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Screening for High-Familial-Risk Women

  • Athina VourtsisEmail author
Chapter
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Abstract

Women with a high familial breast cancer risk have an increased likelihood of developing breast cancer and a subsequent increased risk of developing contralateral malignancy. Therefore, additional surveillance has been recommended to reduce risks. Mammography, ultrasound and magnetic resonance imaging (MRI) are the three modalities that have been evaluated as screening tools for these women. Breast MRI is the most sensitive screening modality in this setting, especially in younger women, but mammography is also beneficial. Optimal screening may be achieved with a multimodal approach with age-specific protocols that balance sensitivity and cost efficacy.

Keywords

Familial breast cancer Magnetic resonance imaging (MRI) Women at high risk BRCA1 carriers BRCA2 carriers Breast ultrasound Mammography Automated breast ultrasound Tomosynthesis 

6.1 Introduction

In comparison to the general population, women with a family history of breast cancer have an increased risk of developing the disease. This lifetime risk varies according to the number of affected relatives, the degree of relation and the age they were diagnosed. A number of reliable risk assessment tools are available to quantify risk [1, 2, 3].

  1. 1.

    According to the American Cancer Society, the criteria for designating women at high familial risk for breast cancer are: women with a known mutation in BRCA1 or BRCA2 or their untested first-degree relatives; women with Li-Fraumeni syndrome, Cowden’s syndrome, Bannayan-Riley-Ruvalcaba syndrome, hereditary diffuse gastric cancer or Peutz-Jeghers syndrome and their first-degree relatives (see ► Chap.  5 for further details); and women having a lifetime risk equal to or greater than 20–25% according to BRCAPRO or other family history-based models [4]. Other expert bodies, such as the UK NICE guidelines, have slightly different thresholds [5].

     

Breast cancers in BRCA1 mutation carriers are predominantly triple-negative cancers that tend to grow quickly with well-circumscribed and pushing margins and without microcalcifications, making diagnosis with mammography difficult. In addition the prevalence of ductal carcinoma in situ (DCIS) is rare. Suspicious lesions in BRCA2 mutation carriers have a higher chance of being diagnosed on mammography compared to BRCA1 carriers [6]; they have the same immunophenotypic pattern as sporadic cancers with similar rates of ductal, lobular and ER+ cancers and DCIS, suggesting that personalised screening depending on gene mutation type may be appropriate. The age at which screening commences should also be varied by mutation type bearing in mind the earlier onset of cancers in BRCA1 and TP53 gene carriers than for BRCA2 carriers.

Early guidelines for women with a high familial risk recommended screening by clinical breast examination (CBE) and annual mammography starting at the age of 25–30 years [7]. However, mammography screening alone was shown to have a low sensitivity ranging from 14% to 59% in this very young age group, resulting in two-thirds of breast cancers not being diagnosed in a timely manner and being detected as interval cancers before the next screening round [8]. Results from prospective cohort studies have shown magnetic resonance imaging (MRI) has improved performance in the detection of breast cancer in high-risk women compared to X-ray mammography [9]. The emerging evidence that MRI is far more sensitive than mammography led to the endorsement of its use by international societies for the surveillance of high-familial-risk women [10]. MRI, in combination with mammography, performed on an annual basis is an effective imaging protocol for this particular high-risk population [11]. However, a debate is ongoing regarding whether annual surveillance is adequate, especially in BRCA1 carriers, since 2–14% of women present with palpable interval breast cancers after a negative MRI in the past year [11, 12, 13, 14, 15]. This may relate to the very high proliferation rate of triple-negative breast cancers. ◘ Figure 6.1 presents a series of mammograms of a patient diagnosed with a triple-negative, node-positive breast cancer, which emerged 3 months before her annual follow-up with mammogram, indicating the rapid growth of these tumours (see ◘ Fig. 6.1). The evidence for these different imaging modalities in high-risk women is reviewed below.
Fig. 6.1

Mammography in a 52-year-old woman with three sisters diagnosed with breast cancer at ages 45, 49 and 55 years old. Digital mammography was performed annually for the past 5 years. Within 9 months since the last mammogram, the patient presented with a palpable mass. Mammography revealed a mass measuring 2.7 × 1.6 cm, with indistinct borders (rightmost panels). Histopathological examination showed a triple-negative breast cancer with one positive sentinel node

