserved;64 and a number of controlled trials are comparing local excision alone with local excision plus radiotherapy. In the United Kingdom, a national randomized trial to compare these treatments has been
initiated, both groups of patients also being randomized to receive tamoxifen or no systemic treatment.65 The fear that non-malignant disease may be overtreated is also only too real; for example, by recommending bilateral mastectomy for lobular carcinoma in situ (now regarded as but a marker of epithelial instability) or even for the atypical proliferative lesion. Fortunately, this is rare in the United Kingdom, and, although mastectomy for a benign mammographic lesion is not unknown, the formal review system now available should avoid this. The interpretation of these borderline lesions requires great skill and experience, and time; the Royal College of Pathologists has issued guidelines.66-67 It is not an occasional exercise, and is one that must be critically monitored.68 The regular review session with other members of the screening and assessment team is an essential part of a well-run screening programme. And the patient (as she has now become) must be aware of all available facts on the significance of the findings before treatment is discussed. It is relevant that in Sweden the incidence of operations for benign breast disease has not increased as a result of screening,69 and that a study in The Netherlands has not provided support for the suggestion that overtreatment of cancers, that would not otherwise become apparent, has occurred.70
Deficiencies in the programme The decision to recommend single-view mammography as the sole screening method in the UK programme was based on Swedish and Dutch experience. Many British radiologists have been critical of this recommendation, citing a number of retrospective studies that indicate that recall and cancer-detection rates are improved by two views. However, these studies are based on a review of existing films (for references, see ref. 71), and do not represent the 'real-life' situation when a decision for action must be made on available evidence. A prospective study is being initiated in the United Kingdom that will compare not only recall and cancer-detection rates of single- with two-view mammography in different women, but also those generated by two radiologists independently in the same women.72 The recommendation that screening be repeated each three years was also based on Swedish experience. In the Two-Counties study the interval between screens in women over 50 years of age averaged 33 months. Proportional interval cancer rates in that study now suggest that this interval may be too long, and this is supported by experience in Nijmegen.73-74 A second trial has been initiated in the United Kingdom to compare intervals of one and three years.72
JOURNAL OF PUBLIC HEALTH MEDICINE
INCREASED
REDUCED HIP Two-Counties Malmo Nijmegen Utrecht Florence
00
05
10 relative risk
15
20
elativ risk of death from breast cancer in under-55-year-olds. (Reproduced with permission of Nuffield Provincial FIGURE 2 Relative 71 Hospitals Trust.71 )
But what about the young woman? The exclusion of women under 50 years of age in the UK programme was based on lack of evidence of benefit in existing trials (Fig. 2). A recent re-analysis of the HIP data suggests that there is not a threshold of age below which screening was ineffective.75 In both the United States and Sweden, recommendations are that screening should start at 40 years.76-77 Existing data cannot resolve this question, which is being addressed in the national Canadian trial and in Sweden,7* and also in a third national UK trial, in which, in a cohort of women aged 40-41 years, the effect of screening annually for a sevenyear period will be compared with that of participation in the national programme at the age of 50.72 These trials are not inexpensive, and some doubted their justification, but the UK programme presents a unique opportunity to answer these questions.
Breast self-examination No provision was made in the UK service for a clinical examination at basic screen, and experience in Edinburgh and Guildford has supported this view. Nor was any recommendation made to include breast selfexamination (BSE) as an adjunct to the screening
programme. The preliminary results of the TEDBC, in which instruction in BSE was offered in two centres, did not indicate any effect on mortality from breast cancer. However, several recent studies suggest that it may have a beneficial effect on the stage of the disease, and a casecontrol study gives some indication of improved mortality (for references, see ref. 71). The potential role of BSE must be kept under review, but not as a screening test, for it cannot detect a breast cancer in its preclinical detectable phase; although this is not to deny that regular BSE is other than good practice.
Selective screening It would clearly be advantageous were it possible to select for screening those who would benefit most. A series of studies have been reported in which a number of risk factors, particularly those about which enquiry can readily be made - age at menarche, age at first pregnancy, family history, previous benign disease have been applied as discriminants, but they provide little optimism for selective screening (for references, see ref. 71). At present, there seems little hope other than that screening should be applied to all women in a target age group, irrespective of whether they are considered to be particularly at risk.
BREAST CANCER: THE DECISION TO SCREEN
Cost At the time of this report there was only one published study of the cost of screening; but one was in progress in Edinburgh, for which a preliminary report was commissioned.79-S0 Others are now completed, including a large and detailed study from The Netherlands, where the 'best buy' was considered to be single-view mammography at an interval of two years for those of 50-70 years and this has been implemented.11 A recent report from Sweden suggests that one-third of the costs of screening can be offset by savings in other health sectors, and this must also be our aim.*2 The importance of increasing attendance as the most efficient way of increasing life years gained at lower cost cannot be overemphasized.83
is suggested to be solely dependent on oestrogen) could be prevented by the controlled and intermittent administration of progesterone. Recent studies indicating that oral contraceptives increase the incidence of breast cancer in young women lend attraction to this proposal, which might be truly preventive rather than only suppressive of tumour growth."•90 Dietary fat stimulates oestrogen synthesis, and it has been reported from the United States that when women reduce their dietary fat intake from 40 to 20 per cent of caloric needs, plasma oestrogen levels fall significantly, an effect calculated to reduce breast cancer mortality by 20 per cent." There is at present strong promotion for reduction in dietary fat in the United States, which, on general health grounds, perhaps we should emulate.
Prevention
Conclusions
Breast cancer can be prevented only when its cause is known. But this still eludes us. It is known that oestrogenic hormones have a promoting role, and interest is being expressed in interventional studies to reduce this effect. One method is by the administration of the antioestrogen tamoxifen; and evidence is accruing that, in those women included in adjuvant trials in which tamoxifen has been given to one arm, the incidence of second tumours in the contralateral breast is reduced (for references, see ref. 71). Feasibility studies of tamoxifen administration are under way in the United Kingdom and the United States, and proposals for randomized trials in postmenopausal women believed to be at increased risk are being considered.Mtl5 Concerns that long-term tamoxifen therapy may be detrimental (for •example, in causing osteoporosis or thrombosis) are apparently unfounded. For example, the observed reduction in the ratio of low-density lipoproteins to total cholesterol could act beneficially. Of great interest are recent data from the Scottish tamoxifen trial indicating that deaths from acute myocardial infarction are less in those women taking long-term tamoxifen than in controls." Recently it has been suggested that it is not oestrogen alone but its combination with progesterone that promotes breast cancer.87 Epithelial proliferation in the breast is most marked during the luteal phase of the menstrual cycle, when both hormones are present." It is proposed that the ablation of ovarian function in young women by gonadotrophin-releasing hormone would prevent this hormonal flux, well-being being maintained by the administration of oestrogen alone." Not only could this provide absolute contraception, but it could also reduce the incidence of not only breast but ovarian cancer. The increased risk of endometrial cancer (which
It is difficult to conclude other than that screening is beneficial to women who develop breast cancer. In Sweden, the overall mortality from breast cancer is falling,92 and that in Nijmegen and Utrecht, where screening programmes were introduced in the 1970s, has fallen compared with mortality in other Dutch cities.93-9* Mammography is not a good screening test, but it is the best we have. However, screening can only provide benefit if women attend. Studies of reasons for non-response to an invitation to be screened have been reported from Edinburgh.959* They confirm that socio-economic and educational factors do apply, but for the majority of women reasons are family commitments, holidays, or that they just 'could not be bothered'. Lack of motivation is a strong discentive, revealing a very worrying ignorance on all matters concerning breast disease.97 When one considers that the incidence of advanced level disease in the Edinburgh control population, at 38 per cent, was little better than a decade ago, is the same as that reported from Havana, and in great contrast to that reported from Sweden and the United States, it is clear that we have a great deal to learn." Would the money have been better spent on health education - on improving diagnostic and treatment services? My experience of being associated with a service of the highest of quality suggests that these cannot be isolated from other approaches. The attack on breast cancer must be from all fronts: by education, early diagnosis and the provision of diagnostic services. An efficient screening service can provide the catalyst for this attack, and to deny that it is beneficial can only do harm. Better is to positively promote the service we have, and to extend its benefits by providing the same improved facilities for diagnosis and treatment which it has brought about to all women. This requires effort and
10
JOURNAL OF PUBLIC HEALTH MEDICINE
conviction from all health professionals, including, and perhaps in particular, the general practitioner. To stop screening now, without a better alternative to put in its place, would be a rash decision - one at variance with current world opinion, and one to which I could not subscribe.
