Intended for healthcare professionals

Analysis Too Much Medicine

Mapping the drivers of overdiagnosis to potential solutions

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3879 (Published 16 August 2017) Cite this as: BMJ 2017;358:j3879

Re: Mapping the drivers of overdiagnosis to potential solutions: Is the UK ready for an Imaging Biomarker Solution to the Breast Screening Debate?

Thanya Pathirana's article beautifully explains the current problem of "Too much medicine", but in our necessary attempts at de-escalation we must be careful not to throw the baby out with the bath water. Within health screening in particular we must sort out our tool kit and use diagnostic devices that find significant disease, early discovery of which is truly beneficial to the population.

The NHS Breast Screening Programme was set up in 1988. Its rigorous quality assurance surpasses that of other areas of radiology and of medicine. Nevertheless, overdiagnosis is a reality (1,2), and we must also ask why, when we know that finding breast cancer early saves lives (3), is breast cancer still the second commonest cause of oncological mortality for women in the UK?

The explanation for both overdiagnosis and underdiagnosis lies in the diversity of breast cancer biology, improved understanding of which has revolutionised breast cancer treatment and greatly improved survival. An era of personalised cancer therapy has begun, that depended on the revelation that breast cancer is not one disease (4). Breast cancer subtypes demonstrate a vast heterogeneity in presentation, biology, risk of progression, response to treatment and survival outcomes.

Digital mammography is an effective diagnostic tool for breast cancer, but it is best at picking up less aggressive cancers that distort the structure of the breast as they grow or engender calcium deposition. More aggressive, faster growing cancers often replace the surrounding breast tissue without distortion, and can remain undetected mammographically until they are large enough to be felt clinically (5).

Host-related factors also affect the visibility of cancer on mammograms. The density of breast cancer tissue tends to be similar to that of normal glandular breast parenchyma, and therefore, if breasts are predominantly glandular, a cancer is more likely to remain invisible within this tissue mammographically. This variable is known as breast density. At age 50, 50% women have breasts dense enough to obscure a small cancer (6), introducing an unspoken inequality of effectiveness of mammographic screening programmes worldwide.

Targeted breast cancer treatments, developed over the past few decades, depend for their effectiveness on the use of biomarkers to identify particular molecular characteristics and allow treatments tailored to the individual cancer (7). These biomarkers are measured from samples obtained at biopsy or surgery, and are therefore inherently invasive. Imaging biomarkers (IB) are inherently non-invasive and could potentially enable screening targeted to biologically aggressive cancers.

Functional Magnetic Resonance Imaging (MRI) is being evaluated but is not yet included in clinical practice. However, dynamic contrast-enhanced (DCE) MRI is our current standard screening test for young women at high risk of breast cancer (>30% lifetime risk) and demonstrates features associated with biological aggression in breast cancer (8). The trouble with MRI is the high cost of equipment, compounded by long acquisition and interpretation times, making it unsuitable for use in a wider screening population. It remains reserved for those at highest risk despite increasing evidence that it could also benefit average risk women by enabling diagnosis of the aggressive cancers underdiagnosed by mammography (9).

There is now increasing interest worldwide in abbreviated breast MRI. This was first described using the acronym FAST MRI in 2014 and takes far less time to acquire and report than the full-protocol breast MRI (10). Early results imply that this technique could provide a cost-effective screening tool for a wider group of women (11). FAST MRI is best at picking up cancers that are biologically aggressive because it retains elements of the DCE protocol that demonstrate cancer perfusion and enhancement morphology.

Abbreviated MRI holds great promise as an imaging biomarker in a screening application, but large scale studies are necessary to test it rigorously, in terms of effectiveness, patient acceptability and cost, against our standard screening modalities, to ensure that it truly can reduce both overdiagnosis and underdiagnosis. The EA1141 study has recently begun recruiting in USA to compare abbreviated MRI with digital breast tomosynthesis (the most advanced radiographic breast imaging method) for women with dense breasts (12). Since tomosynthesis is still undergoing evaluation itself (13), comparison of FAST MRI with digital mammography would be a more appropriate study for the UK. Mammography is an effective test for most women of screening age, and it may be that the future of effective screening, like that of effective treatment, for breast cancer, lies with a tailored approach for each individual.

The solution to overdiagnosis and underdiagnosis is not to undermine our national breast screening programme that cost-effectively provides quality-assured, standardised population screening (14), but instead to enable high quality research to guide the evolution of that screening programme into a new imaging biomarker age.

References:
1. Gemma Jacklyn, Paul Glasziou, Petra Macaskill and Alexandra Barratt Meta-analysis of breast cancer mortality benefit and overdiagnosis adjusted for adherence: improving information on the effects of attending screening mammography. British Journal of Cancer (2016) 114, 1269–1276. doi:10.1038/bjc.2016.90
2. Pathirana T, Clark J and Moynihan R. Mapping the drivers of overdiagnosis to potential solutions. BMJ 2017; 358: j3879 doi: 10.1136/bmj.j3879
3. Saadatmand S, Bretveld R, Siesling S et al. Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173797 patients. BMJ 2015;351: h4901
4. Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, METABRIC Group, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borrensen-Dale A-L, Brenton JD, Tavare S, Caldas C and Aparicio S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012; 486: 346-352
5. Sung JS, Stamler S, Brooks J, Huang T, Dershaw DD, Lee CH, Morris EA and Cornstock CE. Breast cancers detected by screening MR imaging and mammography in patients at high risk: Method of detection reflects tumor histopathologic results. Radiology 2016; 280: 716-722
6. American College of Radiologists publication; BI-RADS Atlas 5th edition 2013: ISBN No: 9781559030168 (Breast Composition Categorisation) p123-132
7. Duffy MJ, Harbeck N, Nap M, Molina R, Nicolini A, Senkus E and Cardoso F. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). European Journal of Cancer 2017; 75: 284-298
8. Yamamoto S, Han W, Kim Y, Du L, Jamshidi N, Huang D, Kim JH and Kuo MD. Breast Cancer: Radiogenomic biomarker reveals associations among dynamic contrast-enhanced MR Imaging long noncoding RNA and metastasis. Radiology 2015;275: 384-92
9. 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
10. Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers R-D and Bieling HB. Journal of Clinical Oncology 2014;32: 2304-2310
11. Chlor CM and Mercado CL Abbreviated MRI Protocols: Wave of the Future for Breast Cancer Screening. American Journal of Radiology 2017; 208: 284-289
12. Kuhl C. Invited commentary: Abbreviated breast MRI for screening women with dense breast: The EA1141 Trial. British Journal of Radiology 2017 epublished ahead of print
https://doi.org/10.1259/bjr.20170441
13. Gilbert FJ, Tucker L, Gillan MG, Willsher P , Cooke J, Duncan KA, Michell MJ, Dobson HM, Lim YY, Purushothaman H, Strudley C, Astley SM, Morrish O, Yooung KC and Duffy SW. Health Technology Assessment 2015;19::i-xxv, 1-136. The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme – a multicentre retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone
14. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG and Wilcox M - The Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. British Journal of Cancer 2013; 108: 2205-2240

Competing interests: No competing interests

12 November 2017
Lyn I Jones
Consultant Radiologist
J. A. Dunn Professor of Clinical Trials and Head of Cancer Trials at Warwick Clinical Trial Unit, University of Warwick, UK, A. Marshall Principal Research Fellow at Warwick Clinical Trials Unit, University of Warwick, UK and Christiane K Kuhl Professor and Clinical Director of Radiology and Neuroradiology at the University of Aachen, Germany
Bristol Breast Care Centre
Southmead hospital, North Bristol NHS Trust