Breast Cancer Screening (Above Average Risk Women)

• Breast cancer is the most common cancer in women worldwide. In Australia, one in seven women will develop breast cancer in their lifetime and it is one of the leading causes of mortality with more than 3000 estimated deaths in 2015. Males also develop breast cancer, although it is less common - the lifetime risk of a male being diagnosed with breast cancer is 1 in 550 1.
• The aim of breast cancer screening is early detection of breast cancer so that prognosis can be improved by early intervention.
• Breast screening programs are designed such that the benefits of reduced breast cancer mortality are balanced with the potential harms of screening including false-positives, overdiagnosis and radiation exposure 2.
• Overdiagnosis is known to occur in breast screening and refers to breast cancer diagnosed by screening that would not otherwise have been diagnosed during a woman’s lifetime.
• Overdiagnosis is thought to increase with age. It is not possible to precisely predict at diagnosis which cancers might represent overdiagnosis. The exact incidence of overdiagnosis in each risk category is yet uncertain and management is best discussed with the specialist breast team.
• Women at above-average risk for breast cancer and high breast density will experience greater screening benefits than other groups and warrant more intensive screening 3.
• Mammography is the only screening modality to have been shown, to date, in many trials, to decrease breast cancer mortality 4-6.
• There are multiple international expert consensus guidelines 7 including, but not limited to:
  • US Preventive Services Task Force (USPSTF) 2024 8, 9
  • European Commission Initiative on Breast Cancer (ECIBC) European Guidelines 2020 10
  • European Society of Breast Imaging (EUSOBI) 2024 11
  • American College of Radiology (ACR) 2023 5, 12, 13
  • Cancer Australia 2015 14
  • American College of Physicians (ACP) 2019 15
  • American College of Obstetricians and Gynecologists (ACOG) 2017 16
  • National Comprehensive Cancer Network (NCCN) 2024 17
  • American Cancer Society (ACS) 2015 18
  • European Society of Medical Oncology (ESMO) 2019 19
• There is some variation in the definition of risk groups. The evidence comparing the effectiveness of these different parameters in breast screening strategies is inconclusive 20.
• Note that many of the above guidelines are directed to women of average risk for breast cancer.

Risk Factors 11, 21, 22

Multiple factors affect the individual risk for development of breast cancer:

• Female sex
  • Sex ratio approximately 100F:1M
• Age
  • About 80% of patients with breast cancer are individuals aged >50 years old while at the same time more than 40% of those are more than 65 years old
• Ethnicity
  • Black women and those of Ashkenazi Jewish descent are at higher risk of genetic mutations (see below)
  • Black women are at risk for breast cancer at a younger age
• Age at menarche
  • Early age at menarche is a risk factor
• Age at menopause
  • Early menopause (natural or surgically induced) lowers the risk
• Reproductive history
  • First full-term pregnancy at an early age along with a subsequently increasing number of births are associated with a reduced risk of breast cancer
• Breastfeeding
  • A longer duration of breastfeeding reduces the risk
• Obesity
  • Obesity, particularly in post-menopausal women, increases breast cancer risk
• Family history
  • This is a major factor associated with breast cancer risk
  • Approximately 13–19% of patients diagnosed with breast cancer report a first-degree relative affected by the same condition
  • The risk of breast cancer significantly increases with an increasing number of first-degree relatives affected
  • The risk might be higher when the affected relatives are under 50 years old
  • A family history of ovarian cancer - especially those associated with BRCA1 and BRCA2 genetic mutations - might induce a greater risk of breast cancer
  • Although a family history of breast cancer is common, only a small percentage of breast cancers will be associated with an inherited genetic mutation
• Mammographic density
  • Generally, the greater the breast tissue density the greater the breast cancer risk
• Genetic mutations
  • Two major genetic mutations are associated with a high penetrance - BRCA1 and BRCA2 (mainly inherited in an autosomal dominant manner, however sporadic mutations are also commonly reported)
  • Other genes with high penetrance include TP53, CDH1, PTEN, and STK11
  • The above also carry an increased risk of ovarian cancer
  • Genes associated with breast cancer but at a lower degree of penetrance compared to BRCA1 and BRCA2 include ATM, PALB2, BRIP1, or CHEK2
• Personal history of breast cancer or non-cancerous breast disease
  • Risk increased with past history of breast cancer
  • Risk increased by history of atypical hyperplasia, carcinoma in situ, as well as other proliferative or non-proliferative lesions
• Previous radiotherapy
  • Increased risk in patients who receive radiation therapy before the age of 30 years
• Hormone Replacement Therapy (HRT)
  • HRT, especially taken for longer than 5 or 7 years, increases the risk of breast cancer
• Alcohol and smoking
  • Both excess alcohol consumption and smoking increase breast cancer risk
• White race
  • Breast cancer incidence is highest among white women