15
Acknowledgements
18
The monograph for the HM Queen Elizabeth, the Queen Mother, Fellowship, on which this lecture was based, was written while a Visiting Scientist to the National Cancer Institute. I am most grateful to Dr Bruce Chabner and his colleagues in the Division of Cancer Treatment and its Medicine Branch for the opportunity to spend a year in this remarkable institution and for the use of its facilities. In particular, I would like to thank Dr Kenneth Cowan for welcoming me to his breast clinic andresearchlaboratories and Ms Kathy Moore, who prepared the manuscript, for her superb secretarial skills.
References 1
2
3
4
5
6
7
8 9
10
11
12
13
14
Parliamentary Debates (Hansard), Vol. I, second series, Report of House of Commons, 25 February 1987. Breast cancer screening. Report to the Health Ministers of England, Wales, Scotland and Northern Ireland by a Working Group chaired by Sir Patrick Forrest. London: Her Majesty's Stationery Office, 1987. Shapiro S, Venet W, Strax P, et al. Ten-to-fourteen-year effect of screening on breast cancer mortality. J Nat Cancer Inst 1982; 69: 349-355. Tabar L, Fagerberg CJG, Gad A, et al. Reduction in mortality from breast cancer afler mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985; 1: 829832. Verbeek ALM, Hendricks JHCL, Holland R, et al. Reduction of breast cancer mortality through mass screening with modern mammography: first results of the Nijmegen project, 1975-1981. Lancet 1984; 1: 1222-1224. Collette HJA, Day NE, Rombach JJ, DeWaard F. Evaluation of screening for breast cancer in a non-randomised study (the DOM project) by means of a case-control study Lancet 1984; 1: 1224-1226. Facts on cancer. London: Annual Report of the Cancer Research Campaign, 1988. Washington Post, 21 January 1990. Silverberg E, Boring GC, Squires TS. Cancer statistics. CA 1990; 40: 9-26. Glass AG, Hoover RN. Rising incidence of breast cancer: relationship to stage and receptor status. J Nat Cancer Inst 1990; 82: 693-696. Forrest APM. Lister Oration: Breast cancer - 121 years on. J R Coll Surg Edinb 1989; 34: 239-248. Keynes G. Radium treatment of carcinoma of the breast. Lancet 1928; 2: 108-111. Keynes G. Carcinoma of the breast: the unorthodox view. Proc Cardiff Med Soc 1953; 4: 40-49. Azzopardi JG. Problems in breast pathology. London: J.B. Saunders, 1979.
16
17
Page DL, Anderson TJ. Diagnostic hislopathology of the breast. Edinburgh: Churchill-Livingston, 1988. Liotta LA. Gene products which play a role in cancer invasion and metastases. Breast Cancer Res Treat 1988; 11: 113-124. Brinkley D, Haybittle JL. A 15-year follow-up study of patients treated for carcinoma of the breast. Br J Radio! 1968; 41: 215-221. Easson EC, Russell MH. The curability of cancer in various
sites. L o n d o n : Pitman, 1968. " Brinkley D , Haybittle J L . Long-term survival of women with breast cancer. Lancet 1984; 1: 1118. 20 Rutqvist L E , Wallgren A. Long-term survival of 458 young breast cancer patients. Cancer 1985; 55: 658-665. 21 Haybittle J L . The evidence for cure in female breast cancer. In: Bulbrook R D , Taylor D J , eds. Commentaries on
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
research in breast disease. Vol. 3. New York: Alan Liss, 1983: 181-194. Early Breast Cancer Triallists' Collaborative G r o u p . Effects of adjuvant tamoxifen a n d of cytotoxic therapy o n mortality in early breast cancer. A n overview of 61 randomized trials a m o n g 28 896 women. N Engl J Med 1988; 319: 1681-1691. Carter C L , Allen C, Henson D E . Relation of tumor site, lymph node status a n d survival in 24 740 breast cancer cases. Cancer 1989; 6 3 : 181-187. Koscielny S, T u b i a n a M , Le M G , Valleron A J . Breast cancer: relationship between the size of the primary t u m o u r a n d the probability of metastatic dissemination. Br J Cancer 1984; 49: 709-715. Periodic mammographies and the risk of radio-induced cancers. Draft R e p o r t of E E C E S O Advisory G r o u p , 1990. Bailar J C . M a m m o g r a p h y : a contrary view. Ann Intern Med 1976; 84: 77-84. Skrabanek P. False premises a n d false promises of breast cancer screening. Lancet 1985; 2: 316-320. Wright C J . Breast cancer screening: a different look at the evidence. Surgery 1986; 100: 594-597. Roberts M M . Breast screening: time f o r a rethink? Br MedJ 1989; 299: 1153-1155. Isacsson S O , Larsson L G , J a n z o n L. D e b a t t o m m a m m o grafi. Lakartidnmgen 1985; 82: 2672-2673. F a r n d o n J R , Nicholson S. E d i n b u r g h trials of screening of breast cancer. Lancet 1990; 335: 1290-1291. S h a p i r o S, Venet W , Stratx P, Venet L. Periodic screening for breast cancer. The Health Insurance Plan Project and its sequelae 1963-1986. Baltimore: The Johns Hopkins University Press, 1988. Tabar L, Fagerberg CJG, Day NE. The results of periodic one-view mammography screening in a randomised controlled trial in Sweden. Part II. Evaluation of the results. In: Day NE, Miller AB, eds. Screening for breast cancer. Toronto: Hans-Huber, 1988: 39-44. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two-county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Commun Hlth 1989; 43: 107-114. Aron JL, Prorok PC. An analysis of the mortality effect in a breast cancer screening study. Int J Epidemiol 1986; 15: 36-43. Habbema JDF, van Oortmarssen GJ, van Putten DJ, Lubbe JT, van der Maas J. Age-specific reduction in breast cancer mortality by screening. Analysis of the results of the Health Insurance Plan of Greater New York study. J Nat Cancer Insl 1986; 77: 317-320.
BREAST CANCER: THE DECISION TO SCREEN 37
38
39
40
41
42
43
44
45
46
47
48
49
50
51 52
33
54
35
36
37
Verbeek A L M , Hendriks J H L C , Holland R. M a m m o graphic screening a n d breast cancer mortality: agespecific effects in the Nijmegen project 1975-82. Lancet 1985; 1: 865-866. Palli D , Rosselli del T u r c o M , Buiatti E, eI al. A case-control study of the efficacy of a non-randomised breast cancer screening program in Florence (Italy). Ini J Cancer 1986; 38: 501-504. Palli D , Turco M R , Buitta E, C i a t t o S, Crocetti E, Paci C. Time interval since last screening test in a breast cancer screening p r o g r a m m e . A case-control study in Italy. J Epidemiol Commun Hlth 1989; 43: 241-248. Andersson I, Aspergen K, J a n z o n L, el al. M a m m o g r a p h i c screening a n d mortality from breast c a n c e r the M a l m o m a m m o g r a p h i c screening trial. Br MedJ 1988; 2 0 7 : 9 4 3 948. U K Trial of Early Detection of Breast Cancer G r o u p . First results on mortality reduction in t h e U K trial of early detection o n breast cancer. Lancet 1988; 2: 411-415. Roberts MM, Alexander FE, Anderson TJ, el al. The Edinburgh trial of screening for breast cancer. Lancet 1990; 335: 241-246. T a b a r L, Duffy S. M a l m o m a m m o g r a p h i c screening trial. Br MedJ 1989; 298: 4 8 - 4 9 . Brinkley D , Haybittle JL, Alderson M R . Death certification in cancer of the breast. Br MedJ 1984; 289: 465-467. Baines CJ, McFarlane DV, Miller AB. Sensitivity and specificity of first screen mammography in 15 NBSS centres. J Can Assoc Radio! 1988; 39: 273-276. Barenidsen GW. Effects of radiation on the reproductive capacity and proliferation of cells in relation to carcinogenesis. In: Upton AC, Albert RE, Burns FJ, Shore RE, eds. Radiation carcinogenesis. Amsterdam: Elsevier, 1986: 85-105. Modan B, Chetrit A, Alfaridarg E. Increased risk of breast cancer after low-dose irradiation. Lancet 1989; 1: 629630. Dean C, Roberts MM, French K, Robinson S. Psychiatric morbidity after screening for breast cancer. J Epidemiol Commun Hlth 1986, 40: 71-75. Ellman R, Angeli N, Christians A, Moss S, Chamberlain J, Maguire P. Psychiatric morbidity associated with screening for breast cancer. Br J Cancer 1989; 60: 781-784. Frisell J, Eklund G, Hellstrom L, Glas U, Somell A. The Stockholm breast cancer screening trial - 5-year results and state at discovery. Breast Cancer Res Treat 1989; 13: 79-87. Report. Br MedJ 1989, 299: 877-878. Kirkpatrick AE, Law J. The usefulness of a moving grid in mammography. Br J Radiol 1989; 58: 257-258 Forrest APM. The Welbeck Memorial Lecture 1988. Radiology and breast cancer. Radiol Today 1988; 55: 13-20. Pritchard J. Quality assurance guidelines for mammography. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Aitken RJ, Macdonald HL, Kirkpatnck AE, Anderson TJ, Chetty U, Forrest APM. The outcome of surgery for non-palpable mammographic abnormalities. Br J Surg 1990; 77: 673-676. Azavedo E, Svane G, Ancr G. Stereotactic fine-needle biopsy in 2594 mammographically detected non-palpable lesions. Lancet 1989; I: 1033-1035. Ciatto S. Usefulness of needle aspiration in a screening programme. In: Ziant G , ed. Practical modalities of an efficient screening for breast cancer in the European
51
59
60
61
62
63
64
63
66
67
M
69
70
71
72
73
74
II
Community. International Congress Series 865. Amsterd a m : Excerpta Medica, 1989: 83-94. Peeters P H M , Verbeek A L M , Hendricks J H C L , van Bon M J H . Screening for breast cancer in Nijmegen: report of six screening rounds 1975-86. Ini J Cancer 1989; 4 3 : 2 2 6 230. Siedman H , Gelb SK, Silverberg E, et al. Survival experience in the Breast Cancer Detection Demonstration Project. CA 1987; 37: 258-290. Aitken RJ, Forrest A P M , Chetty U , et al. Assessment of non-palpable m a m m o g r a p h i c abnormalities: c o m p a r i son of a screening clinic and a breast clinic. Submitted for publication. Lundgren B. Screening for breast cancer: a view from the front line. Biomed Pharmacother 1988; 42: 443 446.