6.2 Breast MRI

Breast MRI provides the highest diagnostic sensitivity of the three modalities for screening high-risk women with evidence suggesting that an additional 30% of cancers would have been diagnosed as interval cancers between screening rounds if a multimodality approach had not been employed [16]. ◘ Table 6.1 summarises the results of the main studies [9, 11, 15, 16, 17, 18, 19, 20, 21] comparatively examining the sensitivity/specificity of mammography, breast US and MRI (see ◘ Table 6.1).
Table 6.1

Results of the main studies comparatively examining the sensitivity/specificity of mammography, breast US and MRI

     

Sensitivity %

Specificity %

Studies

Country

Sample size

Age range

No of cancers

MRI

Mammography

Ultrasound

MRI

Mammography

Ultrasound

Warner (2004)

Canada

236

25–65

22

77

36

33

95

99

96

Kriege (2004)

The Netherlands

1909

25–70

50

80

33

Not examined

90

95

Not examined

Kuhl (2005)

Germany

529

30+

43

91

33

40

97

97

91

Leach (2005)

United Kingdom

649

35–49

35

77

40

Not examined

81

93

Not examined

Lehman (2005)

USA – international consortium

390

25+

4

100

25

Not examined

95

98

Not examined

Weinstein (2009)

USA

609

25–80

20

71

33

17

79

94

88

Kuhl (2010)

Germany

687

25–71

27

93

33

37

98

99

98

Sardanelli (2011)

Italy

501

25+

52

91

50

52

97

99

98

Riedl (2015)

Austria

559

22–83

40

90

38

38

89

97

97

6.2.1 Sensitivity, Specificity and Cancer Detection Rates with MRI Screening

The overall sensitivity of MRI in women at high familial risk varies between different studies from 71% to 100%. Importantly the sensitivity is not modified by the density of the breast [24]. A meta-analysis of 11 studies showed a sensitivity of 77% for the performance of MRI alone and 94% when MRI was combined with mammography, compared to 39% for mammography alone [22]. One of the explanations that has been given regarding the variation between published studies is the unusual MRI imaging features in this group. Frequently, these tumours demonstrate benign kinetic features and often present with non-mass like enhancement [23]. Additionally, these lesions appear with smooth, non-infiltrative borders, without architectural distortion or space-occupying effects on T1- or T2-weighted images. Consequently, the specificity of MRI in these populations varies between 79% and 95%. These particular features give an explanation for the lower detectability of familial breast cancer and emphasises that the significance of this type of finding should not be underestimated when identified [23].

The cancer detection rate reported for MRI alone in different prospective cohort studies ranges from 8.2 to 15.9 per 1000 [9, 11, 16, 18, 22]. Different studies demonstrate similar or increased detection rates in BRCA1 and BRCA2 mutation carriers and their first-degree relatives compared to women with a family history of breast/ovarian cancer with no documented mutation [24]. Additionally, the detection rate of MRI varied among different age groups. Chiarelli and colleagues identified a higher cancer detection rate for MRI alone in women who were over 50 years old compared to women younger than 50 years old [25]. A number of studies have suggested that in high-risk women, MRI has an increased sensitivity in identifying multifocal and multicentric disease, compared to breast ultrasound and mammography [11, 24].

The ability of MRI to detect breast cancers, virtually uninfluenced by the density of breast parenchyma in familial high-risk women [21], led the National Institute for Health and Care Excellence [5] and the GC-HBOC [26] to recommend annual MRI alone, and not in combination with mammography, for familial high-risk women between the ages of 30 and 39, who do not have a prior diagnosis of the disease. It has been recommended by some that the starting age for MRI screening should be adjusted according to the age of diagnosis in the youngest affected relative, with MRI screening commencing 5 years earlier than this age, and according to the type of mutations (BRCA1, BRCA2 or TP53) as age-specific risks vary [27]. UK NICE guidelines advise MRI screening should commence at age 20 in TP53 gene carriers compared to age 30 in BRCA gene carriers [5]. Most recommendations suggest continuing intensified surveillance, including MRI, at least until the age of 50. Nevertheless, Sardanelli and colleagues found that the effectiveness of MRI continues even after the age of 50 [24]. However, cost issues must also be taken into account by health funding agencies when developing guidelines.

6.2.2 Interval Cancer Rates in MRI

The rates of interval cancers in familial high-risk patients undergoing MRI surveillance may be as high as 40% [11]. Annual MRI surveillance is associated with a significant increase in the incidence of smaller size cancers in BRCA2 carriers. However, this was less frequently observed in BRCA1 carriers, where some women presented with palpable interval cancers, between 6 and 12 months after a normal annual screening MRI [28]. This observed difference might be due to the faster rate of tumour growth in BRCA1 carriers, given the fact that BRCA1-associated cancers are frequently triple negative and of basal phenotype, which are usually high grade and with a very high proliferation index [22]. Interestingly, Tilanus-Linthorst and colleagues [29] reported a significant difference in the doubling time of tumours between BRCA mutation carriers and noncarriers. The reported doubling time for carriers was 45 days compared to 84 days for noncarriers [29]. Therefore, some high-risk screening programmes recommend 6-month surveillance with CBE and/or breast ultrasound in addition to regular annual screening with MRI or alternating MRI and mammography every 6 months, so BRCA1 carriers are offered a shorter interval between screening rounds.

