- Email: [email protected]
Screening for breast cancer
BREAST
Assessment of therapeutic responses: UICC criteria
Screening for breast cancer
Response category Complete response Partial response
M Reddy
Stable disease Progressive disease
Definition Complete disappearance of lesion >50% reduction of bi-dimensional product ≤25% increase or ≤50% decrease of bi-dimensional product >25% increase of bi-dimensional product or appearance of a new lesion
Ros Given-Wilson
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.
5
Serial assessment by blood tumour markers (e.g. CA15.3, carcinoembryonic antigen) is objective, reproducible and costeffective. Biochemical assessment correlates or predates UICC assessment in monitoring systemic therapy. Palliative care: although systemic therapy can prolong survival in suitable patients, at some stage of the disease it will be inappropriate to pursue further systemic therapy. This may be for a variety of reasons, such as: • resistance to a previously effective therapy • intolerance to an ongoing therapy • deterioration in condition where further therapy is considered inappropriate • the patient choosing to discontinue active anti-cancer treatments. Palliative care can be applied throughout all stages of metastatic breast cancer. It aims to lessen the symptoms caused by metastatic disease (and sometimes by the treatment). Physical and non-physical needs must be addressed. These include: • pain control (by the stepwise use of various analgesics, nerve block, radiotherapy, etc.) • drainage of fluids such as pleural and pericardial effusions and ascites (including pleurodesis) • the use of corticosteroids and radiotherapy for brain metastases. Bone is usually the first site of metastases in breast cancer. These patients often have oestrogen receptor-positive tumours and tend to respond to endocrine therapy, resulting in prolonged survival; the five-year survival for bone-specific metastases is about 20%. Palliative measures are therefore particularly important. Problems arising from bone metastases are pain, hypercalcaemia and skeletal complications (e.g. fractures, compression of the spinal cord). Increasing use of bisphosphonates (zoledronic acid given i.v. every 3–4 weeks is effective) has significantly reduced these problems. Orthopaedic intervention, including prophylactic surgery to prevent fracture in weight-bearing areas, should be considered. Other needs of the patient are psychological (e.g. depression, fear, anger, see ‘Psychological care of the surgical patient’, page i), social (e.g. domiciliary and financial circumstances) and spiritual; these can be tackled by involving the appropriate disciplines.
The evidence for breast screening The major risk factors for breast cancer (age, female sex, family history) 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.
Breast cancer survival and stage at diagnosis
100
UICC stage Stage 1 (84%)
% survival
80
Stage 2 (71%)
60 Stage 3 (48%)
40
20
Stage 4 (18%)
0 1
2
3
4
5
Years after diagnosis Source: www.cancerresearchuk.org
1
M Reddy y is a Consultant Radiologist at St George’s Hospital, London, UK. Ros Given-Wilson is a Consultant Radiologist at St George’s Hospital, London, UK.
SURGERY
155
© 2004 The Medicine Publishing Company Ltd
BREAST
Cumulative mortality rates in women aged 40–74: the Swedish Two Counties Trial
The WHO principles of breast 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
The 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.
control
200
150
study
100
50
0 1
2 3 4 5 Years since randomization
6
7
Source: Tabar L, Fagerberg C J, Gad A et al. Lancett 1985; 1: 829–32. Reprinted with permisssion from Elsevier.
3
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.
Bias: there are three major sources of bias which must be considered when assessing the effectiveness of screening. 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
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: Blanks R G, Moss S M, McGahan C E et al. BMJJ 2000; 321: 665–9. Reprinted with permission from the BMJ Publishing Group.
4
SURGERY
156
© 2004 The Medicine Publishing Company Ltd
BREAST
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 ‘gold standard’ method of evaluating screening is by randomized controlled clinical trials using breast cancer mortality as an endpoint.
The screening policy of the NHSBSP Age Views Frequency Protocol
Reduction in mortality (Figures 3 and 4): 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%; probability (P) <0.0001) for women aged 50–74 (assuming a 70% rate of uptake).
5
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 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.
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 to 64 to 50 to 70. The number of views taken has increased from single-view 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 15% (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 under way 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.
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: • masses/asymmetries • areas of distortion • clustered microcalcifications. Recall is initiated only for suspicious lesions, rather than clearly benign disease (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
Organization of screening Screening in the UK is offered by 95 breast screening units. Quality 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.
