Screening for breast cancer

BREAST CANCER

Screening for breast cancer

Breast cancer survival and stage at diagnosis

M Reddy 100

Ros Given-Wilson

UICC stage Stage 1 (84%)

% survival

80

60 Stage 3 (48%)

40

Screening is the identification of individuals within an asymptomatic population who have (or who are likely to develop) specified disease, at a time when intervention may result in the improvement of the prognosis of the disease. Breast cancer is the most common cancer in women in the UK. More than 39,000 women are diagnosed with breast cancer in the UK each year; 80% of these cancers occur in post-menopausal women. The UK NHS Breast Screening Programme (NHSBSP) was launched in 1989 and provides screening for women aged 50 years and over, using X-ray mammography.

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Stage 4 (18%)

1

2

3

4

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Years after diagnosis Source: www.cancerresearchuk.org

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The evidence for breast screening

Bias There are three major sources of bias which must be considered when assessing the effectiveness of screening.

The major risk factors for breast cancer (age, female sex, family history, see pages 8–14) cannot be avoided. Survival is closely related to the stage of diagnosis (Figure 1). Attention is focused on screening methods, which allow early detection, thus bringing forward the time of diagnosis and improving the prognosis of breast cancer. The World Health Organization (WHO) has defined ten principles for screening (Figure 2). The sensitivity of the test should be high (most of the positive cases are detected). The sensitivity of mammography varies due to a number of factors (e.g. breast density, use of hormone replacement therapy, number of views, numbers of readers of films), but the overall sensitivity is 80–90% (50–64 age group). The specificity of the test should be high (a low number of false-positives). The specificity of mammographic screening is up to 95%, but varies due to the same factors that make sensitivity variable.

Lead-time bias is the time difference between when a cancer is detected by screening and the theoretical time it would have taken to present clinically. In some women, the detection of a cancer will not alter prognosis, but will lengthen the time the woman lives with the diagnosis of cancer. In these women, the apparent survival time following diagnosis will be lengthened without influencing the time of death. Length-time bias: some low-grade, slow-growing tumours (invasive and non-invasive) may never have become clinically apparent. Screening detects and treats what may have remained occult disease. Selection bias arises because women who choose to participate in screening are potentially more aware of their health. This may influence management and prognosis. These potential biases in the evaluation of screening trials make it unwise to use prognostic factors (e.g. tumours detected, length of survival following diagnosis) as measures of the effectiveness of screening. The optimum method of evaluating screening is by randomized controlled clinical trials using breast cancer mortality as an endpoint.

M Reddy MBBS MRCP FRCR is a Consultant Radiologist at St George’s Hospital, London, UK. She qualified from St. Bartholomew’s Hospital, London, and completed her training in radiology at Guy’s Hospital, London. She is a general radiologist with subspecialty training in breast radiology. She works within the southwest London NHS breast screening programme and has a special interest in breast MRI.

Reduction in mortality There is unequivocal evidence from eight randomized controlled clinical trials (conducted in five countries since the early 1960s) that population screening with mammography alone can reduce mortality from breast cancer. Meta-analysis of combined data from these trials shows that mammography reduces the mortality from breast cancer by 24% (95% confidence interval (CI) 13–33%;

Ros Given-Wilson MBBS MRCP FRCR is a Consultant Radiologist at St George’s Hospital, London, UK. She trained at Cambridge and St Thomas’ Hospital and established the breast screening unit at St George's Hospital. Her research interests include breast imaging and screening, and computer-aided detection.

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Cumulative mortality rates in women aged 40–74: the Swedish Two Counties Trial

The WHO principles for screening • • • • • • • •

Condition should be an important health risk Natural history should be well understood Recognizable early stage Early treatment should be beneficial Suitable test should be available Test should be acceptable Adequate facilities for diagnosis and treatment Repeat screening is required where disease has insidious onset • Physical and psychological harm should be less than benefit of detection • Costs balanced against benefits

Cumulative breast cancer deaths

250

2

probability (P) < 0.0001) for women aged 50–74 (assuming a 70% rate of uptake) (Figure 3).

study

100

50

1

2 3 4 5 Years since randomization

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Source: Tabar L, Fagerberg C J, Gad A et al. Lancet 1985; 1: 829–32. Reprinted with permisssion from Elsevier.

