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Interval Cancers and Duty of Candour, a UK Perspective

Interval Cancers and Duty of Candour, a UK Perspective Purpose of Review Interval cancers are defined as a cancer presenting in the interval following a negative screen. Interval cancers are important because they reduce confidence in the screening programme and have relatively worse prognostic features than screen-detected cancers. This review will look at the rates of interval cancers in the UK Breast screening programme and other population-based breast screening programmes in Europe. It will discuss the latest UK classification and look at factors affecting interval cancer rates. It will examine the pathological features of interval cancers and their mortality impact. It will also discuss the introduction of Duty of Candour and its relevance and impact in breast screening. Recent Findings It will report on the effect of newer technologies on interval cancer rates. Summary Interval cancers are not unexpected in population-based screening programmes. They are known to have relatively worse prognosis than screen-detected cancers and therefore the accurate monitoring of interval cancers is important both for quality improvement and education. The impact of newer technologies on interval cancer rates is currently limited as the studies are ongoing. . . . Keywords Breast cancer Interval cancers Duty of candour Breast density Introduction latest UK classification and look at factors affecting interval cancer rates. It will examine the pathological features of inter- An interval breast cancer is a cancer that is diagnosed in be- val cancers and their mortality impact. tween screening episodes after a woman has received a “nor- It will also discuss the introduction of Duty of Candour and mal” result. They are important because they reduce confi- its relevance and impact in breast screening. dence in the screening programme and have relatively worse prognostic features than screen-detected cancers. This review will look at the rates of interval cancers in the UK Breast screening programme and other population-based Definition, Classification and Standards breast screening programmes in Europe. It will discuss the The majority of screening programmes specify an interval cancer as an invasive cancer but it is important to remember This article is part of the Topical Collection on Breast Cancer Imaging and Screening when comparing programmes that some programmes also in- clude ductal carcinoma in situ (DCIS) [1]. In the UK, cases of * Eleanor Cornford DCIS are not included in the UK definition but will still un- eleanor.cornford@nhs.net dergo a review process. * Nisha Sharma Another problem with comparing rates between different nisha.sharma2@nhs.net programmes is the availability of up-to-date validated data. Certainly in the UK the most recent published national data Thirlestaine Breast Unit, Cobalt House, Gloucestershire Hospitals refers to screening years 2006–2008 [2], although data is Foundation Trust, Thirlestaine Road, Cheltenham, available more readily at regional level. Gloucestershire GL53 7AS, UK 2 In the UK, guidance produced by Public health England Breast Unit, Level 1 Chancellor wing, Leeds Teaching Hospital in 2017 states three reasons to report and monitor interval NHS Trust, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK 3 cancers [3� ] University of Leeds, Leeds LS2 9JT, UK 90 Curr Breast Cancer Rep (2019) 11:89–93 1. To monitor rates of interval cancers in conjunction with The UK has quality standards for all aspects of the Breast rates of screen-detected cancer to provide information on Screening programme. The standards for interval cancer rates whole programme performance. were updated in 2017 and are as follows: 2. To support education and learning objectives for screen- <12 months—0.65/1000, 12 < 24 months—1.4/1000, 24 ing services and individuals. This helps improve the qual- <36 months—1.65/1000 (compared with < 24 months—1.2/ ity of the service provided to women. 1000, 24 < 36 months—1.4/1000 in previous standards) [7]. 3. So that women who have had an interval cancer can un- The rates were increased to reflect the background inci- derstand whether any abnormality was present on their dence increase since 1995 and also split into three rates for previous films and if they wish to receive the information. each year to allow greater accuracy. All of these are important. With regard to number 3, from the outset of the National Health Service Breast Screening Programme, women in the UK have always had the opportu- Factors Affecting Interval Cancer Rates nity to discuss findings from review of their previous images with a clinician involved in their care, a process referred to as Rates are affected by ascertainment methods, screening “Disclosure of Audit”.More recently “Duty of Candour” has round length, underlying background breast cancer inci- been introduced in the UK and this will be discussed more dence within a given population, and also risk factors. fully later in the review [4� ]. To achieve accurate data, robust systems need to be in The most recently available national data from the UK place with good communication between cancer regis- quotes the following statistics [2]. tries and both screening and symptomatic breast ser- vices. In a three yearly screening programme, the inter- & Of 1,625,063 women screened in 2007/8 val cancer rate goes up by approximately 75% in the & Overall interval cancer rate in 3 years following screen third year which is why most countries in Europe have (50–64) = 2.86/1000 adopted two yearly programmes. In a three yearly & Interval cancer rate in 2 years following