SURGERY
50–70 years: by invitation 70+ years: by request only Two views at all screens Three-yearly Integrated multidisciplinary approach Nationally agreed standards, protocols and quality review
157
© 2004 The Medicine Publishing Company Ltd
BREAST
a
Irregular spiculate malignancy (arrows) in the a upper and b inner aspect of the left breast.
b
6
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%
ASSESSMENT Multidisciplinary Triple approach Clinical NORMAL Majority SCREENING CYCLE 3 yearly
Radiological Pathological
SURGICAL REFERRAL <1% Positive predicted value 78%
7
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 visits which audit all aspects of the performance of the unit. Problems with breast screening 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.
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
SURGERY
158
© 2004 The Medicine Publishing Company Ltd
BREAST
False-positive screens result in recall to assessment; 70–90% of women recalled 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 exceed those with benign disease by a ratio of 6 to 1.
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. Radiation exposure: X-ray mammography uses ionizing radiation and the mean absorbed dose to an average-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 to a lifetime risk of cancer of 1 in 9. The benefit of early detection and treatment outweighs the risks in this age group.
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 cases, when the prior screening mammograms are received, an abnormality will be seen at the site where the final cancer develops (i.e. which has been missed). These are called 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. In the next two years, the Department of Health plan to introduce a national policy of ‘disclosure of audit’, whereby women who are diagnosed with an interval cancer will be offered the results of this review.
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 contrast-enhanced MRI (Figure 9). Digital mammography allows the image to be displayed on a high-resolution computer screen. One advantage of a digital image is that computer-aided detection can be applied to assist analysis.
Quality assurance targets of the NHSBSP Objective 1 Maximize the number of eligible women attending for screening
Criteria Percentage of eligible women who attend for screening
Standard 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 biopsy
≥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).
8
SURGERY
159
© 2004 The Medicine Publishing Company Ltd
BREAST
b Axial T1-weighted scan post-contrast showing intense uptake in an irregular mass in the right breast (arrow), suggesting carcinoma.
a Axial T1-weighted MRI scan showing a low signal intensity region (arrow) in the right breast.
9
In computer-aided detection, preset algorithms detect suspicious areas on the mammographic image and place prompts over areas that warrant review by a film reader (FIgure 10).
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 controlled clinical trials from population screening in the UK. In the period 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.
Screening high-risk groups Some women have a significantly increased risk of breast cancer compared to the general population, and may require closer monitoring and specialized screening protocols. 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 are at increased risk of subsequent breast cancer. Such groups are now offered screening.
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.
SURGERY
160
© 2004 The Medicine Publishing Company Ltd
Assessment of therapeutic responses: UICC criteria
Screening for breast cancer
Response category Complete response Partial response
M Reddy
Stable disease Progressive disease
Definition Complete disappearance of lesion >50% reduction of bi-dimensional product ≤25% increase or ≤50% decrease of bi-dimensional product >25% increase of bi-dimensional product or appearance of a new lesion
Ros Given-Wilson
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.
5
Serial assessment by blood tumour markers (e.g. CA15.3, carcinoembryonic antigen) is objective, reproducible and costeffective. Biochemical assessment correlates or predates UICC assessment in monitoring systemic therapy. Palliative care: although systemic therapy can prolong survival in suitable patients, at some stage of the disease it will be inappropriate to pursue further systemic therapy. This may be for a variety of reasons, such as: • resistance to a previously effective therapy • intolerance to an ongoing therapy • deterioration in condition where further therapy is considered inappropriate • the patient choosing to discontinue active anti-cancer treatments. Palliative care can be applied throughout all stages of metastatic breast cancer. It aims to lessen the symptoms caused by metastatic disease (and sometimes by the treatment). Physical and non-physical needs must be addressed. These include: • pain control (by the stepwise use of various analgesics, nerve block, radiotherapy, etc.) • drainage of fluids such as pleural and pericardial effusions and ascites (including pleurodesis) • the use of corticosteroids and radiotherapy for brain metastases. Bone is usually the first site of metastases in breast cancer. These patients often have oestrogen receptor-positive tumours and tend to respond to endocrine therapy, resulting in prolonged survival; the five-year survival for bone-specific metastases is about 20%. Palliative measures are therefore particularly important. Problems arising from bone metastases are pain, hypercalcaemia and skeletal complications (e.g. fractures, compression of the spinal cord). Increasing use of bisphosphonates (zoledronic acid given i.v. every 3–4 weeks is effective) has significantly reduced these problems. Orthopaedic intervention, including prophylactic surgery to prevent fracture in weight-bearing areas, should be considered. Other needs of the patient are psychological (e.g. depression, fear, anger, see ‘Psychological care of the surgical patient’, page i), social (e.g. domiciliary and financial circumstances) and spiritual; these can be tackled by involving the appropriate disciplines.