The Uppsala-Orebro Breast Cancer Study Group. Sector resection with or without postoperative radiotherapy for stage I breast cancer. A randomized trial. J Nat Cancer Inst 1990; 82: 277-282. Bartelink H. Radiotherapy in the management of early breast cancer: a review. Eur J Clin Oncol 1988; 24: 77-82. van Dongen JA, Fentiman IS, Harris JL In situ breast cancer: the EORTC consensus meeting. Lancet 1989; 2: 25-27. UK Coordinating Committee for CanceT Research. Protocol of the UK randomised trial for the management of screen-detected ductal carcinoma in situ (DCISj of the breast. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1989. Department of Health and Royal College of Pathologists Working Group. Draft guidelines for pathologists. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Department of Health and Royal College of Pathologists Working Group. Pathology reporting in breast cancer screening: draft guidelines. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Anderson TJ. Breast cancer screening: principles and practicalities for histopathologists. Rec Adv Histopathol 1989; 14:43-61. H o l m b e r g L, A d a m i H O , Persson I, Lundstrom T, T a b a r L. D e m a n d s on surgical in-patient services after mass m a m m o g r a p h i c screening. Br MedJ 1988; 293: 779-782. Peeters P H M , Verbeek A L M , S t r a a t m a n H , et al. Evaluation of overdiagnosis of breast cancer in screening by m a m m o g r a p h y : results of the Nijmegen p r o g r a m m e . Ini J Epidemiol 1989; 18: 295-299. Forrest, Sir Patrick. Breast c a n c e r the decision to screen. F o u r t h H M Queen Elizabeth, the Queen Mother, Fellowship. L o n d o n : Nuffield Provincial Hospitals Trust, 1990.
The New Forrest Committee. Gray M, ed. NETWORK: NHS Breast Screening Project. Oxford: Cancer Research Campaign, 1988, No. 2: 8. Tabar L, Faberberg G, Day NE, Holmberg L. What is the optimal interval between mammographic screening: an analysis based on the latest results of the Swedish twocounty breast cancer screening trial. Br J Cancer 1987; 55: 547-551. Fagerberg G. Optimum interval between mammographic screening examinations for different age groups. In: Ziant G, ed. Practical modalitiesfor efficient screeningfor breast ameer in the European Community. International Congress Series 865. Amsterdam, Excerpta Medica, 1989: 27-34.
12 73
76
77
78
79
80
81
82
83
84
85
86
JOURNAL OF PUBLIC HEALTH MEDICINE Chu KE, Smart CR, Tarone RE. Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial. / Nat Cancer Inst 1988; 80: 1125-1132. G o r d i l l o C . Breast cancer screening guidelines agreed o n b y AMA and other medically related organizations. JAMA 1989; 262: 1155. Mammographic screening for early detection of breast cancer. Report to National Board of Health and Welfare, Stockholm, 1986. Miller AB. The Canadian national trial. In: Day NE, Miller AB, cds. Screening for breast cancer. Toronto: HansHuber, 1988: 51-58. Gravelle HSE, Simpson PR, Chamberlain J. Breast cancer screening and health service costs. J Hlth Econ 1982; 1: 185-207. C l a r k P R , Fraser N M . Economic analysis of screening for breast cancer. Interim report to Scottish Home and Health Department, 1989. van der Mass DJ. The costs and effects of mass screening for breast cancer. Amsterdam: Medical Technology Assessment, 1988. Jonsson E, Hakansson S, Tabar L. Cost of mammography screening for breast cancer after low-dose irradiation. Lancet 1989; 1: 629-630. DeKonig HJ, van Inerald BM. Cost-benefit evaluation of different screening strategies for breast cancer. In: Ziant G, ed. Practical modalities of an efficient screening for breast cancer in the European Community. International Congress Series 865. Amsterdam: Excerpta Medica, 1989: 121-132. Powles T J , H a r d y J R , Ashley S E , et al. A pilot trial t o evaluate the acute toxicity a n d feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126— 131. Love RR. Prospects for antioestrogen chemoprevention of breast cancer. J Nat Cancer Inst 1990; 82: 18-21. Stewart HJ. The Scottish adjuvant tamoxifen trials in early breast cancer. NTH Consensus Development Conf., June 1990.
87
88
89
90
91
92
93
94
95
96
97
Pike M C , Ross R K , L o b o R A , K e y T J A , Potts M , H e n d e r s o n BE. L H R H agonists a n d t h e prevention of breast a n d ovarian cancer. BrJ Cancer 1989; 60:142-148. Anderson TJ, Battersby S. The involvement of oestrogen in the development and function of the normal breast: histological evidence. Proc R Soc Edinb 1989; 95B: 23-32. UK. National Case-Control Study Group. Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1: 973-982. Olsson H , Moller T R , R a n s t a m J. Early oral contraceptive use a n d breast cancer a m o n g premenopausal women: final report from a study in southern Sweden. J Nat Cancer Inst 1989; 81: 1000-1004. Prentice R, T h o m p s o n D , Clifford C, Gor-bach S, Goldin B, Byar D . Dietary fat reduction a n d plasma estradiol concentration in healthy p o s t m e n o p a u s a l women. J Nat Cancer Inst 1990; 82: 129-134. Adami HO, Malber B, Rutquist LE, Persson I, Ries L. Temporal trends in breast cancer survival in Sweden: significant improvement in 20 years. J Nat Cancer Inst 1986; 76: 653-659. Day NE, Chamberlain J. Screening for breast cancer: workshop report. EXIT J Clin Oncol 1988; 24: 55-59. Hendriks JHCL. Discussion. In: Ziant G, ed. Practical modalities for efficient screening for breast cancer in the European Community. International Congress Series 865. Amsterdam: Excerpta Medica, 1989: 27-34. French K, Porter AMD, Robinson SE, McCallum FM, Howie JGR, Roberts MM. Attendance at a breast screening clinic: a problem of administration or attitudes. Br MedJ 1982; 285: 617-620. MacLean U, Sinfield D. Women who decline screening: report to Health Services Research Committee. / Epidemiol Commun Med 1984; 38: 278-283. Roberts MM, French K, Duffy J. Breast cancer and breast self-examination: what do Scottish women know. Soc Sci Med 1984; 18: 791-797.
