Recommendations from the European Breast Cancer Guidelines

Should tailored screening with magnetic resonance imaging (MRI) based on high mammographic breast density, in addition to mammography, vs. mammography alone be used for early detection of breast cancer in asymptomatic women?

Recommendation

For women who have no symptoms of breast cancer and who have dense breast tissue, the ECIBC's Guidelines Development Group suggests not to have magnetic resonance imaging (MRI) after a negative mammogram but rather to have only the mammogram, within an organised screening programme.

Recommendation strength

  •   Strong recommendation against the intervention
  • Conditional recommendation against the intervention
  •   Conditional recommendation for either the intervention or the comparison
  •   Conditional recommendation for the intervention
  •   Strong recommendation for the intervention

A recommendation can be strong or conditional.

When a recommendation is strong, most women will want to follow it. When a recommendation is conditional, the majority of women want to follow it but may need more discussion with their healthcare professional first.

What would following this recommendation mean for you?

It might be important to speak with your healthcare professional to determine if you have dense breast tissue and what it means for you. You may also wish to discuss if you are at high, average or low risk of breast cancer, and whether you have or do not have any symptoms of breast cancer.

To decide whether it is better to have the additional screening with an MRI or have only a mammogram, you may wish to speak with your healthcare professional about these tests and how you feel about

  • the chances of finding breast cancer or the chance of being called back for further tests when adding an MRI or when having only a mammogram
  • what happens after you have the results of the tests, and
  • your comfort during the tests.

Who is this recommendation for?

  • You are between 45 and 74
  • You do not have symptoms of breast cancer
  • You have already had a screening mammogram that did not show breast cancer
  • You have dense breast tissue

Justification

This recommendation suggests that women with dense breast tissue not have additional screening with an MRI (magnetic resonance imaging) because the overall harms may be greater than having only a digital mammogram. It is uncertain whether having additional screening with an MRI may find more breast cancers (1 to 4 more per 1000 women) than having only a digital mammogram. It is not known whether finding more breast cancers leads to finding more advanced cancers or fewer deaths.

When MRI is added to digital mammography screening, more women who turn out not to have cancer may have to come back for more tests and unnecessary tests. There may also be side effects caused by the contrast agent that needs to be given intravenously when having the MRI. Having both tests may also mean more visits to the screening service.

More research is being done now that will provide more information in the future about additional screening with an MRI in women with dense breast tissue.

The ECIBC’s Guidelines Development Group noted that the costs to a country would be higher when MRI is provided in addition to a mammogram in a screening programme. There are also too few MRI machines available and access to the machines is not equal.

Considerations

Subgroup

The GDG used indirect evidence from women in whom MRI is recommended. This recommendation is for the women specified in the question. In very high risk women (BRCA genes) the balance of desirable and undesirable health effects is different.

Implementation

The GDG did not feel that there is a current trend towards women receiving MRI-tailored screening for dense breast in practice, and therefore no considerations required for this conditional recommendation against using MRI-tailored screening.

Monitoring and Evaluation

The GDG did not feel that there were any monitoring and evaluation considerations as MRI-tailored screening for women with high mammographic breast density was not felt to be currently conducted in practice.

Research Priorities

Not all GDG members felt that there is a need for further research. GDG members acknowledged that there are clinical trials ongoing regarding MRI-tailored screening for women with high breast density. Research priorities included:
1. Research into the balance of effects, including the potential risk of adverse events due to contrast reaction or IV procedures is required for MRI.
2. Research to improve the specificity of MRI-tailored screening.

Evidence

Download the evidence profile

Assessment

Background

Breast cancer is the second most commonly diagnosed cancer in the world (1.67 million cases diagnosed in 2012) and ranks as the fifth cause of death from cancer overall (522 000 deaths in 2012) (Ferlay 2012).

Screening programmes play a crucial role in early breast cancer detection; they can increase the chance of survival as well as reduce disease specific mortality. Mammography remains the best method to detect breast cancer in an early stage. However, mammography has a lower sensitivity and specificity in women with radiologically dense breasts (Gilbert 2015). The use of different screening strategies including other imaging modalities, in addition to mammography, might improve early detection of breast cancer in women with higher mammographic breast density. Dense breast tissue is made up mostly of ductal structures and connective tissue, while non-dense breast tissue is mostly fatty. Breast density is seen only on mammograms.