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ity assurance (see below) is provided by Regional Quality Assurance Reference Centres and organized nationally by the National Screening Office. Information provided for women considering and undergoing screening emphasizes the disadvantages and benefits of screening, allowing women to make an informed choice.

Invitation Women between the ages of 50 and 53 are invited. Thereafter, they are screened at three-yearly intervals until the age of 70, after which they may self-refer for screening. The first screen is the prevalent screen: all subsequent screens are incident screens. The target population is identified from computerized records held by Primary Care Trusts and invited for screening at a static centre or a mobile screening van.

Basic screen The basic screen involves mediolateral-oblique and cranio-caudal views of each breast, which are then read by specialist film readers (at least one of whom is usually a radiologist). If there is no sign of cancer, the patient is informed by letter. When any suspicious abnormality is suspected, the patient is recalled to a multidisciplinary assessment clinic for further evaluation.

Assessment Multidisciplinary assessment clinics are usually held in the basescreening unit. Women recalled from screening are offered triple (clinical, radiological, pathological) assessment. The most common abnormalities seen on a mammogram which lead to recall are:

Organization of screening Screening in the UK is offered by 95 breast screening units. Qual-

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The NHSBSP The Forrest Report was published in 1986 and recommended that a programme of mammographic screening for women aged 50 and over (using three-yearly single-view mammography) should be established in the UK. It also recommended that management should use an integrated multidisciplinary approach, and that there should be nationally agreed standards and quality assurance. The screening programme has been subject to continuous and rigorous evaluation since its inception. It is still evolving: as new evidence emerges, changes are implemented which improve performance. Major changes since the inception of the NHSBSP have included extension of the age of women invited from 50–64 to 50–70. The number of views taken has increased from a single view of each breast to double-views at all rounds of screening. Double-reading of a mammogram by two independent readers increases the sensitivity for cancer detection by 10–15%. Most screening units in the UK use double-reading (although it is not a national policy). The frequency of screening has been evaluated recently by a clinical trial comparing annual with three-yearly screening. Although the size of the tumours in the ‘annual’ group was smaller, there was no significant difference in stage between cancers detected with annual screening and those with three-yearly screening. Shortening the screening interval may not be cost-effective on a population basis. Screening for women aged < 50 years is under evaluation. The reduction in mortality for women invited for screening aged 40–49 years is about 11% (95% CI 8–32%; P = 0.2). However, the overall incidence of cancer is lower in this group, and cancers have a shorter sojourn time (i.e. cancers arise at a shorter interval than in other age groups) and require more frequent screening (ideally annually). Initial results from an age trial currently underway in the UK suggest that, although some mortality benefit is observed, population screening in this group may not be cost-effective. Screening protocols are shown in Figure 5.

control

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Age-standardized mortality rates (all ages) for female breast cancer, England and Wales, 1950–2000 45

Rate per 100,000 women

40 35 30 25

30% reduction in mortality in last 10 years, 6% attributable to NHSBSP

20 15 10 5 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Year of death

Source: Office for National Statistics. Cancer Trends in England and Wales 1950–1999. (www.statistics.gov.uk/statbase/Product.sp?vInk=4822).

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• masses/asymmetries • areas of distortion • clustered microcalcifications. Recall is initiated only for suspicious lesions, rather than clearly benign diseases (e.g. cysts, fibroadenomas, benign calcifications). Women who are invited for assessment will have access to a breast care nurse before and during the assessment clinic. They will undergo clinical examination and appropriate further imaging (e.g. ultrasound, specialized magnification mammographic views). Any persisting, suspicious or indeterminate lesion is biopsied (usually core biopsy under ultrasound or stereotactic guidance). Each stage of the triple assessment is graded according to the level of suspicion. When there is a discrete lesion and needle biopsy has been undertaken, management is usually decided at a multidisciplinary meeting. The usual outcomes of assessment are: • discharge of patients if findings are normal or benign • referral for definitive treatment if malignancy is proven (Figure 6).