Vol. 13, No. 1, pp. 2-12 Printed in Great Britain
Breast cancer: the decision to screen A. P. M. Forrest
On 25 February 1987, the Secretary of State for Health and Social Security, having considered a report by a working group, announced in the House of Commons that the Government was to implement a national breast screening service, with all necessary back-up assessment and diagnostic facilities, treatment facilities, counselling and after-care - and training for key groups of staff.1-2 The evidence supporting this decision was based on two controlled randomized trials in which population screening by mammography (and in one by clinical examination) had been offered on a random basis, and two case-control studies in which the screening history of women dying from breast cancer was compared with that of healthy controls.^ The results of all four studies were consistent with the conclusion that mammographic screening was 'good news'. The cost of providing the service had been assessed, and was reasonable compared with other essential health needs. As new funding had been provided to support this new service, it was not introduced at the cost of denying other health requirements. The proposed service was not only for the provision of screening mammography; it was comprehensive, covering all stages of the screening process: the screening test, assessment of a mammographic abnormality, a surgical biopsy when required, and the treatment of screen-detected cancers. It was considered on available evidence that the service should be offered only to women of 45-64 years of age, who would be invited for single oblique-view mammogram each three years. But these were initial recommendations, to be modified as new information arose.
gram was not a diagnostic investigation, but only determined whether a mammogram was normal or not, arrangements for the further investigations of abnormalities, and if necessary a surgical biopsy, needed to be made. This was best achieved by the formation of multidisciplinary 'teams' with the necessary skill and experience to apply the techniques used, i.e. additional mammographic and magnification views, ultrasonography, fine-needle aspiration and cytology, if necessary, under stereotaxic guidance. The provision of facilities for assessment has varied, and they may be provided in the screening clinic, in the hospital, or partly in both. An advantage in having the more sophisticated investigations hospital-based is that the services of the assessment team - surgeon, radiologist and cytologist - are available also to symptomatic patients. It must be emphasized that assessment is a multidisciplinary exercise, and that although a woman may well prefer the privacy of a doctor's consulting room, her interests are best served by the 'team' approach. And that a biopsy, should it be required, is performed by a surgeon and radiologist experienced in the technique of removing impalpable lesions, supported by a pathologist conversant with the difficulties of interpreting screen-detected particularly the borderline lesion and the specialized techniques required. Treatment also had to be considered. If screening is to appeal, a woman should expect that this should be less radical than had she found the lump herself. The safety of conservative treatment of small invasive and noninvasive cancers is not yet established, and a woman must also be aware of the need for clinical trials; one reason why counselling and frank discussion of available options is a critical part of all stages of the screening
The screening procedure The provision of facilities for basic mammographic screening was based on population needs, assuming that one mammography unit would examine 70 women a day, that 70 per cent of invited women would accept, that 10 per cent would be recalled for additional tests, and that provision would be made for self-referred women over 60 years of age. As a screening mammo-
Scottish Cancer Trials Office, Medical School, Teviot Place, Edinburgh EH8 9AG. A. P. M. FORREST, Professor Emeritus, University of Edinburgh •The HM Queen Elizabeth, the Queen Mother, Fellowship Lecture, given under the aegis of the Nuffield Provincial Hospitals Trust (delivered in Edinburgh on 19 June 1990).
© Oxford University Press 1991
BREAST CANCER: THE DECISION TO SCREEN programme. Considering the state of mammography in the United Kingdom, the introduction of a comprehensive screening service, including the training of personnel, was an enormous undertaking. That it has been accomplished is due to the enthusiasm and commitment of remarkable people involved in all stages of the programme.
Why screen? In the western world, breast cancer is a disease of substantial proportions. In the United Kingdom there are 25 000 new cases each year; some 150 000 women live with the disease, and one dies each 30 minutes.7 In the United States, during the 10 years of the Vietnam war, 57000 died from combat, while 330000 women died at home from breast cancer.' England and Wales head the international league for deaths from breast cancer;9 and in all developed countries the incidence of the disease in older women is on the increase, even when earlier diagnosis and better cancer registration are discounted.10 Were breast cancer infectious it would be registrable by law; a step that would allow its true incidence in Britain to be identified and monitored. During this century, our understanding of breast cancer was retarded by the concept that is was primarily a loco-regional disease, spreading by wave-like permeation along lymphatic pathways to be contained by the regional lymph nodes for a considerable time. Embolization of blood vessels was largely discounted; spread to distant sites believed to be a late phenomenon. Eradication of the disease was by radical surgery; hoping that one was in time to remove every cancerous cell. With realization that surgery might fail, the area of local treatment was extended by postoperative radical radiotherapy (for references see ref. 11). Not all agreed with this dogma, but the heated controversy that ensued concentrated on technical detail, disregarding the fact that the big step had already been taken in 1923, when, at the instigation of Professor George Gask, Geoffrey Keynes introduced treatment by intense irradiation alone, later to become, with local excision of the tumour, a viable alternative to mastectomy, allowing preservation of the breast.12 Keynes also recognized the illogicality of radical surgery, knowing that it was early dissemination of the disease that accounted for its fatal consequences. He suggested, rightly, that unless repelled by some other form of treatment the invaders were bound to gain the upper hand in the end - a statement as true today as in his time.13 Current understanding For screening to succeed it must be able to detect breast
cancer before dissemination with the formation of micrometastases has occurred. Originating in the epithelium of the secreting lobule of the breast, and preceded by a series of atypical proliferative changes, a cancer is initially non-invasive and confined by the basement membrane. 1413 But should a further series of fundamental changes in the genetic structure of the malignant cells allow them to degrade the basement membrane, to migrate into lymphatic and vascular capillaries and to circulate," the scene is set for the formation of micrometastases as forerunners of clinical relapse and death. This is not a rapid process, for breast cancer can be slowgrowing; a disease that 'disseminates early but may recur late'.17 Supporting evidence Two facts support this concept of the natural history of breast cancer. First, statistical cure of symptomatic invasive breast cancer has not been demonstrated; thus long-term follow-up studies have failed to uncover a group of disease-free survivors whose 'annual death rate from all causes is similar to that of a normal population group of similar age and sex'.18 Even 30-40 years after the local treatment of invasive breast cancer, excess deaths still occur from metastatic disease."-20 This does not imply that all women who develop breast cancer die from it. Some 30 per cent have no further evidence of the disease during their lifetime and therefore are personally cured. But this definition of cure includes the woman who, within a month of her mastectomy, is run over by a bus.21 Second, systemic treatment either by chemotherapy or the antioestrogen tamoxifen administered at the time of local treatment postpones relapse and prolongs life, confirmed by a recent meta-analysis of 61 randomized trials including over 28000 women.22 The effect, although modest, is real; and new trials of more potent chemotherapeutic compounds and longer-term tamoxifen therapy are beginning to show greater benefit. A threshold But is there an early stage of breast cancer at which treatment confers greater benefit? By definition, noninvasive cancer is at such an early stage, and, provided no areas of microinvasion are present, is curable by local surgery. However, the timespan of non-invasive cancer is long, and its earlier detection by screening cannot be expected to have an immediate effect on mortality. This depends upon whether there is an early stage of invasive cancer during which it can be detected before dissemination. Evidence in support is available from studies in which the size of the primary tumour at the time of local treatment has been related to the state of the axillary lymph nodes. A recent analysis of 25000 women with
JOURNAL OF PUBLIC HEALTH MEDICINE breast cancer included in the SEER programme of the National Cancer Institute has indicated that for invasive cancers of less than 1 cm in diameter the incidence of axillary-node involvement was less than 20 per cent and five-year survival over 95 per cent, comparing favourably with approximate figures of 50-60 per cent for all cancers.23 Small cancers without axillary-node involvement may still be aggressive, and the study from France, in which the parameter for early dissemination was the development of metastatic disease over a follow-up period of 25 years, is relevant. For those with a tumour of 1 cm or less in diameter at the time of primary treatment, this number did not exceed 20 per cent. These studies do not indicate that all small invasive cancers are non-aggressive, but that the treatment of invasive breast cancers when of small size is more likely to have a favourable outlook. A 1-cm tumour contains 1 billion cells. With an estimated doubling time of 2-5 months it would take 15 years for such a tumour to replicate from a single cell.23 There is no certainty of monoclonal origin; but equally no doubt that all breast cancers 'sojourn' for variable periods of time in a preclinical asymptomatic phase during which they are not palpable on clinical examination. However, they can be detected by mammographic imaging. Further, there is unequivocal evidence that the treatment of breast cancer at this early stage confers a mortality advantage that is greater than that observed by any other means.