Due to lack of evidence using the breast density BIRADS (Breast Imaging Report and Database System) classification edition 5, the GDG decided to base the recommendation on the previous breast density BIRADS classification assuming that the results are comparable for the two versions. Therefore, for the purpose of this clinical guideline, one of the following criteria classifies as dense breast:
(1) BIRADS category scale: III-IV score.
(2) For studies reporting quantitative percent density, a dense area of 50% as roughly equivalent to BIRADS III-IV (BIRADS III would be 50-75% and BI-RADS IV would be greater than 75%).
(3) For those studies reporting the old Wolfe categories: BIRADS III would be P2 and BIRADS IV corresponding DY. The most commonly considered supplemental screening modalities to digital mammography are hand-held ultrasound, automated whole breast ultrasound, digital breast tomosynthesis, and breast magnetic resonance imaging.

Management of Conflicts of Interest (CoI): CoIs for all Guideline Development Group (GDG) members were assessed and managed by the Joint Research Centre (JRC) following an established procedure in line with European Commission rules. GDG member participation in the development of the recommendations was restricted, according to CoI disclosure. Consequently, for this particular question, the following GDG members were recused from voting: Roberto d'Amico, Chris de Wolf, Axel Gräwingholt, Miranda Langendam. Cary van Landsveld-Verhoeven was restricted from voting, as a preventive measure, as the CoI information was not provided, but after its provision it was assessed and no CoI were found.
For more information please visit http://ecibc.jrc.ec.europa.eu/gdg-documents

Is the problem a priority?
Yes *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Research Evidence
Breast cancer ranks as the fifth cause of death from cancer overall (522 000 deaths in 2012) and while it is the most frequent cause of cancer death in women in less developed regions (324 000 deaths), it is now the second cause of cancer death in more developed regions (198 000 deaths) after lung cancer (Ferlay 2012).

Breast cancer screening with additional screening modalities might improve the early detection of breast cancer in women with mammographically dense breast tissue. Although digital mammography (DM) has become an accepted standard of care in screening and diagnosis of breast cancer, up to 30% of breast cancers are not detected by standard screening (Gilbert 2015). This percentage is even higher in women with dense breasts and in women under 50 years of age (Gilbert 2015). In women with dense breasts, risk of breast cancer is increased (McCormack, 2006), and cancers may be masked and missed on mammography due to superposition of tissue; as a result, there might be an excess of late stage disease (stages II and III) (Gierach 2012).
Additional Considerations

The GDG selected this question as a priority for the ECIBC.

How substantial are the desirable anticipated effects?
Moderate *
* Possible answers: ( Trivial , Small , Moderate , Large , Varies , Don't know )
Research Evidence
The included studies did not assess the outcomes of: breast cancer mortality, stage of breast cancer, interval cancer rate, rate of mastectomies, and provision of chemotherapy or adverse effects (including radiation exposure, radiation induced cancers-related to radiation dose, overdiagnosis related adverse effects, false positive related adverse effects).

DIRECT EVIDENCE:
Outcomes№ of participants
(studies)
Follow up
Quality of the evidence
(GRADE)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)
Risk with standard screening regimenRisk difference with tailored screening with magnetic resonance imaging (MRI)
Breast cancer detection rate (incremental cancer detection rate per exam)811
(1 observational study)

LOW
-2219 more cancers detected per 100,000 exams

Interval cancer rate0
(1 observational study)

LOW
-No interval cancer were observed.