In a small proportion of cases, the results of triple assessment will be: • uncertain but suspicious, and diagnostic surgical excision is required • uncertain but probably benign, and short-term follow-up (6–12 months) may be started (< 0.25% of screened women). Up to 70% of lesions detected by screening requiring surgery are impalpable and localization is needed. This may use skin marking or placement of a hook wire percutaneously, using ultrasound or stereotactic guidance. The screening process is shown in Figure 7.

Quality assurance Each step of the screening process is bound by rigorous quality assurance guidelines, including performance targets (Figure 8). This should include the main quality assurance targets and national results. All breast-screening units are required to regularly submit performance data to regional Quality Assurance Reference Centres. All units are subject to three-yearly, multidisciplinary quality assurance visits, which audit all aspects of the performance of the unit.

The screening policy of the NHSBSP Age

50–70 years: by invitation

Problems with breast screening

70+ years: by request only

Screening for cancer can induce high levels of anxiety, particularly in women who are recalled for assessment. Anxiety is minimized by: • ensuring prompt processing of screening films • expediting assessment appointments • providing adequate information and support at all points of the screening process.

Views

Two views at all screens

Frequency

Three-yearly

Protocol

Integrated multidisciplinary approach Nationally agreed standards, protocols and quality review

False-positive screens These result in recall to assessment; 70–90% of women recalled

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a

Irregular spiculate malignancy (arrows) in the a upper and b inner aspect of the left breast.

b

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Breast screening process Women aged 50–70 years identified via general practitioner

Women aged over 70 years

INVITATION

REQUEST FOR SCREENING

MAMMOGRAPHIC SCREEN NORMAL 90 97%

RECALL 3 10%

NORMAL Majority SCREENING CYCLE 3 yearly

ASSESSMENT Multidisciplinary Triple approach Clinical

Radiological Pathological

SURGICAL REFERRAL <1% Positive predictive value 70–90%

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cases, when the prior screening mammograms are reviewed, an abnormality will be seen at the site where the cancer subsequently develops (i.e. which has been missed). These are false-negative cases. For every 1000 negative screens, 2.4 women are likely to present with interval cancer in the next three years. It has been routine practice in screening programmes in the UK to review the prior films of women presenting with interval cancer. Women who develop significant breast symptoms following a negative screen may be falsely reassured. Patient information offered at the time of screening emphasizes the need to continue to be ‘breast aware’ and not to ignore breast symptoms.

will be normal or have benign disease. Some women will undergo needle biopsy or even diagnostic surgery for benign disease. However, the accuracy of needle biopsy is improving, hence this figure is steadily decreasing. The number of women referred for surgery after screening for malignant disease exceeds those with benign disease by a ratio of 6 to 1. False-negative screens False-negative screens are inevitable in any population screening programme because mammography cannot be 100% sensitive. Interval cancers are cancers diagnosed following a negative screen and before the next scheduled screening. In about 20% of these

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Quality assurance targets of the NHSBSP Objective

Criteria

Standard

1 Maximize the number of eligible women attending for screening

Percentage of eligible women who attend for screening

80% < 2.5 mGy

2 Limit radiation dose a invasive cancers

P ≥ 3.6/1000 I ≥ 4.2/1000

b in situ cancers

P ≥ 0.4–0.9/1000 I ≥ 0.5–1.0/1000

c SDR

≥ 1.0

4 Minimize the number of women screened who are recalled for further tests

Recall rates from screening

P < 7% I < 5%

5 Ensure majority of cancers are diagnosed without surgery

Percentage of women with non-operative diagnosis of cancer by cytology or core biospy

≥ 90%

6 Minimize interval cancers

Rate of cancers presenting: a in 2 years after negative screen b in the 3rd year after negative screen

3 Maximize the number of cancers detected

7 Minimize delay for treatment of cancer detected by screening

Percentage of women admitted for treatment within 2 months of assessment following positive screen

1.2/1000 screened 1.4/1000 screened 100%

P: Prevalent screen; I: Incident screen; SDR: Standardized detection ratio; mGy: milliGray (unit of absorbed radiation).