6.2.3 Decline in Mortality Rate: Survival Rate

Despite the higher sensitivity of MRI compared to mammography, it remains unclear whether MRI leads to decreased mortality from breast cancer. Up until now, no randomised trial has been designed to directly compare mortality reduction offered by mammography versus MRI; the existing evidence is only indirect and further research is urgently needed.

The estimated indirect benefit that has been achieved from MRI surveillance is derived from downstaging of breast cancer, where the small size and noninvasiveness of breast cancers have been used as reasonable proxy indices for cancer survival [11]. In BRCA1-associated breast cancer diagnosed in an MRI-based surveillance programme, the 10-year survival rate for cancers less than 1 cm was 93%, compared to 58% for cancers measuring from 1 to 2 cm [30]. Documented evidence has shown that BRCA1 tumours are more aggressive and that size is not an ideal criterion for improved survival since these tumours tend to metastasize early and small tumours may often already have positive lymph nodes [31]. According to earlier studies, BRCA1 patients had a 73–74% 5-year survival [32, 33]. Nevertheless, a more recent study reported a 10-year survival equal to 81%; data suggested that once prognostic factors are taken into account, the outcome among carriers is similar to noncarriers [34].

Apart from the high cost, the most important problems regarding breast MRI are its low specificity, high false-positive recall rates and low sensitivity for detecting DCIS; nevertheless, the latter seems of minor importance since DCIS is rare in BRCA 1 carriers. With continual improvements in MRI technology, specificity has improved. In addition, mammography and second look ultrasound substantially increases the specificity of MRI [35]. Modern MRI units, with high field strength, with a minimum standard of at least 1.5 Tesla, a dedicated bilateral breast coil, quality control visits on a regular basis and experienced radiologists are some of the requirements for high-quality MRI screening. In addition, substantial reporting expertise is needed and some health systems recommend double reading to ensure quality. Furthermore MRI examination is not feasible in certain women due to claustrophobia or contraindications, such as pacemakers, metallic implants, morbid obesity (many scanners have a weight limit), inability to lie prone for up to an hour or renal dysfunction precluding the use of contrast agents [36]. Cost prohibits its use for many health economies in the world.

In a recently published work, Kuhl and colleagues introduced an ultra-fast, 3-min, breast MRI for cancer screening. The results of this study showed that ultra-fast breast MRI substantially reduces the time of image acquisition as well as it decreases the reading time and cost of the exam, displaying a comparable sensitivity and specificity to that of conventional MRI in the screening setting [37].

6.3 Mammography

Randomised controlled trials have shown that in general population mammography is the only screening modality that reduces breast cancer-specific morbidity and mortality [38, 39]. The sensitivity of mammography varies depending on the pattern of breast tissue and can range from as high as 98% in fatty breasts to as low as 30–40% in women with dense breasts [40].

Although screening mammography has been suggested in women with high familial breast cancer risk under the age of 50, its efficacy has been disappointing in BRCA carriers [15, 25]. Several studies have demonstrated low sensitivity in BRCA mutation carriers, leading to a high rate of interval cancers, ranging from 29% to 50%, while 40–56% of patients had nodal involvement at the time of diagnosis, and 20–78% of invasive tumours were larger than 1 cm in size [9, 41].

The lower performance of mammography in this group of women compared to the general population has been attributed to several factors; one of them is the early onset of disease associated with these mutations, at a time in a woman’s life when breast density is high. This adversely affects mammographic sensitivity. It should be declared that there is a concern if the benefit of the reduction in the mortality rate among younger carriers outweighs the potential increased risks caused by radiation injury, since implicated genes (such as BRCA1/BRCA2) are involved in the DNA repair mechanism [42]. This is a cause for special concern in TP53 gene carriers, and guidelines generally recommend MRI screening only for such women.

Another study by Kriege and colleagues​ [15] highlighted the higher sensitivity of mammography compared to MRI for detecting DCIS in women with a familial or genetic predisposition. In contrast, mammography had a lower sensitivity for the detection of invasive cancers (40.0%) compared to the sensitivity of MRI (71.1%); however, the specificity and positive predictive value of MRI in this study were lower than those of mammography.

