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Review

Breast cancer screening and management

A Patrick M Forrest and Elaine D C Anderson

MJA 1999; 171: 479-484

Synopsis - Introduction - Why screen for breast cancer? - Evidence for screening - Screening programs - Breast self-examination - Familial breast cancer - Management of screen-detected breast cancer - The future -- specialised, multidisciplinary services - Acknowledgements - References - Authors' details
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Synopsis
  • Mammographic screening to detect preclinical cancer was introduced when it was realised that once breast cancer became symptomatic it could not be cured regularly by local surgery, as early systemic dissemination had almost invariably occurred.
  • Meta-analysis of randomised controlled trials of screened versus unscreened women has demonstrated a mortality benefit approaching 30% in screened women (> 50 years of age) seven to nine years from the start of the trials.
  • The UK and Australian breast screening programs are compared. Differences in the design are largely a result of differences in the healthcare systems in the two countries.
  • Breast self-examination, although still recommended by many Australian practitioners, is not an appropriate screening method, as it does not affect breast cancer death rates.
  • About 5% of women have familial breast cancer (associated with mutations of BRCA1 or BRCA2). Women at high risk are screened at an earlier age and at more frequent intervals.
  • Current best practice management of screen-detected breast cancer, including surgery, radiotherapy, assessment of the axilla, and systemic therapy, is summarised.
  • Women with symptomatic breast disease ideally should be treated by a specialised multidisciplinary service, which can provide sophisticated diagnosis and treatment as well as supportive care.

Introduction In 1987, the UK government initiated screening for breast cancer by a single medial-lateral oblique view of each breast every three years for all women aged 50-64 years.1 The breast screening program in Australia -- BreastScreen -- began in 1991 and provides two-view mammographic screening at two-year intervals, mainly for women aged 50-69 years.2


Why screen for breast cancer?
Screening was introduced when long term follow-up studies showed that most women with symptomatic breast cancer could not be cured by local surgery.3,4 Breast cancer was not a slowly progressive, locoregional disease; early systemic dissemination with the formation of distant micrometastases was the rule. Proof of this has now come from unequivocal evidence that systemic treatment, either by anti-oestrogens or chemotherapy, significantly prolongs survival in women with symptomatic disease.5-7

Mammographic screening can detect cancer of the breast in its preclinical phase (ie, before it is palpable). The success of screening depends in part on the size of the tumour and whether the cancer has spread to the axillary lymph nodes, but the tumour's biological aggressiveness also needs to be taken into account. The excision of small tumours which are markedly undifferentiated may save lives in the short term, but it is the detection of small tumours while still of favourable grade which is likely to confer the greatest long term benefit.


Evidence for screening
Evidence that mammographic screening reduces mortality comes from randomised trials comparing mortality from breast cancer of women invited to be screened with women without any intervention. Recent meta-analyses have demonstrated a mortality benefit approaching 30% in women over 50 years of age seven to nine years from the start of the trials.8,9 In the 70% of women who accepted the invitation, mortality reduction is obviously larger.

The 14-year follow-up of one of these six randomised trials,10 initiated in Edinburgh in 1978 and including over 22 000 women, indicated a reduction in breast cancer deaths of 21% (relative risk [RR], 0.79; 95% CI, 0.60-1.02), which bordered on significance. As patients diagnosed with breast cancer after the conclusion of the trial (when both study and control groups were eligible for screening) could not have influenced the mortality rate, a further analysis was performed with patients censored 10 years after entry. The 29% mortality reduction was significant (RR, 0.71; 95% CI, 0.53-0.95), and this mortality advantage was no less in women 45-50 years of age than in older women.10


Screening programs
In the NHS Breast Screening Programme in the United Kingdom, the need for quality at every stage of the screening process has been emphasised, and national coordinators and regional advisory committees publish annual reports which include regularly revised targets against which performance can be measured (Boxes 1 and 2).11

Australia's program, BreastScreen, which began in 1991, has a different design and less standardisation than in the UK program, largely because Australian general practitioners and surgeons work as independent providers. Women aged 50-69 years are eligible for two-yearly screening, but younger women, 40-50 years, and those over 70 years are screened on request. Women in the target group are invited to take part by direct mailouts based on the electoral roll, and 1996-1997 compliance rates were 52.2%.2 Two-view mammography is used, and double reading of mammograms is mandatory. However, the experience of radiologists reading mammograms, the protocols for assessment of screen-detected lesions, and arrangements for surgical biopsies and their pathological interpretation vary greatly between clinics and between States and Territories. National evaluation is only now under way.