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Radiation exposure X-ray mammography uses ionizing radiation and the mean absorbed dose to an averaged-sized breast is 1–2.5 milliGray (mGy) per single view. Ionizing radiation can induce malignancy. For women of screening age, the risk of inducing a cancer is 1 per 100,000 examinations, compared with a lifetime risk of cancer of 1 in 9. The benefit of early detection and treatment outweighs the risks in this age group.

The advantages of such imaging include the production of instantaneous images without the need for processing, manipulation of images electronically to change contrast or magnify an area, which can be of great help in assessing difficult cases such as those with dense breast tissue (often seen in younger women), and avoiding problems with storage. Digital images have potential to be analysed with computeraided detection (CAD). Using CAD, pre-set algorithms detect suspicious areas on the mammographic image and place prompts over areas that warrant review by a film reader (Figure 10).

Other imaging modalities Several other imaging methods are used in conjunction with mammography for diagnosis. No other technique has been as extensively investigated or been proven to be as useful a screening tool as mammography. Modalities include high-frequency gray scale ultrasound with Doppler facilities and ultrasound contrast medium, and contrastenhanced Magnetic Resonance Imaging (MRI) (Figure 9).

Screening high-risk groups Some women have a significantly increased risk of breast cancer compared with the general population (see pages 8–14), and may require closer monitoring and specialized screening protocols. MRI appears to be the most sensitive technique for detecting breast cancer in young, high-risk women. Family history About 5% of breast cancer has a significant genetic component. The two most investigated genetic mutations are BRCA-1 and BRCA-2. They are highly dominant gene mutations, which convey a high risk (80% at age 70) of carriers developing breast cancer. Women who are at a significantly (two or three times) increased risk of breast cancer may be offered screening before the age of 50 years via symptomatic family history clinics. A number of other high-risk groups exist; women treated below the age of 30 (particularly in childhood) with mantle radiotherapy

Digital mammography Digital mammography is a new technique which is increasingly gaining acceptance in symptomatic breast work and is likely to eventually replace the conventional film/screen process. Its use in screening is currently under evaluation. In conventional mammography the image is produced by exposing the compressed breast to x-rays, which pass through the tissue, exposing a film plate. In digital mammography, the x-rays emerging from the breast are recorded by an electronic digital detector instead of film. This image can be displayed on a high resolution computer screen or printed onto film.

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a Axial T1-weighted MRI scan showing a low signal intensity region (arrow) in the right breast.

b Axial T1-weighted scan post-contrast showing intense uptake in an irregular mass in the rigth breast (arrow), suggesting carcinoma.

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controlled clinical trials from population screening in the UK. In the period from 1991 to 2001, despite a rising incidence of breast cancer, mortality for breast cancer in the UK fell by 30%. Of this, 6% is thought to be attributable to the first effects of screening for breast cancer, which did not cover the entire population of the UK until 1995 (Figure 4).

The future It is estimated that the major portion of the 25% reduction in mortality achievable with screening in women aged > 50 years will come in the next decade. This will be in addition to the reduction in mortality already achieved from a combination of factors: better awareness; early detection; multidisciplinary management and routine use of systemic chemotherapy and adjuvant treatments. 

10 Cranio-caudal digital images with a computer-aided detection prompt (asterisk) over a suspicious mass in the outer aspect of the right breast.

for Hodgkin’s lymphoma are at increased risk of subsequent breast cancer. Such groups are now offered screening.

Results of screening The NHSBSP screens 1.5 million women annually and is in the process of expanding to invite women up to the age of 70 (Figure 5); 6.6. cancers are detected per 1000 women screened nationally, with a recall rate of about 6%. The uptake of screening invitations is currently 75%. The standardized detection ratio (SDR, cancer detection rate adjusted for age and incidence of breast cancer) allows direct comparison of numbers of cancers detected with the outcome of the Swedish Two Counties Trial (which was used as a benchmark while developing the UK programme). An SDR of 1 indicates equivalent performance to the Two Counties Trial. The UK SDR is 1.3, showing that 30% more cancers are being detected by the UK programme than in the Swedish study. This allows prediction of a reduction in mortality, similar to that found in randomized

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