Dissent Not all agreed that the decision to implement screening for breast cancer was correct.26"31 The main points of dissent were (1) the working group was biased; experts who acted with undue haste so that their conclusions were premature; (2) mortality benefit was overemphasized; women 'hoodwinked' into believing treatment was effective for screen-detected disease; (3) risks from radiation, psychological effects, unnecessary biopsies and overtreatment outweighed potential benefits; (4) there were faults in the suggested programme; selective screening had not been considered; (5) resources would have been better spent on other aspects of health care or on scientific research into cause and prevention. The working group and its conclusions The working group neither was biased nor acted with
undue haste. It was well balanced between specialties, interests, sex and countries. It had available to it updates of the HIP (Health Insurance Plan, New York) and Two-Counties (Sweden) randomized trials, now published, which strongly support the initial conclusions.32" 34 Re-examination of the HIP statistical tapes by other authorities had confirmed that the mortality advantage in that trial was beyond doubt, and the power and design of the Two-Counties trial could not be questioned.33-36 Since then, three additional case-control studies comparing- breast cancer mortality in 'ever-screened' and 'never-screened' women have been reported, all indicating significant benefit.37"39 When only those women over 50 years of age are considered, the mortality advantage from screening is greater than that reported overall (Fig. 1), and this is further increased when the delay between the introduction of screening and first evidence of benefit, which depends on the efficiency of the screening process, is discounted. It is difficult to imagine that in the face of this evidence the working group would now change its views. But account must be taken of recent reports indicating that neither in the Malmo or Edinburgh randomized trials nor in the British Comparative Trial of Early Detection of Breast Cancer (TEDBC) has a significant mortality advantage overall been observed;40"42 although in the Malmo trial and the TEDBC this has now emerged in the sixth and seventh years. Admittedly, the results of the British and Malmo trials are disappointing, but before condemning screening on this account one must consider whether the design, response rates and efficiency of screening were less than ideal. Design
The statistical power of both the Malmo and Edinburgh trials has been questioned. However, a greater confounding influence in the Malmo trial was that 24 per cent of a sample of the control population had at least one mammogram. Twenty per cent of cancers in the control group were detected by mammography, of which 11 per cent were non-invasive. When compliance is taken into account, the trial compared screening mammography in 74 per cent of study women versus 24 per cent of controls.43 The UK. TEDBC was not a randomized trial, and it now appears that the adjustment for expected mortality, at least in Edinburgh, may have been faulty. Further, the 'cluster' randomization by general practice in the Edinburgh trial has not provided comparable groups. Unlike other randomized trials, all-cause mortality in study and control populations differs markedly, mainly on account of cardiovascular deaths.
BREAST CANCER: THE DECISION TO SCREEN
REDUCED
INCREASED adjusted for 70% compliance
HIP Two-Counties Molmo Edinburgh Nijmegen Utrecht Florence
00
0-5
10
1-5
20
relative risk FIGURE 1 Relative risk of death from breast cancer in over-55-year-olds. (| is adjustment for compliance in case-control studies). (Reproduced with permission of Nuffield Provincial Hospitals Trust.)
Response
Extent of benefit
Compared with compliance in Sweden, that in the British studies was poor. In Edinburgh, only 60 per cent of invited women attended for the first screen; many did not return. In the TEDBC, 51 per cent of cancers were detected in 28 per cent who did not attend for screening, compared with 30 in 10 per cent in the Two-Counties trial.
Concern that the mortality benefit of breast screening is not reflected in a reduction of total all-cause mortality has no substance. In the age group that benefits, breast cancer accounts for a relatively small proportion of all deaths. Even in the Two-Counties trial, the expected reduction in all-cause mortality could not exceed 1 per cent.34 Numerically, the number of lives 'saved' in these trials is small, but if extrapolated to all women with the disease becomes substantial. Were a 30 per cent reduction in mortality achievable in the United Kingdom, over 1500 deaths would be prevented in women of 50-64 years. Only women with breast cancer can benefit from breast cancer screening, and for them the potential gain is substantial.
Efficiency Estimates of efficiency suggest that performance in Edinburgh was not comparable to that of Swedish or Dutch centres. The sensitivity of mammography, determined by the rates at which cancers surfacing after a negative screen (interval cancer rates), were higher than in these centres, particularly when those detected at the intervening 'clinical-only' examinations were taken into account. Further, the stage of cancers detected was less favourable in Edinburgh than in Sweden.42 In neither British study was the certified cause of death verified, which, considering likely errors, is a necessary precaution.44 More detailed analyses are clearly required.
Risks Radiation In a recent survey of the 15 Canadian trial centres, the dose to breast from two-view mammography ranged
JOURNAL OF PUBLIC HEALTH MEDICINE 43
from 1-3 to 2-6 mGy. Considering the small dose of radiation received from modern mammographic equipment, fears of radiation risk are unfounded. The doses of radiation given for diagnosis or therapy or on account of atomic warfare were far in excess. It has been calculated that exposure of the adult breast to 1 -5 mGy would cause only one extra case of breast cancer per 2 million women per year,** and then only after a latent period of 10 years. A large case-controlled study from Israel suggests that small doses of radiation can increase breast cancer risk, but only when exposure occurs at an age of 5-9 years, during the early active stages of breast development.47 The breast of a 50-year-old woman is involuting; its epithelium atrophic. Psychiatric morbidity Studies now reported from Edinburgh and Guildford suggest that risks of psychiatric morbidity from screening have also been overstated.48*' One study investigated only the effect of attending for screening; the other also that of recall following the detection of a mammographic abnormality. Both used the General Health Questionnaire to assess psychiatric morbidity before and at 3-6 months after screening. In Edinburgh this was supplemented by interview. Neither study showed excess morbidity as a result of screening. Women recalled for review did have significantly increased morbidity from anxiety, but, provided the diagnosis was benign, this did not last; nor was it any greater than that observed in women attending a symptomatic hospital clinic. Serious and lasting morbidity was observed only in women proven to have cancer; again, similar to that in symptomatic cases. This is not to say that women are not anxious, even if not morbidly so, but anxiety can be reduced by short waiting times and good communications. Recall To allay anxiety, recall rates must be kept to a minimum. These depend on the quality of the screening mammogram, and of its interpretation. In Sweden, 5 per cent of women are recalled for additional mammography and just over 1 per cent for full examination.50 In Britain, initial recall rates have averaged 7-4 per cent; in some centres they are much greater.31 With the incorporation of moving grids in mammographic units, dense films from so-called dysplastic breasts are not now common.52 Poor-qualityfilmsare a rare cause of recall. In the Lothian mobile mammography study, only 1 per cent of women were recalled for this reason, faulty packing being the main cause.53 Mandatory training and accreditation of radiographers by their college is ensuring high standards of practice. Radiologists interpreting screening films must also
work to a very high standard, and, as was suggested in the Pritchard report, should read thefilmsfrom at least 6000 women each year.54 This report provides comprehensive advice on all aspects of mammographic screening, including the evaluation of equipment, the performance of screening, and the identification of deficiencies. Endorsed by the Royal College of Radiologists, its recommendations are being applied. Considering lack and poor quality of mammography in the United Kingdom at the time of the working group report, the development of efficient mammographic screening has been a remarkable achievement. Biopsy A breast biopsy is bound to cause serious anxiety. It can also cause physical morbidity; and by distorting the breast it can compromise the interpretation of subsequent mammograms. Unnecessary biopsies must be avoided. This is particularly important for the nonpalpable lesion, removal of which in Britain usually involves a hospital stay and general anaesthetic. The assessment of a mammographic abnormality is initially the responsibility of the radiologist. It was considered that an additional mammographic view would be the likely first step in assessment, but with experience it has become apparent that all recalled women should have a clinical examination. Should the mammographic abnormality be palpable, its further investigation byfine-needleaspiration (FNA) cytology is straightforward and can provide a definitive diagnosis without the need for further X-rays. It is the impalpable abnormality that requires additional imaging - further views, magnification mammography and ultrasonography - and, if these are suspicious of cancer, a surgical biopsy. But, as in the palpable lesion, cytology is becoming an essential aid, although the need for stereotaxic radiological guidance increases its complexity. Should a diagnosis of cancer be confirmed by stereotaxic aspiration cytology, a biopsy is no longer appropriate. The further management of the patient, including the operation, is for cancer. Before stereotaxic FNA was available, we found that a 'diagnostic' operation for an impalpable cancer resulted in incomplete removal of half, necessitating the unpleasantness and risks of a second operation.35 Cytology also may confirm the simplicity of a mammographic abnormality which is not believed to be malignant, supporting a decision to observe rather than remove it. In Stockholm, 2005 women with nonpalpable mammographic lesions believed radiologically and cytologically to be benign have been observed over a period of 2-6 years.56 In only one case was cancer missed. From Italy it has been reported that the
BREAST CANCER: THE DECISION TO SCREEN introduction of stereotaxic aspiration cytology reduced benign biopsies by one-third.57 The rate of biopsies and the ratio of benign-tomalignant histology provide an indication of the quality of the assessment. Sweden and The Netherlands provide the standard, but British rates, although higher, are still reasonable;54-58 contrasting with those in countries where the multidisciplinary nature of assessment and the need for a team approach are not accepted.59 A review of our experience of over 350 localization biopsies for non-palpable lesions has confirmed the value of this team approach. 60 Rates of benign-tomalignant biopsies were greatly reduced in those women who had been referred through the screening service, with its system of a formal review, compared with those seen at a symptomatic breast clinic where the decision for biopsy was made on the basis of the radiological report. All women with suspected mammographic abnormalities, irrespective of their source of reference, should have the benefit of formal review before a decision to biopsy is advised. Overtreatment Successful screening detects a large number of invasive cancers when they are still of small size. In the Edinburgh trial, the proportion of cancers amenable to conservation therapy in the population invited for screening now far exceeds that in the control population, both being treated by the same surgical team. In Gavleborg, Sweden, where screening has been in operation for many years, 75 per cent of invasive cancers are less than 2 cm, and are treated by local excision alone.61 Trials are in progress to determine whether this is adequate treatment. A three-year follow-up report of that from Uppsala indicates a local relapse rate of 7-6 per cent; survival is not compromised.62 In Scotland, small invasive cancers are being included in a trial in which tumours of 4 cm and less are treated by local excision and systemic therapy (most often by tamoxifen) with subsequent randomization for radiation or no further local treatment. Mammographic screening also detects a larger number of tumours at a non-invasive stage; for these the risk of overtreatment is real. Admittedly, non-invasive cancer of ductal origin is cured by mastectomy, and some surgeons advise and women prefer this once-forall radical approach, particularly as there is doubt concerning the efficacy of radiation therapy in in situ disease.63 In Europe the consensus view is that the breast should be conserved;64 and a number of controlled trials are comparing local excision alone with local excision plus radiotherapy. In the United Kingdom, a national randomized trial to compare these treatments has been