screen (50–64) = screening programme, if round length is significantly 1.61/1000 less than 36 months, interval cancer rates would fall & Overall interval cancer rate in 3 years following screen whilst the converse would be true if round length was (50–70) = 2.95/1000 significantly longer. & Interval cancer rate in 2 years following screen (50–70) = Risk factors for development of interval breast cancers are 1.64/1000 high breast density, age, current use of hormone replacement therapy, and family history of breast cancer [8–11]. High Tornberg et al. compared the interval cancer rates in six breast density increases risk in two ways. It has a masking European countries with organised, population-based screen- effect but also it is an independent risk factor for breast cancer. ing and found rates of interval breast cancers ranged from 8.4 In addition to these factors, it has also been shown that to 21.3 per 10,000 screenings [5]. there is an association between the detection and treat- The following classification system for radiological review ment of high grade DCIS and subsequent prevention of of interval cancers has been used in the UK since 2017 [3� ] invasive interval cancers. Duffyetal. obtainedaggregate data for DCIS diagnoses for women aged 50–64 years 1. Satisfactory—Normal or benign mammographic features who were invited to and attended mammographic breast 2. Satisfactory with learning points—Seen with hindsight, screening from April 2003 to March 2007 (from the difficult to perceive, not obviously malignant National Health Service Breast Screening Programme). 3. Unsatisfactory—Appearance is obviously malignant Patient-level data for interval cancer arising in the 36 months after each of these were also analysed. The This varies slightly from the previous classification where cat average frequency of DCIS detected at screening was 3 was defined as—Appearance suspicious of malignancy [6]. 1.60 per 1000 women screened. There was a significant The majority of interval cancers fall into category 1 (ap- negative association of screen-detected DCIS cases with proximately 77%), whilst category 2 accounts for approxi- the rate of invasive interval cancers. Ninety percent of mately 16% and category 3 approximately 7% [2]. It is likely units had a DCIS detection frequency within the range that with the updated classification system the percentage of of 1.00 to 2.22 per 1000 women; in these units, for every category 3 interval cancers will decrease. This will therefore three screen-detected cases of DCIS, there was one fewer make it difficult to ascertain whether any decrease is due to invasive interval cancer in the next 3 years [12]. The true improvements in the screening programme or solely to challenge for radiologists is to recall intermediate/high the updated classification system. grade DCIS and not overcall cases of low grade DCIS. Curr Breast Cancer Rep (2019) 11:89–93 91 Radiological Features screen-detected cancer or the detection of slow-growing tu- mours [20–22]. As discussed, earlier monitoring and surveillance of interval cancers is very important. In the UK, the NHSBSP makes recommendations regarding the review process. It states that Effect of New Technologies on Interval Cancer a minimum of two reviewers should review the images, that Rates the previous screening mammograms, with all prior images that were available at the time of screening, should be There has been a transition from screen film mammography reviewed by the readers independently and that the diagnostic (SFM) to full field digital mammography (FFDM) in most images should then be reviewed to confirm that any subtle or screening programmes. Published data on the effect on inter- suspicious signs detected on the previous screening images val cancer rates has mainly been at unit or regional level, match the site of the confirmed breast cancer on the diagnostic showing mixed data but certainly no increase in interval can- images [3� ]. However, the exact method of review varies cer rates [23, 24]. Sankatsing et al. have recently published widely which may account for variation in reported interval national data from the Dutch screening programme assessing cancer rates. The ideal review method would involve blinded the effect of the transition to FFDM. Data of 7.3 million review of cases interspersed with normal screening mammo- screens in women aged 49–74, between 2004 and 2011, were grams. In reality due to time and clinical commitments, many linked to the Netherlands Cancer Registry to obtain data on interval cancer reviews are informed which naturally intro- interval cancers. They found that during the transition from duces bias into the process with the reviewer more likely to SFM to FFDM, there was a significant rise in cancer detection classify a case as category 2 or 3 than if the process was rate and a stable interval cancer rate, leading to increased blinded. The mammographic features most likely to be missed programme sensitivity. Although the recall rate increased, pro- are asymmetric densities, ill-defined masses, subtle distor- gramme specificity remained high [25]. Hoff et al. looked at tions, and calcification [13, 14]. the mammographic features and found that in previous mam- mograms of cancers missed at FFDM there was a non- significant trend towards a higher % of asymmetric densities Pathological and Biological Features (27 vs 10%, P = 0.007) and a lower % of calcifications (18 vs 34%, P = 0.185) compared with those missed at SFM [24]. In terms of detection, some tumours particularly lobular The use of computer aided detection (CAD) has not may have subtle mammographic appearances or even be been shown to reduce recall rates [26]. Digital