Breast cancer is one of New Zealand’s leading health issues (Ministry of Health, 2012). New Zealand is among the top 20 countries in the world with the highest incidence of breast cancer with approximately 85 per 100,000 citizens diagnosed (World Cancer Research Fund International, 2015). In 2012, it was found that breast cancer was the most commonly registered cancer among women in New Zealand (Ministry of Health, 2012).
Screening mammography plays a large role in attempting reduce the incidence of invasive breast cancer in New Zealand by detecting pre-invasive lesions so they can be removed/treated early (National Screening Unit, 2014c). Breast density greatly affects how a mammogram translates to an image, with areas of denser tissue appearing much lighter than areas of less dense tissue (Yaffe, 2008). This led to exploring whether the composition of tissue within the breast has an impact on the ability of mammograms to detect tumours. Therefore, does breast density affect the accuracy of screening mammography?
The following PECOT model helped to formulate this research question:
Information relating to question
Women aged 45 – 69
In New Zealand, this is the age range at which BreastScreen Aotearoa’s free breast screening programme is available to women.
Women with dense breasts who underwent alternative methods of screening on top of mammography, and/or those who had more frequent mammograms
Are women with dense breasts who undergo multiple methods of screening, diagnosed earlier than those who relied solely on mammography screening for a diagnosis.
Comparison / Control
Women who received mammography screening only
Does this affects the efficiency of diagnosis, and the prevalence of breast cancer.
Alternative methods of screening (such as Breast MRI, Breast Ultrasound, and Molecular Breast Imaging) resulting in a higher incidence of tumours being detected earlier in women with dense breasts.
Breast cancer is very prevalent in New Zealand. Using alternative screening methods on top of mammography in those with dense breasts increases the likelihood of early detection of tumours while they are smaller and more easily treated, thus reducing the number of deaths by breast cancer in New Zealand.
The progression of breast cancer differs from patient to patient, as does the stage at which the cancer is detected by screening. Therefore there shall be no time constraint.
In recent years, extensive research has emerged identifying breast density as an independent risk factor for breast cancer, and an inverse correlation between breast density and mammographic sensitivity (Martin & Boyd, 2008). Further research, however, suggests that there is little information available about the implications of breast density and appropriate protocol in the New Zealand context.
This literature review explores the effect of breast density on mammography sensitivity and breast cancer risk, supplemental screening methods available in New Zealand and elsewhere around the world, and the effects of breast density reporting legislation.
Breast density and mammography sensitivity
A screening mammogram is a low-dose, safe x-ray that has the ability to detect breast cancer before it can be felt or seen (The New Zealand Breast Cancer Foundation, 2013). During a screening mammogram, each breast, in turn, is firmly held between two plates while the x-ray is taken (National Screening Unit, 2014b). On the resulting film, areas of low-density tissue (e.g. fat) appear translucent/dark, and areas of dense tissue such as tumours appear whiter (U. S. National Institute of Biomedical Imaging and Bioengineering, 2013).
A woman’s breast is comprised of 2 main components: fibroglandular tissue (which is made up of stroma and epithelium) and fat tissue (Yaffe, 2008). Fat is of low density, and is therefore more transparent to x-rays than dense fibroglandular tissue (Yaffe, 2008). This means that areas of fat appear dark on a mammogram, whereas areas of dense fibroglandular tissue appear light, thus showing up as a similar shade to tumours (Boyd, Martin, Yaffe, & Minkin, 2011). The area of dense fibroglandular tissue is referred to as mammographic density, and is often expressed as a percentage of the total breast area. (Yaffe, 2008). This is referred to as percent mammographic density (PMD) (Boyd et al., 2011). Therefore the radiographic appearance of the breast varies greatly among women of different percent mammographic densities due to differences in composition of fat, stroma and epithelium and corresponding radiographic attenuation (Boyd et al., 2007). Because tumours and fibroglandular tissue both show up as light areas on a mammogram, relatively high percent mammographic density means less chance of distinguishing a tumour from fibroglandular tissue (Freer, 2015; Winkler, Raza, Mackesy & Birdwell, 2015). This ‘masking effect’ leads to increased risk of cancers manifesting within one year of a mammogram in women with denser breasts (interval cancers) (Freer, 2015).