• It is recommended that women undergo risk assessment for breast cancer around the age of 25 years 5, 17, 22. National Comprehensive Cancer Network (NCCN) guidelines 2024 17 also recommend clinical breast examination at this encounter.
• Earlier assessment may be indicated if there is a strong family history of early-onset cancer.
• There are several established methods of risk stratification 23-26 based on the use of a number of different models, including some self-assessment tools e.g. Peter MacCallum 28, 29. These models are generally based on the presence and strength of family history, the presence of genetic mutations associated with breast cancer (such as BRCA1 and BRCA2 23), and other recognised risk factors (see HS2.) 17, 22 including breast tissue density.
• These models are used for risk assessment of individual patients, to decide whether to recommend genetic testing and to predict which patients may benefit from high risk screening. There are benefits and limitations to each model and calculated risk can vary according to which model is used 24.
• Since numerous factors contribute to risk, no single method of classification or definition is used to classify individual women into a specific category.
• Risk categories are most often defined by estimated lifetime risk.
• There has been growing interest in risk-stratified breast screening whereby individualised risk assessment may inform screening frequency, starting age, screening instrument used, or decision not to screen. This has the potential to be beneficial at the population level, but the net health benefit will depend on the particular risk-based strategy and requires further assessment 27.
• One model is the iPrevent breast cancer risk assessment and risk management decision support tool developed by the Peter MacCallum Cancer Centre in Australia 28, 29, an online tool which provides an estimation of the risk of developing breast cancer. This is one of several tools available that allow women to self-assess their cancer risk 29.
• Clinical evaluations of risk-stratified screening are currently limited and further studies of their clinical usefulness are required 30.
• Breast cancer risk is most frequently divided into three categories - average, intermediate and high 5 - although the European Society of Breast Imaging (EUSOBI) guidelines 2024 11 subdivide high risk into “Intermediate high” (women with highly positive family history but without known genetic mutations) and “Very high” (women with high penetrance genetic mutations and women with a history of chest radiotherapy between 10 and 30 years of age).

Breast cancer risk is most frequently divided into three categories - average, intermediate and high 5, although the European Society of Breast Imaging (EUSOBI) guidelines 2024 11 subdivide high risk into “Intermediate high” (women with highly positive family history but without known genetic mutations) and ‘Very high’ (women with high penetrance genetic mutations and women with a history of chest radiotherapy between 10 and 30 years of age).

• Generally regarded as a lifetime risk (LTR) of 15-20% (some authorities use LTR of 1 in 8 to 1 in 4)
• The intermediate increased risk category (according to the European Society of Breast Imaging (EUSOBI) 11) includes women with a highly positive family history but no known genetic mutations as well as those with low-penetrance genetic mutations such as CHEK2 and BARD1.
• The relative risk of heterogeneously dense and extremely dense breasts (compared to average density) are 1.2 and 2.1 respectively 5. Therefore, some authorities consider women with extremely dense breasts to be in higher than average risk categories for screening even in the absence of other increased risk factors for breast cancer 5.
• Evidence-based screening recommendations are complex in this group of women, for several reasons including:
  • the interplay between breast density and other risk factors
  • some publications have grouped intermediate-risk women with average-risk or high-risk women
  • the absence of data on the use of supplemental screening modalities specific to intermediate-risk women; this creates difficulties in developing guidelines for these women 5
• Starting age for screening
  • Consideration should be given for starting before age 40 in some women if intermediate increased risk 5, 13, dependent on strength of family history, history of a previous biopsy showing atypical ductal hyperplasia or lobular carcinoma in situ, and women with a past history of breast cancer 11.