breast occult. In addition, small high grade cancers may appear tomosynthesis has been introduced in many countries as well-defined masses and be misinterpreted as benign. with most large-scale studies demonstrating improved Studies looking at the pathology, biology, and prognosis cancer detection rates. However, unless there is a corre- of interval cancers have consistently found that they sponding reduction in interval cancer rates, the implica- have poorer prognostic features compared with screen- tion is that there will be little impact on mortality. It is detected cancers. Consistent findings are larger size, still early days for results from the major studies but higher grade, and node positivity [1]. there have been several recent publications. Houssami There is also published work on biomarkers. Collett et al. et al. examined interval breast cancers ascertained at 2- found that a basal epithelial phenotype (express cytokeratin and year follow-up for women involved in the “Screening P-cadherin) is more frequent in interval breast cancers compared with tomosynthesis or standard mammography” with screen-detected tumours. Patients with interval cancers were (STORM) population-based trial. In the study group, more likely to be younger, have dense breasts, ER negative tu- the interval cancer rate was 1.23/1000 screens (95% CI mours, and p53 expression [15]. Data from other authors is mixed 0.56 to 2.34). In concurrently screened women who but the majority have found a higher proportion of triple negative attended the same screening services and received 2D- tumours and over expression of HER 2 in interval cancers mammography, the interval cancer rate was 1.60/1000 [16–19]. Interestingly, Holm et al. compared biological markers screens (95% CI 1.14 to 2.17). They concluded that the in interval cancers in non-dense breasts (≤ 20% mammographic interval breast cancer rate amongst screening participants density) with interval cancers in dense breasts (> 40.9% mammo- in the STORM trial was marginally lower than estimates graphic density) and found that the cancers in the low density amongst 2D-screened women [27� ]. Skaane et al. have breasts were phenotypically more aggressive [10]. also published interval cancer data from the results from Breast cancer-specific survival in interval cancer is worse the prospective population-based Oslo Tomosynthesis than in screen-detected cancer. However, this difference may Screening Trial. They found that although there was an partly be explained by lead or length time bias, resulting in an increase in cancer detection rate and increased specificity there was no change in interval cancer rates [28]. artificial increase in survival time due to the early diagnosis in 92 Curr Breast Cancer Rep (2019) 11:89–93 Duty of Candour and if it is felt that there was either a process failure or that interpretation fell below an expected standard then DOC reg- Up until 2015, breast patients were offered results of interval ulations should apply. As part of the collaborative work, it was cancer review according to “Disclosure of Audit” guidance [29]. also felt necessary to produce new guidance on interval can- This was a document produced by the NHSBSP and covered cers to ensure a clearer and more consistent approach. As communication regarding interval cancers. It covered suggested stated earlier, this resulted in Category 3 changing from methodology for the review process with advice on when and Unsatisfactory—Appearance suspicious of malignancy [6]to how to communicate in an open way whilst still minimising Unsatisfactory—Appearance is obviously malignant [3� ]. It distress to both patients and professionals. This had to change was felt that this made clearer the link between classification following the introduction of Duty of Candour (DOC). and what action is warranted. It is still too early to assess what DOC is a Care Quality Commission (CQC) regulation (num- impact this legislation will have on the breast screening pro- ber 20) published in April 2015 in response to the Francis report gramme but certainly the PHE publications make it easier to (this was a report into incidents at a NHS hospital trust) [30, 31]. ensure consistency across different units. The key points about DOC are that NHS organisations must act in an open and transparent way when things go wrong, they must tell users as soon as practicable about notifiable safety incidents Conclusions and results of investigations and that they must apologise. This applies to all aspects of NHS care. There is evidence that open Interval cancer rates within the context of breast screening are communication reduces risk of litigation. important metrics. Interval cancers are known to have relative- Within the act a “notifiable safety incident” means “any ly worse prognosis than screen-detected cancers and therefore unintended or unexpected incident that occurred in respect of the accurate monitoring of interval cancers is important. This a service user during the provision of a regulated activity that, is particularly the case when new imaging technologies are in the reasonable opinion of a health care professional, could recommended to replace 2D digital mammography as a result in, or appears to have resulted in—the death of the screening tool. Tomosynthesis has been shown to be a prom- service user, where the death relates directly to the incident ising screening tool but the data regarding the impact on in- rather than to the natural course of the service user’sillnessor terval cancer rates is limited as many studies are still ongoing. underlying condition, or severe harm, moderate harm or prolonged psychological harm to the service user” [30]. It