It is important that breast density assessment is included in mammography screening reports as it gives the referring clinician a good indication of the patient’s mammographic sensitivity (or lack thereof), and their relative risk for breast cancer (Winkler et al., 2015). In New Zealand, it is expected by the Ministry of Health that breast density be reported in every mammogram report using BI-RADS (Breast Imaging Reporting and Data System) and/or a percentage score (Ministry of Health, 2013). BI-RADS describes breasts as being in one of four categories: class 1 = predominantly fatty, class 2 = scattered fibroglandular densities, class 3 = heterogeneously dense, and class 4 = extremely dense (Checka, Chun, Schnabel, Lee & Toth, 2012). By acknowledging breast density using BI-RADS or a percentage (PMD) in every mammography report, the referring clinicians are able to inform patients with dense breast tissue that in their case, mammography may be less sensitive, and their risk for breast cancer going undetected by mammography may potentially be higher than that of women with less dense breasts (Winkler et al., 2015).
Primary healthcare nurses should have an in-depth knowledge of the effects of breast density on mammography sensitivity so they can inform and educate patients while they are involved in BreastScreen Aotearoa’s free breast screening programme and encourage regular self-examination. Educating patients may give them the confidence to discuss the implications of breast density with their general practitioner or referring clinician, and determine an appropriate course of action if they are found to have relatively high percent mammographic density (Abdelaziz, Salem, Zaki & Atteya, 2015). All women participating in the BreastScreen Aotearoa programme are entitled to services from a breastcare nurse. One of the main roles of a breastcare nurse is to facilitate communication between health professionals and the patient (National Screening Unit, 2014a).
Breast density and breast cancer risk
The development of invasive breast cancer can be prevented by early detection by mammogram and treatment of pre-invasive breast lesions (Alowami, Troup, Al-Haddad, Kirkpatrick & Watson, 2003). Not only are women with a high percentage mammographic density at risk of developing breast cancer due to pre-invasive lesions going undetected by mammogram, it is now proven that there is a correlation between breast density and the risk of developing breast cancer (Boyd et al., 2010; Chen, Gulsen, & Su, 2015).
Radiologist, John Wolfe, first suggested that there was a correlation between breast density and the risk of developing breast cancer in 1976 (Wolfe, 1976). He devised four patterns, which are now known as the Wolfe grades, which underpin different breast densities. The N pattern has the lowest breast cancer risk and is characterized by predominantly fat tissue in the breast. P1 and P2 patterns are associated with higher levels of breast cancer risk, and are characterized by progressively higher levels of fibroglandular tissue in the breast. The DY pattern corresponds to the highest risk of developing breast cancer and is characterized by predominantly dense fibroglandular tissue in the breast (Wolfe, 1976; Yaffe, 2008).
In more recent years, the tool, BI-RADS, was established for qualitative descriptors of breast density in mammographic reporting (class 1 = predominantly fatty, class 2 = scattered fibroglandular densities, class 3 = heterogeneously dense, and class 4 = extremely dense), and corresponding percentages of breast density were added in 2003 by the American College of Radiology: class 1 = less than 25%, class 2 = 25–50 % class 3 = 51–75%, and class 4 = more than 75% dense tissue (Checka et al., 2012). Studies have shown that women with percentage mammographic density of 75% or more are four to six times more likely to develop breast cancer than those with little or no dense breast tissue (Boyd et al., 2007).
Breast density ultimately refers to the amount of stromal and epithelial tissue (fibroglandular tissue) in the breast. Breast cancers most commonly originate in epithelial cells, therefore, an individual with more epithelial tissue would have a higher chance of developing breast cancer within their epithelial cells (Freer, 2015). Breast cancer often manifests due to alterations in cellular pathways and gene expression within breast epithelial cells. On top of this, disturbances in epithelial-stromal interactions may also contribute to tumorigenesis, plus altered expression of proteins within the stroma is linked to the progression of tumours (Alowami et al., Troup, 2003).
Differences in mammographic density reflect variations in mitotic activity and susceptibility to genetic damage of breast cells (Martin & Boyd, 2008). Cell proliferation and mutagenesis (genetic damage by mutagens to proliferating cells) may be largely responsible for increased risk of breast cancer associated with increased breast density (Martin & Boyd, 2008). It has been proven that endocrine stimulation to cell proliferation by blood levels of IGF-I (Insulin-like Growth Factor 1) and prolactin is positively correlated with breast density and breast cancer risk (Martin & Boyd, 2008).
With this knowledge that higher breast density is correlated to increased risk of breast cancer, it is extremely important that appropriate screening is undertaken in those with denser breast tissue, especially when mammography alone is deemed less effective. This may mean supplemental screening should be considered and suggested by the patient’s general practitioner or referring clinician.
Supplemental screening methods
The inclusion of breast density information in a mammographic report using BI-RADS and/or a quantitative percentage is imperative as this allows the referring clinician to identify whether adjunctive screening and risk reduction is required (Winkler et al., 2015).