Breast cancer screening guidelines vary for women at intermediate increased risk 31. The American College of Radiology (ACR) recommends annual screening starting at age 40 with mammography or DBT 5.

• Mammography
  • Analogue (film/screen) mammography has largely been replaced by digital mammography.
  • The advantages of digital mammography over film mammography are 6:
    • The ability to post-process the image by changing contrast and magnification
    • Greater contrast resolution
    • Lower average radiation dose
    • The ability to store and send images electronically
  • There are two main types of digital imaging systems which represent advancing, improving technology - computed radiography (CR) where a cassette-based removable detector is inserted into an external reading device to generate an image, and direct radiography (DR) where the image is transmitted directly to the radiologist’s workstation.
  • Full-field digital mammography is a DR technique which has a reported cancer detection rate that is greater than film and CR 32, 33. It is significantly more accurate than film in young women aged <50, women with dense breasts, and premenopausal and peri-menopausal women 34 and is the most common mammography technique used in Australia.
  • Standard mammography involves two views: cranio-caudal and medio-lateral oblique.
  • The diagnostic accuracy of mammography is enhanced through the use of magnification views (magnified, coned compression views), which visualise only a small area of breast tissue but give better contrast resolution and spatial detail.
  • Standardised reporting systems such as the Breast Imaging Reporting and Data System (BI-RADS) by the American College of Radiology have been developed to improve communication between physicians 35.
  • Another standardised reporting system currently in use in Australia requires a description of the following characteristics:
    • Location
    • Size
    • Mass lesion s-shape, margins, associated calcifications
    • Asymmetric density
    • Significant calcification - distribution, shape
    • Architectural distortion
  • Mammography is not as sensitive in detecting abnormal lesions in dense breast tissue 11, 17, 36, 37.
• Digital Breast Tomosynthesis (DBT)
  • DBT is a quasi-3D x-ray technique that involves multiple low-dose projections acquired across an arc over each breast 11. These images are reconstructed into a series of stacked images, as well as providing a ‘synthetic’ mammogram or a full-field digital mammogram 5.
  • DBT has been shown in several international trials to increase cancer detection rates (CDR) and decrease recall rates compared with mammography (summarised in 5, 9, 36). However, results have varied across screening settings, and currently there is limited and conflicting evidence on interval cancer rates (a surrogate for screening effectiveness).
  • A 2023 review 38 concluded that CDR improves most in biennial screening settings, with little or no improvement in annual screening.
  • Incremental increase in cancer detection of 1.6-3.2 per 1000 DBT screening examinations and 2.2% pooled decrease in recall rate compared to digital mammography.
  • Recall rates are decreased with DBT in situations where there is a background of high recall settings - most studies reported from the USA 11, 38, 39.
  • In Europe, where there is a background of fewer recalls, DBT has resulted in no difference, or slightly higher recall rates 11, 39.
  • DBT is increasingly used in the USA and Europe 11.
  • However, any benefits of DBT are limited in women with very high breast density.
  • There is some evidence that DBT increases detection of indolent, slow-growing tumours, thus perhaps increasing the overdiagnosis rate 11.
  • The synthetic mammograms produced (which correspond to 2D reconstructions of DBT datasets) can be used as an alternative to additional mammography projections 11.
  • Studies of the rates of interval cancers after DBT are showing mixed results 13, 39-45.
  • ACR and National Comprehensive Cancer Network (NCCN) recommend DBT 5, 17.
• MRI
  • MRI (with and without IV contrast) increases cancer detection rate and reduces interval cancers but increases the recall rate (compared to mammography) 5.
  • For most women at higher-than-average risk (and those with very dense breasts), the supplemental screening test is MRI. For those unable to undergo MRI, ultrasound or contrast-enhanced mammography (CEM) should be considered 13.
  • A 2022 review 46 concluded that multiple studies have shown that intermediate-risk women may be suitable candidates for screening MRI, given the high detection rates of early-stage cancers and acceptable false-positive rates.
• Contrast-enhanced mammography (CEM)
  • The modern technique of CEM uses a dual-energy technique, also known as contrast-enhanced spectral mammography (CESM).
  • CEM/CESM can be used instead of a standard digital mammogram in certain situations, including where there is a lifetime risk of breast cancer of 1:4-1:2 or where there is a high clinical suspicion of breast cancer. It can also be helpful as an alternative to MRI for problem-solving or where MRI is contraindicated.
  • In a recent meta-analysis and systematic review 47 CEM had high performance for breast cancer detection especially with joint interpretation of low-energy and recombined images, including for a subgroup with dense breasts. However, although patients in a breast cancer screening setting were included, the study also included symptomatic patients.
  • A further systematic review 48 confirmed the potential of CEM as a supplemental screening imaging modality, even for intermediate increased risk women, including females with dense breasts and a history of breast cancer. This study found CEM and contrast-enhanced MRI (CE-MRI) to be equally accurate.
  • Data on the performance of CEM for breast cancer screening is accumulating 13, 49 but not yet robust. CEM has shown superior sensitivity compared with DM alone (87.5%-90.5% vs 50.0%-52.4%) and achieved an incremental CDR (ICDR) of 6.6 to 13.1 per 1,000, but with a decrease in specificity. The absolute CDR for CEM was 15.5, similar to that for MRI. A prospective multi-center trial ‘Contrast Enhanced Mammography Imaging Screening Trial (CMIST)’ comparing the screening performance of DBT with that of CEM in women with dense breasts at average to intermediate increased risk for breast cancer is underway.
  • The interim results from the BRAID study 50, a randomised clinical trial in which supplemental screening with abbreviated MRI, automated whole breast ultrasound (ABUS) and CEM are compared in women with dense breasts with a negative full-field digital mammogram have shown CEM to have a cancer detection rate of 19.2 per 1000 examinations, non-significantly different from that of abbreviated MRI. CEM and abbreviated MRI detected three times as many invasive cancers compared with ABUS, with cancers being half the size.