Breast self-examination
Breast self-examination (BSE) can detect symptomatic breast cancer at an earlier stage, but it does not appear to influence mortality. A recent American Cancer Society study compared 177 602 women who practised BSE during the preceding 13 years with 272 554 women who did not, and found similar breast cancer death rates in the two groups.12 The UK Trial of Early Detection of Breast Cancer (TEDBC)13 involved 300 000 women in eight health districts, two with mammographic screening centres, two where BSE was taught by trained nurses, and four where neither form of intervention was available. At 16 years the relative risk of death from breast cancer in women attending the two screening clinics was reduced by 27% (RR, 0.73; 95% CI, 0.63-0.84), but there was no risk reduction in the two BSE centres (RR, 0.99; 95% CI, 0.87-1.12).

Three randomised trials to evaluate the effect of BSE on breast cancer mortality are under way in St Petersburg and Moscow,14 and Shanghai.15 Preliminary results of the Shanghai study, which included over 250 000 women, found a similar incidence and an identical number of breast cancer deaths among BSE subjects and controls.15 BSE has greatly increased biopsy rates, with the number of benign lesions detected in the BSE group being twice those of the controls.15 These findings indicate that women should be aware of their breasts as part of general body awareness and seek medical help when their breasts look or feel abnormal, but the promotion of regular BSE is not justified.


Familial breast cancer
Some 20% of women with breast cancer report a "family history", but only about 5% are truly familial cancers, with the proportion being greater in women under 45 years at diagnosis (Box 3).


Management of screen-detected breast cancer
A recent audit of 500 screen-detected invasive cancers treated in Scottish hospitals found that 75% were under 1 cm in size and 70% node negative.30 Mastectomy is not necessarily the best treatment for such cancers; some surgeons believe that local excision alone is appropriate. However, the results of five randomised trials show a high local relapse rate if radiotherapy is not also given (Box 4).31-35 After nine years of follow-up in the US National Surgical Adjuvant Breast Project B-06 (NSABP B-06) trial, the relapse rate reached 43%.36 As these trials included tumours of 2.5-4 cm in size, the need for radiotherapy in small (< 1 cm) tumours of low grade and special histological type is unknown.

Some surgeons believe that if tamoxifen is given after local excision radiotherapy can be avoided. The Scottish Conservation Trial, in which all 585 patients were prescribed adjuvant systemic therapy (tamoxifen or CMF [cyclophosphamide-methotrexate-5-fluorouracil]) appropriate to the oestrogen-receptor status of the tumour, indicated that this was not so.35 After six years of follow-up, locoregional relapse rates in the non-irradiated group were 24.5%, compared with 5.8% in those irradiated. This does not mean that no patients can safely be treated by local excision alone, but that more precise methods of selection are required before this can be recommended.

A number of factors affect relapse rates after local excision and radiotherapy. These include tumour size, the extent of an in-situ component and histological grade. However, the need for complete excision with "clear margins" overrides other considerations, and it is essential that surgeons ensure accurate margin assessment. Biopsy of the excision cavity (cavity shavings) is reported to increase the accuracy of margin assessment.37

The axilla Some surgeons still perform complete dissection of the axilla for all invasive breast cancers; others advise routine radical radiotherapy. Neither approach is logical; an uninvolved axilla needs no treatment. Trials in Edinburgh have shown that sampling fewer axillary nodes (four nodes) provides adequate information on axillary node status, but, as this requires exposure of the axilla under general anaesthesia, it is appropriate only if radiotherapy is the preferred treatment for the involved axilla.38-40