Compliance with Ethical Standards became apparent very soon after the act was introduced that this would have a major potential impact on the breast screen- Conflict of Interest Eleanor Cornford and Nisha Sharma declare no conflicts of interest relevant to this manuscript. ing programme, staff morale and recruitment as there was the perception by some NHS Hospitals that any interval breast Human and Animal Rights and Informed Consent This article does not cancer constituted a notifiable safety incident! Collaborative contain any studies with human or animal subjects performed by any of work between Public Health England, the CQC and screening the authors. representatives resulted in the publication of a new document, Open Access This article is distributed under the terms of the Creative the aim of which was to advise on best practice in NHS Commons Attribution 4.0 International License (http:// Screening programmes to ensure compliance with DOC reg- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, ulations [4� ]. It explains that screening tests are not 100% distribution, and reproduction in any medium, provided you give appro- accurate so will have false negatives and false positives and priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. these should not automatically trigger DOC. It emphasises that interval cancers are not “unexpected” and that the screen- References ing information leaflet provided to all breast screening patients should inform that screening is not 100% accurate. The NHSBSP now also provides a leaflet to give to women at time Papers of particular interest, published recently, have been of cancer diagnosis if they are in the screening age group highlighted as: informing her that a review of any previous screening mam- � Of importance mograms will take place. It is imperative to remember that patient choice is very important and that she may not wish 1. Houssami N, Hunter K. The epidemiology, radiology and biologi- cal characteristics of interval breast cancers in population mammog- to know results of this review. This is her right and DOC raphy screening. NPJ Breast Cancer. 2017;3:12. respects that. Clinicians also need to remember that timing 2. Michalopoulos D, Dibden A, Duffy SW. National collation of of disclosure is very important and we cannot apply “As soon breast screening interval cancer data 2006–2008. published 2015. as reasonably practicable” as it may not be in her best interest. 3.� Guidance on Interval cancers, Reporting, classification and moni- The review involves examining both the process and imaging toring of interval cancers and cancers following previous Curr Breast Cancer Rep (2019) 11:89–93 93 assessment 2017 PHE publications, gateway number: 2017216. 19. Caldarella A, Puliti D, Crocetti E, Bianchi S, Vezzosi V, Apicella P, et al. Biological characteristics of interval cancers: a role for bio- This documents helps define how interval cancers are classified to ensure that there is standardisation within the UK. This is markers in the breast cancer screening. J Cancer Res Clin Oncol. important regarding education but also auditing practise going 2013;139:181–5. forward. 20. van der Waal D, Verbeek ALM, Broeders MJM. Breast density and breast cancer-specific survival by detection mode. BMC Cancer. 4.� Guidance on applying Duty of Candour and disclosing audit re- 2018;18:386. sults, 2016. PHE publications gateway number: 2016343. This is 21. Allgood PC, Duffy SW, Kearins O, O'Sullivan E, Tappenden N, an important document outlining the processes regarding Duty Wallis MG, et al. Explaining the difference in prognosis between of Candour and Disclosure of audit. It emphasises the impor- screen-detected and symptomatic breast cancers. Br J Cancer. tance of being honest and objective when dealing with interval 2011;104:1680–5. https://doi.org/10.1038/bjc.2011.144. cancers. 22. Mook S, Van’t Veer LJ, Rutgers EJ, Ravdin PM, van de Velde AO, 5. Tornberg S, Kemetli L, Ascunce N, Hofvind S, Anttila A, Sèradour van Leeuwen FE, et al. Independent prognostic value of screen B, et al. A pooled analysis of interval cancer rates in six European detection in invasive breast cancer. J Natl Cancer Inst. 2011;103: countries. Eur J Cancer Prev. 2010;19:87–93. 585–97. https://doi.org/10.1093/jnci/djr043. 6. Quality Assurance Guidelines for Breast Cancer Screening 23. Nederend J, Duijm LE, Louwman MW, Coebergh JW, Roumen RM, Radiology NHSBSP Publication No 59, 2011. Lohle PN, et al. Impact of the transition from screen-film to digital 7. NHS BSP Consolidated standards, 2017 PHE publications gateway screening mammography on interval cancer characteristics and number: 2016720. treatment—a population based study from the Netherlands. Eur J 8. Boyd NF, Huszti E, Melnichouk O, Martin LJ, Hislop G, Chiarelli Cancer. 2014;50(1):31–9. https://doi.org/10.1016/j.ejca.2013.09.018. A, et al. Mammographic features associated with interval breast 24. Hoff SR, Abrahamsen AL, Samset JH, Vigeland E, Klepp O, cancers in screening programs. Breast Cancer Res. 2014;16(4): Hofvind S. Breast cancer: missed interval and screening-detected 417. https://doi.org/10.1186/s13058-014-0417-7. cancer at full-field digital mammography and screen-film 9. Wanders JOP, Holland K, Karssemeijer N, Peeters PHM, Veldhuis mammography—results from a retrospective review. Radiology. WB, Mann RM, et al. The effect of volumetric breast density on the 2012;264(2):378–86. https://doi.org/10.1148/radiol.12112074. risk of screen-detected and interval breast cancers: a cohort study. 