INDIRECT EVIDENCE:

Outcomes№ of participants
(studies)
Follow up
Quality of the evidence
(GRADE)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)
Risk with standard screening regimenRisk difference with tailored screening with magnetic resonance imaging (MRI)
Breast cancer detection rate (incremental cancer detection rate per exam)2057
(2 observational studies)

VERY LOW
a,b
-400 more cancers detected per 100,000 exams (from 130 to 680 more cancers detected).
Breast cancer detection rate (incremental cancer detection rate per woman)0
(1 observational study)

LOW
-3350 cancers more per 100,000 women (from 2070 more to 5370 more)








Recall rate 2057
(2 observational studies)

VERY LOW
a,c
- 12,670 women recalled per 100,000 exams (from 11,240 to 14,100 more)




d
  1. Both studies included women with at least one risk factor for breast cancer (Berg 2012) or a cumulative lifetime risk (CLTR) of breast cancer due to a genetic or familial predisposition of 15% or more (Kriege 2006).
  2. Unexplained but unimportant inconsistency with high statistical heterogeneity (I² = 95%, P=0.00).
  3. Unexplained but unimportant inconsistency with high statistical heterogeneity (I² = 96%, P=0.0000).
  4. Incremental recall rate.
* tailored screening using magnetic resonance imaging (MRI) based on breast density

Additional Considerations

Another study (Kuhl 2014) reported results per women. Cancer detection rate provided for that was low (2860 cancer detected per 100.000) than the study by Chen 2016.

The GDG noted that the evidence is not directly comparable because it incorporates study data that looked at a high risk population (BRCA1/2), where the baseline risk is different than women with dense breast.

It was assumed that there would be 1-4/1000 additional cancers detected per woman screened.

As agreement within the GDG for the desirable effects could not be reached, voting among the members without CoI resulted in the following: 18 members voted in favour of 'moderate desirable anticipated effects', and there were no abstentions.

How substantial are the undesirable anticipated effects?
Large *
* Possible answers: ( Large , Moderate , Small , Trivial , Varies , Don't know )
Research Evidence
The included studies did not assess the outcomes of: breast cancer mortality, stage of breast cancer, interval cancer rate, rate of mastectomies, and provision of chemotherapy or adverse effects (including radiation exposure, radiation induced cancers-related to radiation dose, overdiagnosis related adverse effects, false positive related adverse effects).

DIRECT EVIDENCE:
Outcomes№ of participants
(studies)
Follow up
Quality of the evidence
(GRADE)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)
Risk with standard screening regimenRisk difference with tailored screening with magnetic resonance imaging (MRI)
Breast cancer detection rate (incremental cancer detection rate per exam)811
(1 observational study)

LOW
-2219 more cancers detected per 100,000 exams

Interval cancer rate0
(1 observational study)

LOW
-No interval cancer were observed.

INDIRECT EVIDENCE:

Outcomes№ of participants
(studies)
Follow up
Quality of the evidence
(GRADE)
Relative effect
(95% CI)
Anticipated absolute effects* (95% CI)
Risk with standard screening regimenRisk difference with tailored screening with magnetic resonance imaging (MRI)
Breast cancer detection rate (incremental cancer detection rate per exam)2057
(2 observational studies)

VERY LOW
a,b
-400 more cancers detected per 100,000 exams (from 130 to 680 more cancers detected).
Breast cancer detection rate (incremental cancer detection rate per woman)0
(1 observational study)

LOW
-3350 cancers more per 100,000 women (from 2070 more to 5370 more)








Recall rate 2057
(2 observational studies)

VERY LOW
a,c
- 12,670 women recalled per 100,000 exams (from 11,240 to 14,100 more)




d
  1. Both studies included women with at least one risk factor for breast cancer (Berg 2012) or a cumulative lifetime risk (CLTR) of breast cancer due to a genetic or familial predisposition of 15% or more (Kriege 2006).
  2. Unexplained but unimportant inconsistency with high statistical heterogeneity (I² = 95%, P=0.00).
  3. Unexplained but unimportant inconsistency with high statistical heterogeneity (I² = 96%, P=0.0000).
  4. Incremental recall rate.
* tailored screening using magnetic resonance imaging (MRI) based on breast density

Additional Considerations

MRI does not employ ionising radiation but uses radiofrequency and magnetic fields. There are no papers on the radiation dose from ionising radiation with MRI because there is no radiation dose. MRI is generally considered to have less detrimental health effects compared to imaging which uses ionising radiation.

Although no evidence was incorporated on the undesirable effects, the GDG discussed false positives and possible side effects of contrast enhancement including allergic reaction or IV procedure complications that are higher with MRI-based screening for women with dense breast.