For staging the axilla, sentinel node biopsy is under intensive study. The sentinel node or nodes, the first node to which lymph drains from the tumour, can be marked by injecting blue dye or a radioactive marker around the breast tumour.41,42 With the former, visualisation of the axillary contents is necessary, but a radioactive marker allows precise identification of the sentinel node in the operating room with a hand-held gamma probe. The node can be removed with minimal disturbance to other tissues. Some surgeons advocate immediate examination by frozen section, and, if the sentinel node is shown to be involved, a full axillary dissection can proceed. However, frozen section examination is less accurate for node assessment,43 and histopathological examination of the suspected node is preferred practice. If the node can be identified by radionuclear scanning, it can be removed under local anaesthesia before final treatment is planned. Cytokeratin immunostaining improves the accuracy of detection of metastases, but is not appropriate for peroperative assessment.

Many surgeons are already practising sentinel node biopsy, but, as recently stressed, the definition of a best method and its evaluation under controlled conditions is required before sentinel node biopsy can be regarded as an acceptable alternative to axillary sampling or clearance.44,45

Systemic therapy
Despite evidence that ovarian ablation, tamoxifen and chemotherapy appropriate to the oestrogen-receptor status of the tumour increases this benefit, most surgeons do not advise adjuvant systemic therapy in small node-negative tumours.5-7 Yet, a small proportion of these are still aggressive and cause rapid death. There is a need for tumour markers which can predict likely outcomes for these small tumours; in the meantime, histological grade (as used in the Nottingham Prognostic Index), oestrogen-receptor status and possibly expression of C-erb B2 (HER-2) are the only markers routinely available.46

The Nottingham Prognostic Index,47 which combines the size and histological grade of the tumour with the status of the axillary lymph nodes, has been validated in several studies as a reliable prognostic indicator in symptomatic breast cancer.48 This Index has also been applied to predict mortality differences in the UK randomised trial of frequency of screening,49 but in a recent study of its application to the Edinburgh randomised trial of screening we have found that the inclusion of more detailed discrimination of size and also of histological type improves prediction in screen-detected cancers (Dr T J Anderson, Pathologist, Department of Pathology, University of Edinburgh, personal communication).

Ductal carcinoma in situ (DCIS)
Mammographic screening detects an increased number of cases of DCIS,11 but the natural history of the disease is not well understood. In an extensive review of 11 760 excisional breast biopsies performed for accepted benign conditions, 28 DCIS were identified for which a 24-year follow-up was available.50 Invasive breast cancer developed in nine of the 28 patients (32%). However, all were of favourable (non-comedo) type and had been excised, although the completeness of the excision was unknown. These figures may underestimate the true risk in those with more aggressive comedo-type of disease, but it is clear that there is a need for effective treatment.

Some surgeons still advocate mastectomy as the only means of guaranteeing cure, but this can no longer be regarded as best practice for other than extensive disease. In Europe, local excision with radical radiotherapy is the preferred option. Features influencing relapse include size, architecture, the presence or absence of necrosis, and cytological nuclear grade.51 However, the factor of overriding importance is the completeness of surgical excision as indicated by free margins.52 Management options have recently been reviewed,53 and three randomised trials are in progress.

The results of two trials (NSABP B-17 and B-24, and EORTC 10853) have been reported, the EORTC trial in abstract only.54,55 In B-17 local excision alone (403 patients) and local excision plus radiotherapy (411 patients) are compared. At a median follow-up time of eight years, local relapse was reported in 104 (25.8%) of the non-irradiated group (53 invasive) versus 47 (11.4%) of the irradiated patients (17 invasive). The EORTC trial, which included 1011 patients, had a similar design. At a median follow-up time of 51 months, the cumulative incidence of ipsilateral local recurrence was reduced in the radiotherapy arm (9% v 16%), this including both non-invasive and invasive cancers.56 Only limited information on the completeness of excision is available.57 In the B-24 trial, of 1804 women with DCIS treated by local excision and radiation, half were randomly allocated to receive tamoxifen 20 mg daily for 5 years and half to receive placebo. At a median follow-up of 74 months in women treated by tamoxifen, the cumulative incidence of recurrent breast cancer in either breast was 8.0%, compared with 12.7% in the placebo group; 3.9% and 6.5%, respectively, were invasive.55