25. Sankatsing VDV, Fracheboud J, de Munck L, Broeders MJM, van Breast Cancer Res. 2017;19:67. Ravesteyn NT, National Evaluation Team for Breast cancer screen- 10. Holm J, Humphreys K, Li J, Ploner A, Cheddad A, Eriksson M, ing, NETB, et al. Detection and interval cancer rates during the et al. Risk factors and tumor characteristics of interval cancers by transition from screen-film to digital mammography in mammographic density. J Clin Oncol. 2015 Mar 20;33(9):1030–7. population-based screening. BMC Cancer. 2018;18:256. https://doi.org/10.1200/JCO.2014.58.9986. Published online 2018 Mar 5. https://doi.org/10.1186/s12885-018- 11. Lowery JT, Byers T, Hokanson JE, Kittelson J, Lewin J, Risendal B, 4122-2. et al. Complementary approaches to assessing risk factors for inter- 26. Lehman CD, Wellman RD, Buist DS, Kerlikowske K, Tosteson val breast cancer. Cancer Causes Control. 2011;22:23–31. AN, Miglioretti DL. Breast cancer surveillance consortium diag- 12. Duffy SW, Dibden A, Michalopoulos D, Offman J, Parmar D, nostic accuracy of digital screening mammography with and with- Jerkins J, et al. Screen detection of ductal carcinoma in situ and out computer-aided detection. JAMA Intern Med. 2015;175(11): subsequent incidence of invasive interval breast cancers: a retro- 1828–37. https://doi.org/10.1001/jamainternmed.2015.5231. spective population-based study. Lancet Oncol. 2016;17(1):109– 27.� Houssami N, Bernardi D, Caumo F, Brunelli S, Fantò C, Valentini 14. https://doi.org/10.1016/S1470-2045(15)00446-5. M, et al. Interval breast cancers in the ‘screening with 13. Evans AJ,KuttE,RecordC,WallerM,BobrowL,MossS. tomosynthesis or standard mammography’ (STORM) population- Radiological and pathological findings of interval cancers in a based trial. Breast. 2018;38:150–3 This paper is important be- multi-centre, randomized, controlled trial of mammographic cause it suggests that interval cancer rates may be reduced with screening in women from age 40-41 years. Clin Radiol. the introduction of DBT as a screening tool but recognises that 2007;62(4):348–52. more data is required and the studies are ongoing and therefore 14. Hofvind S, Geller B, Skaane P. Mammographic features and histo- these results need to be interpreted with caution. pathological findings of interval breast cancers. Acta Radiol. 28. Skaane P, Sebuødegård S, Bandos AI, Gur D, Østerås BH, Gullien 2008;49:975–81. R, et al. Performance of breast cancer screening using digital breast 15. Collett K, Stefansson IM, Eide J, Braaten A, Wang H, Eide GE, tomosynthesis: results from the prospective population-based Oslo et al. A basal epithelial phenotype is more frequent in interval breast Tomosynthesis Screening Trial. Breast Cancer Res Treat. cancers compared with screen detected tumours. Cancer Epidemiol 2018;169(3):489–96. https://doi.org/10.1007/s10549-018-4705-2. Biomark Prev. 2005;14:1108–12. 29. Disclosure of Audit results in cancer screening advice on best prac- 16. Weber RJ, van Bommel RM, Louwman MW, Nederend J, Voogd tice, Cancer Screening Series No 3 April 2006, ISBN 1 84463 031 AC, Jansen FH, et al. Characteristics and prognosis of interval cancers after biennial screen-film or full-field digital screening 30. CQC Regulation 20: Duty of Candour 2015 Information for all pro- mammography. Breast Cancer Res Treat. 2016;158:471–83. viders: NHS bodies, adult social care, primary medical and dental care, 17. Meshkat B, Prichard RS, Al-Hilli Z, Bass GA, Quinn C, O'Doherty and independent healthcare. www.cqc.org.uk/sites/default/files/ A, et al. A comparison of clinical-pathological characteristics be- 20150327_duty_of_candour_guidance_final.pdf. Accessed Nov 2018 tween symptomatic and interval breast cancer. Breast. 2015;24: 31. Francis R. Report of the Mid Staffordshire NHS Foundation Trust 278–82. Public Inquiry. London: The Stationery Office; 2013. 18. Domingo L, Salas D, Zubizarreta R, Baré M, Sarriugarte G, Barata T, et al. Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screen- Publisher’sNote Springer Nature remains neutral with regard to jurisdic- ing in Spain. Breast Cancer Res. 2014;16:R3. tional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Breast Cancer Reports Springer Journals

Interval Cancers and Duty of Candour, a UK Perspective

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Springer Journals
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Copyright © 2019 by The Author(s)
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Medicine & Public Health; Oncology; Internal Medicine; Surgical Oncology
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1943-4588
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Abstract

Purpose of Review Interval cancers are defined as a cancer presenting in the interval following a negative screen. Interval cancers are important because they reduce confidence in the screening programme and have relatively worse prognostic features than screen-detected cancers. This review will look at the rates of interval cancers in the UK Breast screening programme and other population-based breast screening programmes in Europe. It will discuss the latest UK classification and look at factors affecting interval cancer rates. It will examine the pathological features of interval cancers and their mortality impact. It will also discuss the introduction of Duty of Candour and its relevance and impact in breast screening. Recent Findings It will report on the effect of newer technologies on interval cancer rates. Summary Interval cancers are not unexpected in population-based screening programmes. They are known to have relatively worse prognosis than screen-detected cancers and therefore the accurate monitoring of interval cancers is important both for quality improvement and education. The impact of newer technologies on interval cancer rates is currently limited as the studies are