Additional screening methods for women with dense breasts include magnetic resonance imaging (MRI) and ultrasonography (US) of the whole breast (Berg et al., 2012; Winkler et al., 2015). A study has shown that the percentage of sensitivity with mammography or ultrasound alone is approximately 50%, compared to almost 78% with mammography and ultrasound combined (Berg et al., 2008).
The Ministry of Health “Standards of service provision for breast cancer patients in New Zealand” state that MRI be considered as a screening tool where mammography is not reliable or is inconclusive, i.e. in women with high percentage mammographic density (Ministry of Health, 2013). One study has reported that a mammographic sensitivity percentage of 66% in women with dense breasts increased to 81% with the addition of MRI screening (Sardanelli et al., 2004). This is because, unlike breast density portrayed on mammography, MRI shows a cross-sectional analysis of fibroglandular tissue allowing for an increased chance of detecting pre-invasive lesions (Albert et al., 2015). MRI, however, is usually limited to high-risk women (including those with high percentage mammographic density) due to additional cost, and MRI has a false positive rate of approximately 9% (Checka et al., 2012).
Research has suggested that a recently developed, dedicated breast computed tomography scanner (dbCT) would be beneficial in the initial screening of women with dense breasts (U.S. National Institute of Biomedical Imaging and Bioengineering, 2013). This device allows the breast to be viewed in three dimensions thus enabling the potential to reveal small lesions/tumours usually hidden behind dense breast tissue (U.S. National Institute of Biomedical Imaging and Bioengineering, 2013). The incorporation of PET (positron emission tomography) technology into CT screening also aids in the early detection of breast cancer in women with dense breasts, as PET highlights areas of increased metabolic activity, which could suggest there is a tumour present in that region (Langer, 2010; U.S. National Institute of Biomedical Imaging and Bioengineering, 2013)
While this technology is not used as a first-line supplemental screening tool in New Zealand, the Ministry of Health “Standards of service provision for breast cancer patients in New Zealand” also states that FDG PET-CT should be considered for “assessment of recurrence in women with dense breasts” (Ministry of Health, 2013, p. 36).
Digital mammography has been found to have greater sensitivity than film-screen mammography in women with dense breasts (Freer, 2015). As opposed to a screen-film image receptor, digital mammography uses a detector that produces an electronic signal which analyses the influence of x-rays through the breast at a very wide range. This image is digitized to a computer (Yaffe, 2008). Digital mammography has been found to significantly improve the chance of detecting hormone-negative cancers, which often manifest as interval cancers and are masked by dense tissue in film-screen mammography (Freer, 2015).
Molecular breast imaging (MBI) is another relatively new technology that largely enhances the detection of breast cancer and is significantly cheaper than MRI. MBI involves the injection of a radioactive tracer into the bloodstream through a vein in the arm. Breast cancer cells absorb the radioactive substance more than normal breast cells, thus causing the region to light up when a nuclear medicine scanner is used to scan the breast (Rhodes, Hruska, Phillips, Whaley & O’Connor, 2011). A review of one year’s use of MBI in a specific setting showed that MBI identified an additional 8 to 9 breast cancers per 1000 patients screened in conjunction with mammography (approximately 2-3 per 1000 detected using mammography alone, compared to 10-11 detected using both screening methods) (Rhodes et al., 2011; Tran et al., 2016). This technology is currently available to access in countries such as the United Kingdom, Ireland, and the United States of America, but is not currently recognised as a suitable supplemental screening tool in New Zealand (Rhodes et al., 2011; Business Wire, 2017; Ministry of Health, 2013).
The implementation of supplemental screening would result in fewer incidences of breast cancer patients in the tertiary healthcare setting, as pre-invasive lesions would be more likely to be detected by screening and removed/treated early.
Breast density reporting legislation
In order to ensure supplemental screening in women with dense breasts is undertaken, or at least considered and discussed with patients, many states in the United States of America have introduced breast density laws. Legislation in many states requires patients to be informed of their breast density and the implications of this, including possible decreased sensitivity to mammography and possible increased risk of developing breast cancer (Winkler et al., 2015).