The GDG discussed that the evidence for MRI-based screening demonstrated there would likely be a recall rate of 120 per 100,000 and a false positive rate of 116 per 100,000 women screened.

As agreement within the GDG for the undesirable anticipated effects could not be reached, voting among the members without CoI resulted in the following: 7 members voted in favour of 'moderate undesirable anticipated effects', 11 members voted in favour of 'large undesirable anticipated effects'.

What is the overall certainty of the evidence of effects?
Very low *
* Possible answers: ( Very low , Low , Moderate , High , No included studies )
Additional Considerations

The GDG judged that the overall certainty is very low. The research incorporated screening of high-risk women of a range of ages. Age of screening was identified as a concern by the GDG because younger women have higher breast density and this would impact the false positive rates.

Is there important uncertainty about or variability in how much people value the main outcomes?
Possibly important uncertainty or variability *
* Possible answers: ( Important uncertainty or variability , Possibly important uncertainty or variability , Probably no important uncertainty or variability , No important uncertainty or variability , No known undesirable outcomes )
Research Evidence
No specific studies focusing in MRI were identified. The findings, all from mammography studies, however, are likely to be generalizable to MRI, as both screening tests are associated with similar desirable and undesirable effects (e.g. false positive findings or overdiagnosis).

A systematic review shows that participants in mammography screening programmes place a low value on the psychosocial and physical effects of false positive results and overdiagnosis (JRC Technical Report PICO 10-11, contract FWC443094012015). Women generally consider these undesirable effects acceptable (low confidence). However, these findings are of limited value, mainly given the significant concerns regarding the adequacy of the information provided to women, in order to make an informed decision about participation. Also, acceptability of false positive results is based on studies of participants who have already received a false positive result. Their preferences may differ from the general population. Another finding is that breast cancer screening represents a significant burden for some women due to the associated psychological distress and inconvenience.
Regarding breast cancer diagnosis, there is very limited data available on people's views. One of the main themes identified in the literature is that people disvalue highly the anxiety caused by delays in the receipt of results of diagnostic procedures, or by a lack of understanding of the tests due to suboptimal communication with physicians (moderate confidence). Also, people have a higher overall preference towards more comfortable, brief diagnostic procedures (low confidence).
Additional Considerations

The GDG agreed that there is possibly important uncertainty in the way the women would value the increased detection, in the context of the undesirable effects discussed.

Does the balance between desirable and undesirable effects favor the intervention or the comparison?
Probably favors the comparison *
* Possible answers: ( Favors the comparison , Probably favors the comparison , Does not favor either the intervention or the comparison , Probably favors the intervention , Favors the intervention , Varies , Don't know )
Research Evidence
Evidence from high-risk populations (BRCA 1/2) demonstrated 1-4/1000 more cancers detected. The undesirable effects were a recall rate of 126/1000 and a false positive rate of 122/1000 (estimated from 126 false positives minus 4 true positives).
Additional Considerations

The GDG felt there was possible uncertainty and variation about the values and preferences.

The evidence incorporated was indirect as it is from a high-risk population (BRCA 1/2) that may be a different age and breast density.

The GDG felt that there is a concern about allergic reactions due to contrast use, and the additional procedure of IV placement required for delivery of contrast.

Age of screening was identified as a concern by the GDG because younger women have higher breast density.

As agreement within the GDG for the balance between desirable and undesirable effects could not be reached, voting among the members without CoI resulted in the following: 2 members voted in favour of 'favors the comparison', 9 members voted in favour of 'probably favors the comparison' 5 members voted in favour of 'does not favor either the intervention or the comparison', and 1 member abstained.

It was noted that the patient representatives on the GDG judged that the balance 'probably favors the comparison', due to the assumed increased risk of false positives with MRI-tailored screening, a significant concern for women.

How large are the resource requirements (costs)?
Large costs *
* Possible answers: ( Large costs , Moderate costs , Negligible costs and savings , Moderate savings , Large savings , Varies , Don't know )
Research Evidence
No relevant economic evaluations were identified.

