ongoing. . . . Keywords Breast cancer Interval cancers Duty of candour Breast density Introduction latest UK classification and look at factors affecting interval cancer rates. It will examine the pathological features of inter- An interval breast cancer is a cancer that is diagnosed in be- val cancers and their mortality impact. tween screening episodes after a woman has received a “nor- It will also discuss the introduction of Duty of Candour and mal” result. They are important because they reduce confi- its relevance and impact in breast screening. dence in the screening programme and have relatively worse prognostic features than screen-detected cancers. This review will look at the rates of interval cancers in the UK Breast screening programme and other population-based Definition, Classification and Standards breast screening programmes in Europe. It will discuss the The majority of screening programmes specify an interval cancer as an invasive cancer but it is important to remember This article is part of the Topical Collection on Breast Cancer Imaging and Screening when comparing programmes that some programmes also in- clude ductal carcinoma in situ (DCIS) [1]. In the UK, cases of * Eleanor Cornford DCIS are not included in the UK definition but will still un- eleanor.cornford@nhs.net dergo a review process. * Nisha Sharma Another problem with comparing rates between different nisha.sharma2@nhs.net programmes is the availability of up-to-date validated data. Certainly in the UK the most recent published national data Thirlestaine Breast Unit, Cobalt House, Gloucestershire Hospitals refers to screening years 2006–2008 [2], although data is Foundation Trust, Thirlestaine Road, Cheltenham, available more readily at regional level. Gloucestershire GL53 7AS, UK 2 In the UK, guidance produced by Public health England Breast Unit, Level 1 Chancellor wing, Leeds Teaching Hospital in 2017 states three reasons to report and monitor interval NHS Trust, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK 3 cancers [3� ] University of Leeds, Leeds LS2 9JT, UK 90 Curr Breast Cancer Rep (2019) 11:89–93 1. To monitor rates of interval cancers in conjunction with The UK has quality standards for all aspects of the Breast rates of screen-detected cancer to provide information on Screening programme. The standards for interval cancer rates whole programme performance. were updated in 2017 and are as follows: 2. To support education and learning objectives for screen- <12 months—0.65/1000, 12 < 24 months—1.4/1000, 24 ing services and individuals. This helps improve the qual- <36 months—1.65/1000 (compared with < 24 months—1.2/ ity of the service provided to women. 1000, 24 < 36 months—1.4/1000 in previous standards) [7]. 3. So that women who have had an interval cancer can un- The rates were increased to reflect the background inci- derstand whether any abnormality was present on their dence increase since 1995 and also split into three rates for previous films and if they wish to receive the information. each year to allow greater accuracy. All of these are important. With regard to number 3, from the outset of the National Health Service Breast Screening Programme, women in the UK have always had the opportu- Factors Affecting Interval Cancer Rates nity to discuss findings from review of their previous images with a clinician involved in their care, a process referred to as Rates are affected by ascertainment methods, screening “Disclosure of Audit”.More recently “Duty of Candour” has round length, underlying background breast cancer inci- been introduced in the UK and this will be discussed more dence within a given population, and also risk factors. fully later in the review [4� ]. To achieve accurate data, robust systems need to be in The most recently available national data from the UK place with good communication between cancer regis- quotes the following statistics [2]. tries and both screening and symptomatic breast ser- vices. In a three yearly screening programme, the inter- & Of 1,625,063 women screened in 2007/8 val cancer rate goes up by approximately 75% in the & Overall interval cancer rate in 3 years following screen third year which is why most countries in Europe have (50–64) = 2.86/1000 adopted two yearly programmes. In a three yearly & Interval cancer rate in 2 years following screen (50–64) = screening programme, if round length is significantly 1.61/1000 less than 36 months, interval cancer rates would fall & Overall interval cancer rate in 3 years following screen whilst the converse would be true if round length was (50–70) = 2.95/1000 significantly longer. & Interval cancer rate in 2 years following screen (50–70) = Risk factors for development of interval breast cancers are 1.64/1000 high breast density, age, current use of hormone replacement therapy, and family history of breast cancer [8–11]. High Tornberg et al. compared the interval cancer rates in six breast density increases risk in two ways. It has a masking European countries with organised, population-based screen- effect but also it is an independent risk factor for breast cancer. ing and found rates of interval breast cancers ranged from 8.4 In addition to these factors, it has also been shown that to 21.3 per 10,000 screenings [5]. there is an association between the detection and treat- The following classification system for radiological review ment of high grade DCIS and subsequent prevention of of interval cancers has been used in the UK since 2017 [3� ] invasive interval cancers. Duffyetal. obtainedaggregate data for DCIS diagnoses for women aged 50–64 years 1. Satisfactory—Normal or benign mammographic features who were invited to and attended mammographic breast 2. Satisfactory with learning points—Seen with hindsight, screening from April 2003 to March 2007 (from the difficult to perceive, not obviously malignant National Health Service Breast Screening Programme). 