It is essential that, as with small invasive tumours, eligible patients with DCIS are entered into randomised trials so that best management can be determined on scientific grounds. A recent survey of practice by 110 surgeons in the south of England showed that, although all four options of local excision, radiotherapy and tamoxifen were being used electively, only 27% of patients were included in the UK trial which compares them, a lamentable disregard of the need for evidence-based practice.58


The future -- specialised, multidisciplinary services
Mammographic screening has increased the complexity of breast cancer management. Women with breast cancer must be aware of these complexities, understand the reliability of diagnostic methods, the safety of breast conservation, reasons for not advising systemic therapy and policies of after-care and support. Only then can they participate in decision making. Their questions can no longer be answered with authority by an individual surgeon, but require multidisciplinary input by radiologists, clinical and medical oncologists and pathologists supported by a breast-care nurse or counsellor.

The experience of multidisciplinary assessment within the screening service led to the development of a specialised service in Edinburgh for women with symptomatic breast disease. Initially sited in a small hospital equipped with mammographic and operative facilities, this unit has now been transferred to the large Regional Cancer Centre as the Edinburgh Breast Unit, which, although still having independent diagnostic and inpatient facilities, has ready access to sophisticated diagnostic and treatment methods, including computed tomography and magetic resonance imaging, radiotherapy, chemotherapy and all aspects of supportive care. In the UK, women are coming to expect comprehensive care by breast specialists. In Australia, with its emphasis on provision of healthcare by individual practitioners, as well as problems of distance between the major population centres, such a similar pattern may be more difficult to achieve but is likely to be demanded.


Acknowledgements
We are grateful to Ms Gil Morton for providing facilities in Melbourne for the initial preparation of this paper; to Mrs Ruby Wood for assistance, and to Professor James Garden and the Hunter Research Fund for support.

References
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Authors' details
Department of Clinical and Surgical Sciences, University of Edinburgh, and Edinburgh Breast Unit, Western General Hospital, University of Edinburgh, Edinburgh, Scotland.
A Patrick M Forrest, Kt, MD, FRCS, FRACS(Hon), Professor Emeritus.
Elaine D C Anderson, MD, FRSCEd, Consultant Surgeon and Honorary Senior Lecturer.

Reprints will not be available from the authors.
Correspondence: Sir Patrick Forrest, 19 St Thomas Road, Edinburgh, EH9 2LR, Scotland, UK.
patrick.forrestATed.ac.uk

©MJA 1999
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1: NHS Breast Screening Programme 11
Program instituted
1987
Age of women screened
50-64 years (younger age under trial)
Method of invitation
By personal letter
Compliance rates
Strictly monitored (1995-96, 75.8%)
Frequency of scanning
Every three years (optimum frequency under trial)
Reading of mammograms
By experienced radiologists only (read minimum of 5000 mammograms per year). Double reading variable
Quality assurance/evaluation
For each specialty, regional and national quality assurance groups (including one for monitoring and evaluation) were set up. National coordinators and advisory committees publish annual reports. Strict auditing of clinical and pathological characteristics (size, node status, grade) of screen-detected cancers (Box 2)
Data collection
National Screening Evaluation Unit maintains a database for the whole UK program
Research organisation
National Breast Screening Reseach Committee of the UK Committee for Co-ordination of Cancer Research
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2: Consistency of screening activity in women over 50 years in the UK NHS Screening Programme

Variable1995-961994-95
Women invited1 517 0331 507 605
Acceptance rate75.876.7
Total screened1 222 3891 207 316
Recalled for assessment62 682 (5.1%)63 925 (5.3%)
Breast biopsy6496 (5.3/1000)6334 (5.2/1000)
Benign biopsy2472 (2.0/1000)2000 (1.6/1000)
Cancers detected6664 (5.4/1000) 6500 (5.4/1000)
In situ (% of cancers)19.9%20.0%
Invasive < 15 mm (% of cancers)42.1% 40.9%
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3: Woman with a family history of breast cancer 16-20

Genetic mutations: True familial breast cancer may be associated with mutations of

  • BRCA1, causing breast and ovarian cancers and (in men) an increased incidence of cancer of the prostate;
  • BRCA2, predominantly associated with cancer of the breast but also with other epithelial tumours; or
  • p53, causing the rare Li-Fraumeni syndrome.