initiated, both groups of patients also being randomized to receive tamoxifen or no systemic treatment.65 The fear that non-malignant disease may be overtreated is also only too real; for example, by recommending bilateral mastectomy for lobular carcinoma in situ (now regarded as but a marker of epithelial instability) or even for the atypical proliferative lesion. Fortunately, this is rare in the United Kingdom, and, although mastectomy for a benign mammographic lesion is not unknown, the formal review system now available should avoid this. The interpretation of these borderline lesions requires great skill and experience, and time; the Royal College of Pathologists has issued guidelines.66-67 It is not an occasional exercise, and is one that must be critically monitored.68 The regular review session with other members of the screening and assessment team is an essential part of a well-run screening programme. And the patient (as she has now become) must be aware of all available facts on the significance of the findings before treatment is discussed. It is relevant that in Sweden the incidence of operations for benign breast disease has not increased as a result of screening,69 and that a study in The Netherlands has not provided support for the suggestion that overtreatment of cancers, that would not otherwise become apparent, has occurred.70
Deficiencies in the programme The decision to recommend single-view mammography as the sole screening method in the UK programme was based on Swedish and Dutch experience. Many British radiologists have been critical of this recommendation, citing a number of retrospective studies that indicate that recall and cancer-detection rates are improved by two views. However, these studies are based on a review of existing films (for references, see ref. 71), and do not represent the 'real-life' situation when a decision for action must be made on available evidence. A prospective study is being initiated in the United Kingdom that will compare not only recall and cancer-detection rates of single- with two-view mammography in different women, but also those generated by two radiologists independently in the same women.72 The recommendation that screening be repeated each three years was also based on Swedish experience. In the Two-Counties study the interval between screens in women over 50 years of age averaged 33 months. Proportional interval cancer rates in that study now suggest that this interval may be too long, and this is supported by experience in Nijmegen.73-74 A second trial has been initiated in the United Kingdom to compare intervals of one and three years.72
JOURNAL OF PUBLIC HEALTH MEDICINE
INCREASED
REDUCED HIP Two-Counties Malmo Nijmegen Utrecht Florence
00
05
10 relative risk
15
20
elativ risk of death from breast cancer in under-55-year-olds. (Reproduced with permission of Nuffield Provincial FIGURE 2 Relative 71 Hospitals Trust.71 )
But what about the young woman? The exclusion of women under 50 years of age in the UK programme was based on lack of evidence of benefit in existing trials (Fig. 2). A recent re-analysis of the HIP data suggests that there is not a threshold of age below which screening was ineffective.75 In both the United States and Sweden, recommendations are that screening should start at 40 years.76-77 Existing data cannot resolve this question, which is being addressed in the national Canadian trial and in Sweden,7* and also in a third national UK trial, in which, in a cohort of women aged 40-41 years, the effect of screening annually for a sevenyear period will be compared with that of participation in the national programme at the age of 50.72 These trials are not inexpensive, and some doubted their justification, but the UK programme presents a unique opportunity to answer these questions.
Breast self-examination No provision was made in the UK service for a clinical examination at basic screen, and experience in Edinburgh and Guildford has supported this view. Nor was any recommendation made to include breast selfexamination (BSE) as an adjunct to the screening
programme. The preliminary results of the TEDBC, in which instruction in BSE was offered in two centres, did not indicate any effect on mortality from breast cancer. However, several recent studies suggest that it may have a beneficial effect on the stage of the disease, and a casecontrol study gives some indication of improved mortality (for references, see ref. 71). The potential role of BSE must be kept under review, but not as a screening test, for it cannot detect a breast cancer in its preclinical detectable phase; although this is not to deny that regular BSE is other than good practice.
Selective screening It would clearly be advantageous were it possible to select for screening those who would benefit most. A series of studies have been reported in which a number of risk factors, particularly those about which enquiry can readily be made - age at menarche, age at first pregnancy, family history, previous benign disease have been applied as discriminants, but they provide little optimism for selective screening (for references, see ref. 71). At present, there seems little hope other than that screening should be applied to all women in a target age group, irrespective of whether they are considered to be particularly at risk.
BREAST CANCER: THE DECISION TO SCREEN
Cost At the time of this report there was only one published study of the cost of screening; but one was in progress in Edinburgh, for which a preliminary report was commissioned.79-S0 Others are now completed, including a large and detailed study from The Netherlands, where the 'best buy' was considered to be single-view mammography at an interval of two years for those of 50-70 years and this has been implemented.11 A recent report from Sweden suggests that one-third of the costs of screening can be offset by savings in other health sectors, and this must also be our aim.*2 The importance of increasing attendance as the most efficient way of increasing life years gained at lower cost cannot be overemphasized.83
is suggested to be solely dependent on oestrogen) could be prevented by the controlled and intermittent administration of progesterone. Recent studies indicating that oral contraceptives increase the incidence of breast cancer in young women lend attraction to this proposal, which might be truly preventive rather than only suppressive of tumour growth."•90 Dietary fat stimulates oestrogen synthesis, and it has been reported from the United States that when women reduce their dietary fat intake from 40 to 20 per cent of caloric needs, plasma oestrogen levels fall significantly, an effect calculated to reduce breast cancer mortality by 20 per cent." There is at present strong promotion for reduction in dietary fat in the United States, which, on general health grounds, perhaps we should emulate.
Prevention
Conclusions
Breast cancer can be prevented only when its cause is known. But this still eludes us. It is known that oestrogenic hormones have a promoting role, and interest is being expressed in interventional studies to reduce this effect. One method is by the administration of the antioestrogen tamoxifen; and evidence is accruing that, in those women included in adjuvant trials in which tamoxifen has been given to one arm, the incidence of second tumours in the contralateral breast is reduced (for references, see ref. 71). Feasibility studies of tamoxifen administration are under way in the United Kingdom and the United States, and proposals for randomized trials in postmenopausal women believed to be at increased risk are being considered.Mtl5 Concerns that long-term tamoxifen therapy may be detrimental (for •example, in causing osteoporosis or thrombosis) are apparently unfounded. For example, the observed reduction in the ratio of low-density lipoproteins to total cholesterol could act beneficially. Of great interest are recent data from the Scottish tamoxifen trial indicating that deaths from acute myocardial infarction are less in those women taking long-term tamoxifen than in controls." Recently it has been suggested that it is not oestrogen alone but its combination with progesterone that promotes breast cancer.87 Epithelial proliferation in the breast is most marked during the luteal phase of the menstrual cycle, when both hormones are present." It is proposed that the ablation of ovarian function in young women by gonadotrophin-releasing hormone would prevent this hormonal flux, well-being being maintained by the administration of oestrogen alone." Not only could this provide absolute contraception, but it could also reduce the incidence of not only breast but ovarian cancer. The increased risk of endometrial cancer (which
It is difficult to conclude other than that screening is beneficial to women who develop breast cancer. In Sweden, the overall mortality from breast cancer is falling,92 and that in Nijmegen and Utrecht, where screening programmes were introduced in the 1970s, has fallen compared with mortality in other Dutch cities.93-9* Mammography is not a good screening test, but it is the best we have. However, screening can only provide benefit if women attend. Studies of reasons for non-response to an invitation to be screened have been reported from Edinburgh.959* They confirm that socio-economic and educational factors do apply, but for the majority of women reasons are family commitments, holidays, or that they just 'could not be bothered'. Lack of motivation is a strong discentive, revealing a very worrying ignorance on all matters concerning breast disease.97 When one considers that the incidence of advanced level disease in the Edinburgh control population, at 38 per cent, was little better than a decade ago, is the same as that reported from Havana, and in great contrast to that reported from Sweden and the United States, it is clear that we have a great deal to learn." Would the money have been better spent on health education - on improving diagnostic and treatment services? My experience of being associated with a service of the highest of quality suggests that these cannot be isolated from other approaches. The attack on breast cancer must be from all fronts: by education, early diagnosis and the provision of diagnostic services. An efficient screening service can provide the catalyst for this attack, and to deny that it is beneficial can only do harm. Better is to positively promote the service we have, and to extend its benefits by providing the same improved facilities for diagnosis and treatment which it has brought about to all women. This requires effort and
10
JOURNAL OF PUBLIC HEALTH MEDICINE
conviction from all health professionals, including, and perhaps in particular, the general practitioner. To stop screening now, without a better alternative to put in its place, would be a rash decision - one at variance with current world opinion, and one to which I could not subscribe.