3. Unsatisfactory—Appearance is obviously malignant Patient-level data for interval cancer arising in the 36 months after each of these were also analysed. The This varies slightly from the previous classification where cat average frequency of DCIS detected at screening was 3 was defined as—Appearance suspicious of malignancy [6]. 1.60 per 1000 women screened. There was a significant The majority of interval cancers fall into category 1 (ap- negative association of screen-detected DCIS cases with proximately 77%), whilst category 2 accounts for approxi- the rate of invasive interval cancers. Ninety percent of mately 16% and category 3 approximately 7% [2]. It is likely units had a DCIS detection frequency within the range that with the updated classification system the percentage of of 1.00 to 2.22 per 1000 women; in these units, for every category 3 interval cancers will decrease. This will therefore three screen-detected cases of DCIS, there was one fewer make it difficult to ascertain whether any decrease is due to invasive interval cancer in the next 3 years [12]. The true improvements in the screening programme or solely to challenge for radiologists is to recall intermediate/high the updated classification system. grade DCIS and not overcall cases of low grade DCIS. Curr Breast Cancer Rep (2019) 11:89–93 91 Radiological Features screen-detected cancer or the detection of slow-growing tu- mours [20–22]. As discussed, earlier monitoring and surveillance of interval cancers is very important. In the UK, the NHSBSP makes recommendations regarding the review process. It states that Effect of New Technologies on Interval Cancer a minimum of two reviewers should review the images, that Rates the previous screening mammograms, with all prior images that were available at the time of screening, should be There has been a transition from screen film mammography reviewed by the readers independently and that the diagnostic (SFM) to full field digital mammography (FFDM) in most images should then be reviewed to confirm that any subtle or screening programmes. Published data on the effect on inter- suspicious signs detected on the previous screening images val cancer rates has mainly been at unit or regional level, match the site of the confirmed breast cancer on the diagnostic showing mixed data but certainly no increase in interval can- images [3� ]. However, the exact method of review varies cer rates [23, 24]. Sankatsing et al. have recently published widely which may account for variation in reported interval national data from the Dutch screening programme assessing cancer rates. The ideal review method would involve blinded the effect of the transition to FFDM. Data of 7.3 million review of cases interspersed with normal screening mammo- screens in women aged 49–74, between 2004 and 2011, were grams. In reality due to time and clinical commitments, many linked to the Netherlands Cancer Registry to obtain data on interval cancer reviews are informed which naturally intro- interval cancers. They found that during the transition from duces bias into the process with the reviewer more likely to SFM to FFDM, there was a significant rise in cancer detection classify a case as category 2 or 3 than if the process was rate and a stable interval cancer rate, leading to increased blinded. The mammographic features most likely to be missed programme sensitivity. Although the recall rate increased, pro- are asymmetric densities, ill-defined masses, subtle distor- gramme specificity remained high [25]. Hoff et al. looked at tions, and calcification [13, 14]. the mammographic features and found that in previous mam- mograms of cancers missed at FFDM there was a non- significant trend towards a higher % of asymmetric densities Pathological and Biological Features (27 vs 10%, P = 0.007) and a lower % of calcifications (18 vs 34%, P = 0.185) compared with those missed at SFM [24]. In terms of detection, some tumours particularly lobular The use of computer aided detection (CAD) has not may have subtle mammographic appearances or even be been shown to reduce recall rates [26]. Digital breast occult. In addition, small high grade cancers may appear tomosynthesis has been introduced in many countries as well-defined masses and be misinterpreted as benign. with most large-scale studies demonstrating improved Studies looking at the pathology, biology, and prognosis cancer detection rates. However, unless there is a corre- of interval cancers have consistently found that they sponding reduction in interval cancer rates, the implica- have poorer prognostic features compared with screen- tion is that there will be little impact on mortality. It is detected cancers. Consistent findings are larger size, still early days for results from the major studies but higher grade, and node positivity [1]. there have been several recent publications. Houssami There is also published work on biomarkers. Collett et al. et al. examined interval breast cancers ascertained at 2- found that a basal epithelial phenotype (express cytokeratin and year follow-up for women involved in the “Screening P-cadherin) is more frequent in interval breast cancers compared with tomosynthesis or standard mammography” with screen-detected tumours. Patients with interval cancers were (STORM) population-based trial. In the study group, more likely to be younger, have dense breasts, ER negative tu- the interval cancer rate was 1.23/1000 screens (95% CI mours, and p53 