The evidence for breast screening The major risk factors for breast cancer (age, female sex, family history) 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.
Breast cancer survival and stage at diagnosis
100
UICC stage Stage 1 (84%)
% survival
80
Stage 2 (71%)
60 Stage 3 (48%)
40
20
Stage 4 (18%)
0 1
2
3
4
5
Years after diagnosis Source: www.cancerresearchuk.org
1
M Reddy y is a Consultant Radiologist at St George’s Hospital, London, UK. Ros Given-Wilson is a Consultant Radiologist at St George’s Hospital, London, UK.
SURGERY
155
© 2004 The Medicine Publishing Company Ltd
BREAST
Cumulative mortality rates in women aged 40–74: the Swedish Two Counties Trial
The WHO principles of breast 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
The 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.
control
200
150
study
100
50
0 1
2 3 4 5 Years since randomization
6
7
Source: Tabar L, Fagerberg C J, Gad A et al. Lancett 1985; 1: 829–32. Reprinted with permisssion from Elsevier.
3
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.
Bias: there are three major sources of bias which must be considered when assessing the effectiveness of screening. 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
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: Blanks R G, Moss S M, McGahan C E et al. BMJJ 2000; 321: 665–9. Reprinted with permission from the BMJ Publishing Group.
4
SURGERY
156
© 2004 The Medicine Publishing Company Ltd
BREAST
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 ‘gold standard’ method of evaluating screening is by randomized controlled clinical trials using breast cancer mortality as an endpoint.
The screening policy of the NHSBSP Age Views Frequency Protocol
Reduction in mortality (Figures 3 and 4): 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%; probability (P) <0.0001) for women aged 50–74 (assuming a 70% rate of uptake).
5
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 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.
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 to 64 to 50 to 70. The number of views taken has increased from single-view 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 15% (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 under way 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.
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: • masses/asymmetries • areas of distortion • clustered microcalcifications. Recall is initiated only for suspicious lesions, rather than clearly benign disease (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
Organization of screening Screening in the UK is offered by 95 breast screening units. Quality 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.
SURGERY
50–70 years: by invitation 70+ years: by request only Two views at all screens Three-yearly Integrated multidisciplinary approach Nationally agreed standards, protocols and quality review
157
© 2004 The Medicine Publishing Company Ltd
BREAST
a
Irregular spiculate malignancy (arrows) in the a upper and b inner aspect of the left breast.
b
6
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%
ASSESSMENT Multidisciplinary Triple approach Clinical NORMAL Majority SCREENING CYCLE 3 yearly
Radiological Pathological
SURGICAL REFERRAL <1% Positive predicted value 78%
7
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 visits which audit all aspects of the performance of the unit. Problems with breast screening 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.
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
SURGERY
158
© 2004 The Medicine Publishing Company Ltd
BREAST
False-positive screens result in recall to assessment; 70–90% of women recalled 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 exceed those with benign disease by a ratio of 6 to 1.
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. Radiation exposure: X-ray mammography uses ionizing radiation and the mean absorbed dose to an average-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 to a lifetime risk of cancer of 1 in 9. The benefit of early detection and treatment outweighs the risks in this age group.
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 cases, when the prior screening mammograms are received, an abnormality will be seen at the site where the final cancer develops (i.e. which has been missed). These are called 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. In the next two years, the Department of Health plan to introduce a national policy of ‘disclosure of audit’, whereby women who are diagnosed with an interval cancer will be offered the results of this review.
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 contrast-enhanced MRI (Figure 9). Digital mammography allows the image to be displayed on a high-resolution computer screen. One advantage of a digital image is that computer-aided detection can be applied to assist analysis.
Quality assurance targets of the NHSBSP Objective 1 Maximize the number of eligible women attending for screening
Criteria Percentage of eligible women who attend for screening
Standard 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 biopsy
≥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).
8
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BREAST
b Axial T1-weighted scan post-contrast showing intense uptake in an irregular mass in the right breast (arrow), suggesting carcinoma.
a Axial T1-weighted MRI scan showing a low signal intensity region (arrow) in the right breast.
9
In computer-aided detection, preset algorithms detect suspicious areas on the mammographic image and place prompts over areas that warrant review by a film reader (FIgure 10).
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 controlled clinical trials from population screening in the UK. In the period 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.
Screening high-risk groups Some women have a significantly increased risk of breast cancer compared to the general population, and may require closer monitoring and specialized screening protocols. 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 are at increased risk of subsequent breast cancer. Such groups are now offered screening.
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.
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