15
Acknowledgements
18
The monograph for the HM Queen Elizabeth, the Queen Mother, Fellowship, on which this lecture was based, was written while a Visiting Scientist to the National Cancer Institute. I am most grateful to Dr Bruce Chabner and his colleagues in the Division of Cancer Treatment and its Medicine Branch for the opportunity to spend a year in this remarkable institution and for the use of its facilities. In particular, I would like to thank Dr Kenneth Cowan for welcoming me to his breast clinic andresearchlaboratories and Ms Kathy Moore, who prepared the manuscript, for her superb secretarial skills.
References 1
2
3
4
5
6
7
8 9
10
11
12
13
14
Parliamentary Debates (Hansard), Vol. I, second series, Report of House of Commons, 25 February 1987. Breast cancer screening. Report to the Health Ministers of England, Wales, Scotland and Northern Ireland by a Working Group chaired by Sir Patrick Forrest. London: Her Majesty's Stationery Office, 1987. Shapiro S, Venet W, Strax P, et al. Ten-to-fourteen-year effect of screening on breast cancer mortality. J Nat Cancer Inst 1982; 69: 349-355. Tabar L, Fagerberg CJG, Gad A, et al. Reduction in mortality from breast cancer afler mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1985; 1: 829832. Verbeek ALM, Hendricks JHCL, Holland R, et al. Reduction of breast cancer mortality through mass screening with modern mammography: first results of the Nijmegen project, 1975-1981. Lancet 1984; 1: 1222-1224. Collette HJA, Day NE, Rombach JJ, DeWaard F. Evaluation of screening for breast cancer in a non-randomised study (the DOM project) by means of a case-control study Lancet 1984; 1: 1224-1226. Facts on cancer. London: Annual Report of the Cancer Research Campaign, 1988. Washington Post, 21 January 1990. Silverberg E, Boring GC, Squires TS. Cancer statistics. CA 1990; 40: 9-26. Glass AG, Hoover RN. Rising incidence of breast cancer: relationship to stage and receptor status. J Nat Cancer Inst 1990; 82: 693-696. Forrest APM. Lister Oration: Breast cancer - 121 years on. J R Coll Surg Edinb 1989; 34: 239-248. Keynes G. Radium treatment of carcinoma of the breast. Lancet 1928; 2: 108-111. Keynes G. Carcinoma of the breast: the unorthodox view. Proc Cardiff Med Soc 1953; 4: 40-49. Azzopardi JG. Problems in breast pathology. London: J.B. Saunders, 1979.
16
17
Page DL, Anderson TJ. Diagnostic hislopathology of the breast. Edinburgh: Churchill-Livingston, 1988. Liotta LA. Gene products which play a role in cancer invasion and metastases. Breast Cancer Res Treat 1988; 11: 113-124. Brinkley D, Haybittle JL. A 15-year follow-up study of patients treated for carcinoma of the breast. Br J Radio! 1968; 41: 215-221. Easson EC, Russell MH. The curability of cancer in various
sites. L o n d o n : Pitman, 1968. " Brinkley D , Haybittle J L . Long-term survival of women with breast cancer. Lancet 1984; 1: 1118. 20 Rutqvist L E , Wallgren A. Long-term survival of 458 young breast cancer patients. Cancer 1985; 55: 658-665. 21 Haybittle J L . The evidence for cure in female breast cancer. In: Bulbrook R D , Taylor D J , eds. Commentaries on
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
research in breast disease. Vol. 3. New York: Alan Liss, 1983: 181-194. Early Breast Cancer Triallists' Collaborative G r o u p . Effects of adjuvant tamoxifen a n d of cytotoxic therapy o n mortality in early breast cancer. A n overview of 61 randomized trials a m o n g 28 896 women. N Engl J Med 1988; 319: 1681-1691. Carter C L , Allen C, Henson D E . Relation of tumor site, lymph node status a n d survival in 24 740 breast cancer cases. Cancer 1989; 6 3 : 181-187. Koscielny S, T u b i a n a M , Le M G , Valleron A J . Breast cancer: relationship between the size of the primary t u m o u r a n d the probability of metastatic dissemination. Br J Cancer 1984; 49: 709-715. Periodic mammographies and the risk of radio-induced cancers. Draft R e p o r t of E E C E S O Advisory G r o u p , 1990. Bailar J C . M a m m o g r a p h y : a contrary view. Ann Intern Med 1976; 84: 77-84. Skrabanek P. False premises a n d false promises of breast cancer screening. Lancet 1985; 2: 316-320. Wright C J . Breast cancer screening: a different look at the evidence. Surgery 1986; 100: 594-597. Roberts M M . Breast screening: time f o r a rethink? Br MedJ 1989; 299: 1153-1155. Isacsson S O , Larsson L G , J a n z o n L. D e b a t t o m m a m m o grafi. Lakartidnmgen 1985; 82: 2672-2673. F a r n d o n J R , Nicholson S. E d i n b u r g h trials of screening of breast cancer. Lancet 1990; 335: 1290-1291. S h a p i r o S, Venet W , Stratx P, Venet L. Periodic screening for breast cancer. The Health Insurance Plan Project and its sequelae 1963-1986. Baltimore: The Johns Hopkins University Press, 1988. Tabar L, Fagerberg CJG, Day NE. The results of periodic one-view mammography screening in a randomised controlled trial in Sweden. Part II. Evaluation of the results. In: Day NE, Miller AB, eds. Screening for breast cancer. Toronto: Hans-Huber, 1988: 39-44. Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two-county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Commun Hlth 1989; 43: 107-114. Aron JL, Prorok PC. An analysis of the mortality effect in a breast cancer screening study. Int J Epidemiol 1986; 15: 36-43. Habbema JDF, van Oortmarssen GJ, van Putten DJ, Lubbe JT, van der Maas J. Age-specific reduction in breast cancer mortality by screening. Analysis of the results of the Health Insurance Plan of Greater New York study. J Nat Cancer Insl 1986; 77: 317-320.