    Determining risk: Pedigree analysis is the important first step. In women with more than four family members with a dominant history of breast and ovarian cancer, a mutation of BRCA1 is associated with an 87% risk of either disease. In those with fewer affected family members, penetrance of a mutated gene may be lower, and the risk of breast or ovarian cancer is in the region of 20%-30%. Although breast cancer is more likely to be familial in young women, only a minority have mutations of either gene. In a study of 73 women with breast cancer diagnosed before age 32 years, common mutations of BRCA1 and BRCA2 were detected in only 12% and 2%, respectively. 21

    Genetic clinics: In the United Kingdom, as in Australia, genetic clinics have been established. In the UK, criteria for referral are based on national guidelines. 22 Australian guidelines for genetic clinics, published by the National Breast Cancer Centre, are exemplary and should be stringently followed. 23 The genetic service of the screening clinic in Edinburgh offers screening to women whose risk is three times that of the age-specific population risk (a lifetime risk greater than 24%). Screening starts at age 35 years or five years younger than the first index case and includes an annual physical examination and biennial mammographic examination to the age of 40 years; then annual mammography to the age of 50. In families at very high risk, the screening interval is reduced to 18 months in women over 50 years. Genetic testing of blood is currently used only for research. In those with a dominant family history, germline mutations of BRCA1 and BRCA2 are sought from the index case.

    Prophylactic mastectomy: In a large Mayo Clinic series of 639 women with a family history of breast cancer (214 high risk and 425 moderate risk), prophylactic mastectomy was associated with a reduction in the incidence of breast cancer of at least 90%. 24 Modelling of life-years gained suggests that benefit from prophylactic mastectomy depends on age and penetrance of the gene, and women must be made aware of the likely benefits, risks and costs, while recognising that regular mammographic screening is a viable alternative to mastectomy. 25 The uncritical use of genetic testing has inherent hazards, such as loss of insurance or employment, psychological distress, risk of prophylactic surgery and disruption of family relationships.

    Chemoprevention: In the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial, 13 388 women considered to be at increased risk of breast cancer were randomly allocated to receive tamoxifen or placebo. Over a mean follow-up period of four years, 89 women who received tamoxifen developed invasive cancer compared with 175 cases in the placebo group, a reduction of 49%. 26 Tamoxifen increased the risk of endometrial cancer, pulmonary embolism and deep vein thrombosis. Unfortunately, the NSABP trial was stopped and women in the control group were given tamoxifen before mortality data were available, but two other trials in Milan and London (which to date have shown no reduction in risk) will provide this. 27,28 A large international trial (IBIS) is under way. Raloxifene (a selective oestrogen-receptor modulator), recently reported to decrease the risk of newly diagnosed breast cancer in postmenopausal women with no prior history of breast cancer, 29 may also be suitable for chemoprevention in patients at high risk of breast cancer.
    • Back to text

    4: Trials of conservative therapy for early breast cancer

    TrialNumber of patientsFollow-up (years)Tumour size (cm)Margins
    NSABP B-06* 3118435 4.0Clear
    Toronto 328377.6< 4.0Clear
    Milan 335673.25< 2.5Wide
    Orebro Uppsala 343815 2.0Clear
    Scottish 355856 4.01 cm

    Relapse in ipsilateral breast
    TrialNode positiveSystemic therapyRadiotherapyNo radiotherapy
    NSABP B-06* 3135.4%Node positive7.7%27.9%
    Toronto 32NoneNone11.3% 35.2%
    Milan 3330.5%Node positive0.3%10.2%
    Orebro-Uppsala 34NoneNone2.3%18.4%
    Scottish 3522.9%All5.8%24.5%
    *National Surgical Adjuvant Breast Project (B-06).
    Back to text