Additional Considerations

No research evidence was identified. GDG members discussed costs associated with breast MRI screening including:
- Costs of the technology, capital costs of the machines and the lifetime of the machine
- Time to acquire and read the images, storage of several hundred images
- Training for radiographers and radiologists

The GDG noted that the cost considerations must also include the increased costs that result from the increased recall rate including repeat exams and biopsies.

The GDG noted that the costs of MRI could be estimated to be ten times higher than those for digital mammography.

What is the certainty of the evidence of resource requirements (costs)?
No included studies *
* Possible answers: ( Very low , Low , Moderate , High , No included studies )
Research Evidence
No relevant economic evaluations were identified.

















Does the cost-effectiveness of the intervention favor the intervention or the comparison?
No included studies *
* Possible answers: ( Favors the comparison , Probably favors the comparison , Does not favor either the intervention or the comparison , Probably favors the intervention , Favors the intervention , Varies , No included studies )
Research Evidence
No relevant economic evaluations were identified.














What would be the impact on health equity?
Varies *
* Possible answers: ( Reduced , Probably reduced , Probably no impact , Probably increased , Increased , Varies , Don't know )
Research Evidence
A systematic review was not conducted.
Additional Considerations

The utilisation of cancer screening services may largely depend on the availability of national public screening programmes. There are findings in Europe highlighting that inequalities are larger in countries without population-based screening programmes (Palencia, 2010).

The GDG judged that the impacts on health equity may vary. The GDG felt that the intervention would have different impacts on health equity within countries and between countries.

Within countries, there may be different access for persons who have private insurance or easier access to MRI.

Across countries, the GDG felt that there would be different access to MRI depending on the country’s ability to fund tailored MRI for dense breast.

Is the intervention acceptable to key stakeholders?
Probably no *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Research Evidence
No specific studies on acceptability of MRI screening were identified.
Additional Considerations

The GDG discussed acceptability among different stakeholders:

Policy-makers: increased costs would be a concern for acceptability.
Radiologists: variabile acceptability depending on the professional opinion of radiologists regarding MRI-tailored screening.
Women: probably not acceptable due to increased risk of false positives and risk of adverse events.

The GDG agreed that the intervention is probably not acceptable to key stakeholders.

Is the intervention feasible to implement?
Probably no *
* Possible answers: ( No , Probably no , Probably yes , Yes , Varies , Don't know )
Research Evidence
A systematic review was not conducted.
Additional Considerations

The GDG judged that it would probably not be feasible to implement due to high costs, too few MRI facilities, longer radiologist examination and reading times, increased inequity, and lack of direct evidence on the balance of effects for MRI-tailored screening.

Bibliography

Evidence of effects
  • Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA 2012;307(13):1394-404.
  • Kriege M, Brekelmans CT, Obdeijn IM, Boetes C, Zonderland HM, Muller SH, et al. Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for breast cancer. Breast Cancer Res Treat. 2006;100(1):109-19.
  • Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated Breast Magnetic Resonance Imaging (MRI): First Postcontrast Subtracted Images and Maximum- Intensity Projection-A Novel Approach to Breast Cancer Screening With MRI. J Clin Oncol. 2014;32(22):2304-10.
  • Chen SQ, Huang M, Shen YY, Liu CL, Xu CX. Application of Abbreviated Protocol of Magnetic Resonance Imaging for Breast Cancer Screening in Dense Breast Tissue. Acad Radiol. 2017 Mar;24(3):316-320..
  • Kuhl CK, Strobel K, Bieling H, Leutner C, Schild HH, Schrading S. Supplemental Breast MR Imaging Screening of Women with Average Risk of Breast Cancer. Radiology. 2017 May;283(2):361-370.
Acceptability
  • Lee CI, Cevik M, Alagoz O, Sprague BL, Tosteson AN, Miglioretti DL, Kerlikowske K, Stout NK, Jarvik JG, Ramsey SD, Lehman CD. Comparative effectiveness of combined digital mammography and tomosynthesis screening for women with dense breasts. Radiology. 2015; 274(3): 772-80.
Economic Evidence
  • Not available
Values and preferences
  • For more details about the results see the full report (Contract: FWC 443094 012015 PICO 10-11).