BREAST CANCER: THE DECISION TO SCREEN 37
38
39
40
41
42
43
44
45
46
47
48
49
50
51 52
33
54
35
36
37
Verbeek A L M , Hendriks J H L C , Holland R. M a m m o graphic screening a n d breast cancer mortality: agespecific effects in the Nijmegen project 1975-82. Lancet 1985; 1: 865-866. Palli D , Rosselli del T u r c o M , Buiatti E, eI al. A case-control study of the efficacy of a non-randomised breast cancer screening program in Florence (Italy). Ini J Cancer 1986; 38: 501-504. Palli D , Turco M R , Buitta E, C i a t t o S, Crocetti E, Paci C. Time interval since last screening test in a breast cancer screening p r o g r a m m e . A case-control study in Italy. J Epidemiol Commun Hlth 1989; 43: 241-248. Andersson I, Aspergen K, J a n z o n L, el al. M a m m o g r a p h i c screening a n d mortality from breast c a n c e r the M a l m o m a m m o g r a p h i c screening trial. Br MedJ 1988; 2 0 7 : 9 4 3 948. U K Trial of Early Detection of Breast Cancer G r o u p . First results on mortality reduction in t h e U K trial of early detection o n breast cancer. Lancet 1988; 2: 411-415. Roberts MM, Alexander FE, Anderson TJ, el al. The Edinburgh trial of screening for breast cancer. Lancet 1990; 335: 241-246. T a b a r L, Duffy S. M a l m o m a m m o g r a p h i c screening trial. Br MedJ 1989; 298: 4 8 - 4 9 . Brinkley D , Haybittle JL, Alderson M R . Death certification in cancer of the breast. Br MedJ 1984; 289: 465-467. Baines CJ, McFarlane DV, Miller AB. Sensitivity and specificity of first screen mammography in 15 NBSS centres. J Can Assoc Radio! 1988; 39: 273-276. Barenidsen GW. Effects of radiation on the reproductive capacity and proliferation of cells in relation to carcinogenesis. In: Upton AC, Albert RE, Burns FJ, Shore RE, eds. Radiation carcinogenesis. Amsterdam: Elsevier, 1986: 85-105. Modan B, Chetrit A, Alfaridarg E. Increased risk of breast cancer after low-dose irradiation. Lancet 1989; 1: 629630. Dean C, Roberts MM, French K, Robinson S. Psychiatric morbidity after screening for breast cancer. J Epidemiol Commun Hlth 1986, 40: 71-75. Ellman R, Angeli N, Christians A, Moss S, Chamberlain J, Maguire P. Psychiatric morbidity associated with screening for breast cancer. Br J Cancer 1989; 60: 781-784. Frisell J, Eklund G, Hellstrom L, Glas U, Somell A. The Stockholm breast cancer screening trial - 5-year results and state at discovery. Breast Cancer Res Treat 1989; 13: 79-87. Report. Br MedJ 1989, 299: 877-878. Kirkpatrick AE, Law J. The usefulness of a moving grid in mammography. Br J Radiol 1989; 58: 257-258 Forrest APM. The Welbeck Memorial Lecture 1988. Radiology and breast cancer. Radiol Today 1988; 55: 13-20. Pritchard J. Quality assurance guidelines for mammography. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Aitken RJ, Macdonald HL, Kirkpatnck AE, Anderson TJ, Chetty U, Forrest APM. The outcome of surgery for non-palpable mammographic abnormalities. Br J Surg 1990; 77: 673-676. Azavedo E, Svane G, Ancr G. Stereotactic fine-needle biopsy in 2594 mammographically detected non-palpable lesions. Lancet 1989; I: 1033-1035. Ciatto S. Usefulness of needle aspiration in a screening programme. In: Ziant G , ed. Practical modalities of an efficient screening for breast cancer in the European
51
59
60
61
62
63
64
63
66
67
M
69
70
71
72
73
74
II
Community. International Congress Series 865. Amsterd a m : Excerpta Medica, 1989: 83-94. Peeters P H M , Verbeek A L M , Hendricks J H C L , van Bon M J H . Screening for breast cancer in Nijmegen: report of six screening rounds 1975-86. Ini J Cancer 1989; 4 3 : 2 2 6 230. Siedman H , Gelb SK, Silverberg E, et al. Survival experience in the Breast Cancer Detection Demonstration Project. CA 1987; 37: 258-290. Aitken RJ, Forrest A P M , Chetty U , et al. Assessment of non-palpable m a m m o g r a p h i c abnormalities: c o m p a r i son of a screening clinic and a breast clinic. Submitted for publication. Lundgren B. Screening for breast cancer: a view from the front line. Biomed Pharmacother 1988; 42: 443 446.
The Uppsala-Orebro Breast Cancer Study Group. Sector resection with or without postoperative radiotherapy for stage I breast cancer. A randomized trial. J Nat Cancer Inst 1990; 82: 277-282. Bartelink H. Radiotherapy in the management of early breast cancer: a review. Eur J Clin Oncol 1988; 24: 77-82. van Dongen JA, Fentiman IS, Harris JL In situ breast cancer: the EORTC consensus meeting. Lancet 1989; 2: 25-27. UK Coordinating Committee for CanceT Research. Protocol of the UK randomised trial for the management of screen-detected ductal carcinoma in situ (DCISj of the breast. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1989. Department of Health and Royal College of Pathologists Working Group. Draft guidelines for pathologists. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Department of Health and Royal College of Pathologists Working Group. Pathology reporting in breast cancer screening: draft guidelines. NHS Breast Screening Programme. Oxford: Breast Screening Publications, 1988. Anderson TJ. Breast cancer screening: principles and practicalities for histopathologists. Rec Adv Histopathol 1989; 14:43-61. H o l m b e r g L, A d a m i H O , Persson I, Lundstrom T, T a b a r L. D e m a n d s on surgical in-patient services after mass m a m m o g r a p h i c screening. Br MedJ 1988; 293: 779-782. Peeters P H M , Verbeek A L M , S t r a a t m a n H , et al. Evaluation of overdiagnosis of breast cancer in screening by m a m m o g r a p h y : results of the Nijmegen p r o g r a m m e . Ini J Epidemiol 1989; 18: 295-299. Forrest, Sir Patrick. Breast c a n c e r the decision to screen. F o u r t h H M Queen Elizabeth, the Queen Mother, Fellowship. L o n d o n : Nuffield Provincial Hospitals Trust, 1990.
The New Forrest Committee. Gray M, ed. NETWORK: NHS Breast Screening Project. Oxford: Cancer Research Campaign, 1988, No. 2: 8. Tabar L, Faberberg G, Day NE, Holmberg L. What is the optimal interval between mammographic screening: an analysis based on the latest results of the Swedish twocounty breast cancer screening trial. Br J Cancer 1987; 55: 547-551. Fagerberg G. Optimum interval between mammographic screening examinations for different age groups. In: Ziant G, ed. Practical modalitiesfor efficient screeningfor breast ameer in the European Community. International Congress Series 865. Amsterdam, Excerpta Medica, 1989: 27-34.
12 73
76
77
78
79
80
81
82
83
84
85
86
JOURNAL OF PUBLIC HEALTH MEDICINE Chu KE, Smart CR, Tarone RE. Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial. / Nat Cancer Inst 1988; 80: 1125-1132. G o r d i l l o C . Breast cancer screening guidelines agreed o n b y AMA and other medically related organizations. JAMA 1989; 262: 1155. Mammographic screening for early detection of breast cancer. Report to National Board of Health and Welfare, Stockholm, 1986. Miller AB. The Canadian national trial. In: Day NE, Miller AB, cds. Screening for breast cancer. Toronto: HansHuber, 1988: 51-58. Gravelle HSE, Simpson PR, Chamberlain J. Breast cancer screening and health service costs. J Hlth Econ 1982; 1: 185-207. C l a r k P R , Fraser N M . Economic analysis of screening for breast cancer. Interim report to Scottish Home and Health Department, 1989. van der Mass DJ. The costs and effects of mass screening for breast cancer. Amsterdam: Medical Technology Assessment, 1988. Jonsson E, Hakansson S, Tabar L. Cost of mammography screening for breast cancer after low-dose irradiation. Lancet 1989; 1: 629-630. DeKonig HJ, van Inerald BM. Cost-benefit evaluation of different screening strategies for breast cancer. In: Ziant G, ed. Practical modalities of an efficient screening for breast cancer in the European Community. International Congress Series 865. Amsterdam: Excerpta Medica, 1989: 121-132. Powles T J , H a r d y J R , Ashley S E , et al. A pilot trial t o evaluate the acute toxicity a n d feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126— 131. Love RR. Prospects for antioestrogen chemoprevention of breast cancer. J Nat Cancer Inst 1990; 82: 18-21. Stewart HJ. The Scottish adjuvant tamoxifen trials in early breast cancer. NTH Consensus Development Conf., June 1990.
87
88
89
90
91
92
93
94
95
96
97
Pike M C , Ross R K , L o b o R A , K e y T J A , Potts M , H e n d e r s o n BE. L H R H agonists a n d t h e prevention of breast a n d ovarian cancer. BrJ Cancer 1989; 60:142-148. Anderson TJ, Battersby S. The involvement of oestrogen in the development and function of the normal breast: histological evidence. Proc R Soc Edinb 1989; 95B: 23-32. UK. National Case-Control Study Group. Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1: 973-982. Olsson H , Moller T R , R a n s t a m J. Early oral contraceptive use a n d breast cancer a m o n g premenopausal women: final report from a study in southern Sweden. J Nat Cancer Inst 1989; 81: 1000-1004. Prentice R, T h o m p s o n D , Clifford C, Gor-bach S, Goldin B, Byar D . Dietary fat reduction a n d plasma estradiol concentration in healthy p o s t m e n o p a u s a l women. J Nat Cancer Inst 1990; 82: 129-134. Adami HO, Malber B, Rutquist LE, Persson I, Ries L. Temporal trends in breast cancer survival in Sweden: significant improvement in 20 years. J Nat Cancer Inst 1986; 76: 653-659. Day NE, Chamberlain J. Screening for breast cancer: workshop report. EXIT J Clin Oncol 1988; 24: 55-59. Hendriks JHCL. Discussion. In: Ziant G, ed. Practical modalities for efficient screening for breast cancer in the European Community. International Congress Series 865. Amsterdam: Excerpta Medica, 1989: 27-34. French K, Porter AMD, Robinson SE, McCallum FM, Howie JGR, Roberts MM. Attendance at a breast screening clinic: a problem of administration or attitudes. Br MedJ 1982; 285: 617-620. MacLean U, Sinfield D. Women who decline screening: report to Health Services Research Committee. / Epidemiol Commun Med 1984; 38: 278-283. Roberts MM, French K, Duffy J. Breast cancer and breast self-examination: what do Scottish women know. Soc Sci Med 1984; 18: 791-797.