expression [15]. Data from other authors is mixed 0.56 to 2.34). In concurrently screened women who but the majority have found a higher proportion of triple negative attended the same screening services and received 2D- tumours and over expression of HER 2 in interval cancers mammography, the interval cancer rate was 1.60/1000 [16–19]. Interestingly, Holm et al. compared biological markers screens (95% CI 1.14 to 2.17). They concluded that the in interval cancers in non-dense breasts (≤ 20% mammographic interval breast cancer rate amongst screening participants density) with interval cancers in dense breasts (> 40.9% mammo- in the STORM trial was marginally lower than estimates graphic density) and found that the cancers in the low density amongst 2D-screened women [27� ]. Skaane et al. have breasts were phenotypically more aggressive [10]. also published interval cancer data from the results from Breast cancer-specific survival in interval cancer is worse the prospective population-based Oslo Tomosynthesis than in screen-detected cancer. However, this difference may Screening Trial. They found that although there was an partly be explained by lead or length time bias, resulting in an increase in cancer detection rate and increased specificity there was no change in interval cancer rates [28]. artificial increase in survival time due to the early diagnosis in 92 Curr Breast Cancer Rep (2019) 11:89–93 Duty of Candour and if it is felt that there was either a process failure or that interpretation fell below an expected standard then DOC reg- Up until 2015, breast patients were offered results of interval ulations should apply. As part of the collaborative work, it was cancer review according to “Disclosure of Audit” guidance [29]. also felt necessary to produce new guidance on interval can- This was a document produced by the NHSBSP and covered cers to ensure a clearer and more consistent approach. As communication regarding interval cancers. It covered suggested stated earlier, this resulted in Category 3 changing from methodology for the review process with advice on when and Unsatisfactory—Appearance suspicious of malignancy [6]to how to communicate in an open way whilst still minimising Unsatisfactory—Appearance is obviously malignant [3� ]. It distress to both patients and professionals. This had to change was felt that this made clearer the link between classification following the introduction of Duty of Candour (DOC). and what action is warranted. It is still too early to assess what DOC is a Care Quality Commission (CQC) regulation (num- impact this legislation will have on the breast screening pro- ber 20) published in April 2015 in response to the Francis report gramme but certainly the PHE publications make it easier to (this was a report into incidents at a NHS hospital trust) [30, 31]. ensure consistency across different units. The key points about DOC are that NHS organisations must act in an open and transparent way when things go wrong, they must tell users as soon as practicable about notifiable safety incidents Conclusions and results of investigations and that they must apologise. This applies to all aspects of NHS care. There is evidence that open Interval cancer rates within the context of breast screening are communication reduces risk of litigation. important metrics. Interval cancers are known to have relative- Within the act a “notifiable safety incident” means “any ly worse prognosis than screen-detected cancers and therefore unintended or unexpected incident that occurred in respect of the accurate monitoring of interval cancers is important. This a service user during the provision of a regulated activity that, is particularly the case when new imaging technologies are in the reasonable opinion of a health care professional, could recommended to replace 2D digital mammography as a result in, or appears to have resulted in—the death of the screening tool. Tomosynthesis has been shown to be a prom- service user, where the death relates directly to the incident ising screening tool but the data regarding the impact on in- rather than to the natural course of the service user’sillnessor terval cancer rates is limited as many studies are still ongoing. underlying condition, or severe harm, moderate harm or prolonged psychological harm to the service user” [30]. It Compliance with Ethical Standards became apparent very soon after the act was introduced that this would have a major potential impact on the breast screen- Conflict of Interest Eleanor Cornford and Nisha Sharma declare no conflicts of interest relevant to this manuscript. ing programme, staff morale and recruitment as there was the perception by some NHS Hospitals that any interval breast Human and Animal Rights and Informed Consent This article does not cancer constituted a notifiable safety incident! Collaborative contain any studies with human or animal subjects performed by any of work between Public Health England, the CQC and screening the authors. representatives resulted in the publication of a new document, Open Access This article is distributed under the terms of the Creative the aim of which was to advise on best practice in NHS Commons Attribution 4.0 International License (http:// Screening programmes to ensure compliance with DOC reg- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, ulations [4� ]. It explains that screening tests are not 100% distribution, and reproduction in any medium, provided you give appro- accurate so will have false negatives and false positives and priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. these should not automatically trigger DOC. 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