• Although breast self-examination has been promoted for many years as a screening method to diagnose breast cancer at an early stage, studies have shown that self-detection does not reduce breast cancer-specific mortality 30 and self-examination is no longer routinely recommended 1, 14, 18.
• However, more than half of breast cancers are diagnosed after investigation of a breast change found by the woman or by her doctor 31, hence women are recommended to be aware of the normal look and feel of their breasts and report new or unusual changes to the doctor 14, 15.
• No one method for women to use when checking their breasts is recommended over another 14, 31.
• In 2015 the International Agency for Research on Cancer (IARC) Working Group concluded that there was inadequate evidence that breast self-examination reduces breast cancer mortality when taught or when practiced competently and regularly 51.

• Breast density category on mammography should always be reported.
• Breast density can be scored on a scale from very low density (mostly fatty tissue) to mostly dense (mostly glandular/connective tissue).
• The most commonly used scale for reporting breast density is the American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS) 35, 52, which scores density by category A, B, C or D:
  • Type A (almost entirely fatty): around 10% of women
  • Type B (scattered areas of fibroglandular density): roughly 40% of women
  • Type C (heterogeneously dense): 40% of women have this type of mammographic density, which is considered dense and may obscure small cancers
  • Type D (extremely dense): around 10% of women have extremely dense breasts, which lowers the sensitivity of mammography
• About 40-50% of women have heterogeneously or extremely dense breasts 11.
• Younger women tend to have denser breasts.
• Dense breast tissue is an independent risk factor for breast cancer; women with dense breasts have a higher risk than those with non-dense (fatty) breasts.
• The relative increase in cancer in dense breasts is thought to be 4.6% 53.
• The relative risk of heterogeneously dense breasts and extremely dense breasts (compared to average density) is 1.2 and 2.1 respectively 5.
• Therefore some authorities consider women with extremely dense breasts to be in higher than average risk categories for screening, even in the absence of other increased risk factors for breast cancer 5.
• Mammography is less sensitive in women with dense breasts 36.
• Although overall sensitivity of mammography in all women is in the range of 70% to 85%, the sensitivity can vary significantly with breast density. The sensitivity of mammography is higher in women with fatty breast parenchyma 36, 37.
• The question of supplemental screening in this large group of women has not been fully resolved and recommendations among international expert consensus guidelines vary.
• A recent editorial stated that there is “an urgent need for evidence on the topic of supplemental screening with ultrasound or MRI for women with dense breasts” 54.
• Supplemental tests, in addition to DBT, may be indicated in average risk women with dense breasts.