Consequently, surveillance solely with X-ray mammography in young women with a high familial risk is not adequate, and additional modalities such as MRI or breast ultrasound with high-frequency linear transducers are recommended. The results from published studies are encouraging, as the implementation of a multimodality approach has demonstrated a high performance level in detecting the disease at an earlier stage [43].

Additionally the results of the digital mammographic imaging screening trial (DMIST) suggest that digital mammography could overcome some of the limitations of screen-film mammography [44]. In digital mammography, the X-ray transmission can be varied to enhance the visualisation and conspicuity of subtle anatomical changes that have developed on the background of dense breast parenchyma. Studies have shown the higher sensitivity of digital versus conventional mammography in the detection of microcalcification and subtle masses that have developed in the contour of the breast tissue if the image contrast is adjusted [45]. Therefore, whenever possible, digital mammography should be implemented rather than conventional screen-film mammography for intensified surveillance of women with high familial risk [25, 46].

Due to the limitations of X-ray mammography in this setting, alongside the increased availability and great improvement in MRI, a new strategy for the surveillance of high-risk women younger than 40 has been widely adopted. In 2013 the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) followed later by the United Kingdom (NHS breast screening programme, NHSBSP) modified their screening guidelines, which suggested not to perform mammography in women under the age of 40 without a prior diagnosis of breast cancer and instead undertake high-quality breast MRI screening [5].

The evolution of digital mammography has opened the pathway for the development of digital breast tomosynthesis (DBT), which provides a series of thin slices covering the entire breast parenchyma and therefore improves breast imaging. Currently, however, no studies have demonstrated the value of replacing digital mammography with DBT in women at high familial risk, and further studies are warranted.

6.4 Breast Ultrasound

Supplemental screening with handheld breast ultrasound after mammography in women with dense breasts increases the detection rate for cancer by 2.7–4.6 per 1000 [47]. Importantly, cancers identified with US have been noted to be particularly small invasive cancers with negative lymph nodes. However, breast ultrasound screening in familial high-risk women, in combination with MRI, has been shown to have only a limited value for the detection of the disease [25, 48].

Handheld ultrasound was not designed for screening but for assisting in the differential diagnosis of a palpable or a mammographically detected lesion. Factors hampering the use of ultrasound as a screening modality include operator dependence, variability between different operators, small field of view with the risk of not scanning the entire breast, shortage of qualified personnel to conduct and interpret the exams, lack of standardisation scanning protocols and false-positive findings [49].

Standard breast ultrasound is currently offered in the GC-HBOC screening programme at 6-month intervals [26]. Using US in addition to other screening modalities may also be beneficial in detecting additional impalpable cancers [11] and in the detection of multifocal disease when compared with mammography [24].

Recently, three-dimensional automated breast ultrasound systems have been developed and have opened a new era in ultrasound breast screening. The second-generation Automated Breast Ultrasound System (ABUS) has been FDA approved for screening as a substitute for handheld ultrasound [47]. The automated imaging process of ABUS is faster to acquire and requires less training than handheld ultrasound. Women tolerate it well; according to the study by Zintsmaster and colleagues [50], ABUS was substantially more comfortable than digital mammography and had high patient satisfaction ratings. ABUS overcomes the limitations of handheld ultrasound, as it is operator independent and is based on an automated high-resolution reverse transducer which produces high-volume reconstructed coronal slices that allow better visualisation of architectural distortions due to multifocal or multicentric disease. Thus, evaluating the efficacy and cost-effectiveness of ABUS in familial high-risk women might be a promising consideration for future research.

The contribution of breast ultrasound screening should be considered when there is lack of availability of breast MRI, e.g. due to costs and in women who are unable to tolerate or have contraindications for MRI.

An additional contribution of ultrasound to the screening process is the correlation of sonographic findings with the MRI-detected lesions and guiding their biopsy. Identifying the lesion allows real-time imaging that is less expensive, and in experienced hands, biopsy of the lesion under guidance is easily performed. Additionally, the probability of malignancy increased in the lesions that were detected on MRI and visualised later by ultrasound [51]; thus, ultrasound can be used to increase the specificity of MRI. A short follow-up with breast ultrasound after 6 months is accurate, easier and less expensive to perform for lesions identified on ultrasound that have been characterised with MRI as probably benign.