The first law regarding reporting breast density was passed in Connecticut in 2009 (Goldberg, Mirghani & Woodman, 2016). The Breast Density and Mammography Reporting Act (H.R. 1302) was introduced to U.S. congress (national level) in 2011, requiring breast density reporting be part of every mammography report in every state (Chen, Gulsen & Su, 2015). As of February 2017, 27 states in the U. S. have implemented their own legislation requiring that not only breast density information be included in every mammography report, but also that women be notified of relatively high breast density following a mammogram (DenseBreast-info.org, 2017). In many states, these laws also suggest or require that the clinician offer the patient the option to undergo supplemental screening. However, laws in just 4 states (Indiana, Illinois, New Jersey and Massachusetts), require that any costs associated with supplemental screening for women with increased mammographic density are covered by insurance (Goldberg, Mirghani & Woodman, 2016).
USA breast density laws were put in place in attempt to empower patients and prompt discussion between the clinician and patient, hopefully resulting in additional screening being undertaken (Winkler et al., 2015). However, research has suggested that implementation of these laws and regulations has been inconsistent in some states. Despite ultrasonography being recognised as a beneficial supplemental screening tool among women with dense breasts, it was found that there was great variation in referrals for whole-breast ultrasound screening in Connecticut (Slanetz, Freer & Birdwell, 2015). Some practices were referring 100% of women considered to have high mammographic density, while others were referring none. On top of this, it was found that overall, just 45% of these women being referred for ultrasonography in Connecticut were actually receiving this screening (Slanetz et al., 2015).
This being said, breast density laws and legislation provide opportunities to strengthen therapeutic relationships between clinicians and women receiving breast screening by encouraging conversations about breast density and possible implications (Slanetz et al., 2015). If adhered to correctly, breast density legislation could save many lives otherwise lost due to late detection of invasive breast cancer, as the addition of supplemental screening would mean women would be less likely to develop interval cancers. These laws and subsequent implementation of supplemental screening may be associated with additional costs to the healthcare sector and patients initially, but ultimately would save money as costs associated with chemotherapy and other suitable treatments of breast cancer would be minimised due to a reduction in the incidence of invasive breast cancer.
Improving awareness of breast density and the implications of high percent mammographic density with regard to mammogram sensitivity and breast cancer risk, starts with education. This includes patient, and health professional education. The BreastScreen patient information pamphlet only acknowledges increasing age as a risk factor for breast cancer, thus failing to mention other risk factors such as family history, genetics, and breast density (National Screening Unit, 2014). Perhaps if breast density was outlined as a risk factor in this information given to patients when they join the screening programme, it might prompt patients to question their general practitioner about their own breast density and possible implications.
On top of this, currently, in New Zealand, specialists involved in breast cancer care and those involved in the BreastScreen Aotearoa programme are expected to attend regular breast multidisciplinary meetings to improve their education surrounding breast cancer screening and risk factors (Ministry of Health, 2013). However, this is not expected of general practitioners despite the fact that they are most commonly the health professional to convey the results of a mammogram to a patient and decide whether further screening is required (National Screening Unit, 2014).
The introduction of molecular breast imaging technology in New Zealand could also reduce the incidence of invasive breast cancer in New Zealand. Not only has it been found to significantly increase the detection of breast cancer when used in conjunction with mammography (an additional 8 to 9 breast cancers per 1000 patients screened), it is also significantly more cost effective than MRI (Rhodes et al., 2011; Tran et al., 2016).
Furthermore, the implementation of breast density legislation in the United States of America has been largely beneficial as it strengthens therapeutic relationships between clinicians and women receiving breast screening, by encouraging conversations about breast density and possible implications (Slanetz et al., 2015). Implementing similar legislation here could have a very beneficial effect when it comes to reducing the incidence of invasive breast cancer in New Zealand. Additionally, the Ministry of Health found that the incidence of breast cancer among Māori females was 1.4 times that of non- Māori females between 2010 and 2012 (Ministry of Health, 2015). Generally Māori are associated with a lower socioeconomic status than non- Māori overall (Statistics New Zealand, 2013). Considering a vast portion of breast cancer diagnoses are among Māori in New Zealand, perhaps the implementation of laws requiring costs associated with supplemental screening for women with increased mammographic density be government funded would largely reduce the incidence of and deaths by invasive breast cancer in New Zealand.
To conclude, increased breast density does, in fact, reduce the sensitivity/accuracy of screening mammography (Freer, 2015). Increased percentage mammographic density is also now recognised as an independent risk factor for breast cancer (Boyd et al., 2010). There is a plethora of evidence suggesting that supplemental screening of women with high mammographic density will reduce the incidence of interval cancers and therefore death by invasive breast cancer in New Zealand. The implementation of breast density reporting legislation in New Zealand would also potentially contribute to a decreased incidence of invasive breast cancer. Such legislation would encourage patient/clinician conversations about possible implications of increased breast density, and facilitate supplemental screening to be undertaken (Slanetz et al., 2015).
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