• Digital Breast Tomosynthesis (DBT)
  • The American College of Radiology (ACR), in addition to stating that digital mammography or DBT are appropriate as primary screening modalities, recommends DBT (over 2-D mammography) in women with dense breasts but concludes that there is limited evidence for supplemental screening in average risk women 12.
• Supplemental screening tests to be considered include:
  • Contrast-enhanced digital mammography (CEM)
    • A systematic review 48 confirmed the potential of CEM as a supplemental screening imaging modality, even for intermediate-risk women, including females with dense breasts and a history of breast cancer. This study found CEM and contrast-enhanced MRI (CE-MRI) to be equally accurate. There is accumulating data for a general recommendation in the screening setting, although ACR guidelines suggest CEM as an option as a supplemental screening test 36. The interim results from the BRAID study 50, a randomised clinical trial in which supplemental screening with abbreviated MRI, automated whole breast ultrasound (ABUS) and CEM are compared in women with dense breasts with a negative full-field digital mammogram, have shown CEM to have a cancer detection rate non-significantly different from that of abbreviated MRI.
  • Whole breast ultrasound
    • Mammography plus ultrasound (US) (versus mammography alone) tends to increase the cancer detection rate (CDR) while increasing the recall and biopsy rates and decreasing specificity and has had a variable effect on interval cancer rate 11, 36.
    • Most guidelines do not support the use of US as a supplemental test in average risk women with dense breasts and a normal mammogram.
  • MRI
    • The U.S. Preventive Services Task Force (USPSTF) concludes that there is currently insufficient evidence for or against US or MRI following an otherwise negative mammogram 8.
    • The European Society of Breast Imaging (EUSOBI) supports the use of supplemental scanning with MRI every 2-3 years in women with extremely dense breast tissue 11.
    • The European Commission Initiative on Breast Cancer (ECIBC) Guidelines do not recommend US or MRI 10.
  • Sestamibi MBI is not widely available.
  • Breast Screen Australia 52 does not routinely provide additional screening for women with dense breasts. Breast Screen services in different Australian states vary regarding advising women of their mammographic density. In some states, if they are identified as having dense breasts, women are given follow-up information and advised to see their GP who will then generally perform a clinical breast examination and organise US. However, the evidence for this practice is limited.

See also Risk Stratification

• High risk is usually defined as a > 20% lifetime risk of developing breast cancer.
• The factors that determine high risk categorisation include:
  • Family history: the closeness of affected relatives (1st or 2nd degree) and the number of affected relatives, especially if they developed breast cancer at an early age, will determine the categorisation. (A family history of ovarian cancer in first or second degree relatives may suggest a genetic mutation).
  • The presence of genetic mutations predisposing to breast cancer.
  • Previous chest or mantle radiotherapy at a young age.
  • History of previous breast cancer.
  • History of previous breast biopsy showing pre-cancerous lesions.
  • The above may be compounded by the presence of very dense breasts.
  • The presence of other risk factors (See also Risk Factors) may add further to the degree of risk.
• Various expert guidelines, including National Comprehensive Cancer Network (NCCN) 17, and the American College of Radiology (ACR) 13 and the European Society of Breast Imaging (EUSOBI) 11 recommend screening programmes for women at high risk. There are variations in the details among them 7, but the consensus is that for such women:
  • Screening should start at a younger age than women at average risk. Recommendations vary for starting at age 25-30 years.
  • In patients with a strong family history, it has been suggested that screening should start 10 years before the age of the youngest affected relative, but no later than aged 30 17.
  • Genetic counselling for women with a known or suspected genetic mutation.
  • A clinical encounter should occur every 6-12 months 17.
  • Breast awareness (See also Breast Awareness).
  • Annual screening with contrast-enhanced breast MRI (as in dot points above) should be performed, with the addition of mammography (full-field digital or tomosynthesis) from the ages of 35-40 years. Contrast-enhanced mammography or ultrasound may be used when MRI is not feasible 5, 11, 17.