6.5 Screening During Pregnancy and Lactation

The changes that occur during pregnancy and lactation make the diagnosis of breast cancer difficult. In the general population, breast ultrasound is particularly valuable in differentiating malignant lesions from benign breast conditions during pregnancy, as published studies have reported 100% sensitivity and a 100% negative predictive value [52]. Although mammography is considered safe during pregnancy, it is usually avoided during this period in view of the perceived risks due to the exposure to ionising radiation [53]. Mammography is however performed when there is a high suspicion or histologically proven malignancy [52]. In such cases, the use of lead apron shielding can substantially decrease the dose to the uterus [54].

During lactation, the increased breast volume decreases the sensitivity of mammography; therefore, mammography screening is performed 3 months after discontinuation of lactation. There are no existing guidelines about screening of high-risk women during lactation; nevertheless, it has been suggested that screening mammography can be offered as early as 3 months after delivery in this subgroup of women [52].

In addition, MRI is avoided during pregnancy. The fact that contrast agents cross the placenta raises concerns that gadolinium in the amniotic fluid may exert toxic effects to the foetus. However, no data has been reported on teratogenic effects of gadolinium-based contrast agents in humans [55]. On the contrary, during lactation MRI can be safely performed; however, due to diagnostic challenges imposed by hypervascularity, its use is mainly limited to the preoperative staging of breast cancer.

6.6 Current Recommendations

The EUSOMA recommendations, issued in 2010, have underlined the role of genetic counselling in the assessment and definition of familial high risk (inherited predisposition) for breast cancer. High-risk women include BRCA1, BRCA2, TP53 and other high-risk mutation carriers, their first-degree relatives and women from untested families with a 20–30% lifetime breast cancer risk; annual MRI screening should be offered to them. MRI should be conducted in facilities and programmes following a strictly defined protocol. The age of commencement for annual MRI screening may optimally range from 20 to 30 years depending on mutational type; the upper age limit also remains debatable. Annual MRI is also performed in women already diagnosed with breast cancer; MRI should also be performed within 3 months before prophylactic mastectomy to detect any occult breast cancer. X-ray mammography should be avoided in TP53 mutation carriers and women below 35 years of age, but may be considered from age 35 [27].

In the recent ACR Appropriateness Criteria for Breast Cancer Screening [56], mammography begins at the age of 25–30 years or 10 years before the age at diagnosis of a first-degree relative; nevertheless, the age at onset of screening should not be younger than 25. Mammography and MRI are complementary examinations; both should be performed. On the other hand, ultrasound is performed if a patient cannot undergo MRI.

6.7 Conclusions and Future Perspectives

Evidence derived from published studies has indicated that breast cancer arising in familial high-risk women is an entity with distinct radiological and pathological features compared to cancers arising in the general population. Therefore, its surveillance needs a multimodal strategy tailored according to the subject’s age, breast density, mutation status, accessibility of screening modalities and coexisting personal or medical conditions.

Among all imaging modalities, breast MRI seems to be far more sensitive for the surveillance of women with BRCA1 mutations, whereas mammography provides a satisfactory accuracy in BRCA2 mutation carriers. Breast ultrasound plays an important role in the intervals between screening rounds in the context of a multimodality strategy and when MRI and/or mammography are contraindicated. Notably, none of these modalities alone seem to provide the optimal solution; in a multimodality approach, the limitations of each method are ultimately diminished, offering the best possible approach to this population group.

The evaluation of imaging modalities as screening tools for familial high-risk women is an intensively investigated field. Future studies addressing the role of emerging modalities such as DBT or ABUS seem promising. Studies further assessing the improvement in mortality rates, as well as aiming to shape the optimal multimodality screening regimens, are anticipated.

Key Facts

  1. 1.

    MRI and mammography are effective screening modalities in high-risk women and reduce breast cancer-specific mortality.

     
  2. 2.

    BRCA1 gene carriers often have cancers which may appear benign on imaging due to their pushing borders, and care is needed in their assessment.

     
  3. 3.

    Optimal screening protocols vary with age with MRI being more appropriate in younger women with dense breasts.

     
  4. 4.

    For high-risk women, a multimodal approach is optimal and may overcome the limitations of the different modalities.

     
  5. 5.

    New strategies show promise: digital breast tomosynthesis and automated breast ultrasound (ABUS) may be helpful and are under evaluation.

     
  6. 6.

    Women should be counselled about the pros and cons of screening – the impact of cumulative radiation doses, unnecessary procedures and over-diagnosis and the fact that screening does not guarantee early diagnosis – and all appropriate risk reduction strategies should be discussed (chemoprevention, risk-reducing surgery, lifestyle modification).

     

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Diagnostic Mammography CenterAthensGreece

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