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Open accessJournal ArticleDOI: 10.1038/S41416-020-01152-5

Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project

02 Mar 2021-British Journal of Cancer (Springer Science and Business Media LLC)-Vol. 124, Iss: 5, pp 1009-1017
Abstract: The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes. This was a national, prospective cohort study of DCIS diagnosed during 2003–2012. Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years. DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.

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8 results found

Open accessPosted ContentDOI: 10.1101/2021.03.22.21253209
Esther H. Lips1, Tapsi Kumar2, Anargyros Megalios3, Lindy L. Visser1  +46 moreInstitutions (10)
26 Mar 2021-medRxiv
Abstract: Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

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Topics: Ductal carcinoma (51%), Breast cancer (50%)

1 Citations

Journal ArticleDOI: 10.1093/JJCO/HYAB082
Abstract: Purpose Four clinical active surveillance trials including LORIS, COMET, LORD and LORETTA, are being conducted to assess whether women with low-risk ductal carcinoma in situ can safely avoid surgery. The present study aimed to determine the rate of upstaging to invasive cancer among patients with a preoperative diagnosis of ductal carcinoma in situ and to evaluate the incidence of upstaging in patients meeting the eligibility criteria for four active surveillance clinical trials. Methods The present study initially enrolled 180 patients with 183 calcifications who received the diagnosis of ductal carcinoma in situ by biopsy. Patients were classified as eligible for four clinical trials according to the respective inclusion criteria. Results In total, 152 patients with 155 calcifications were analyzed. Of these, 32 (21%) were upstaged to invasive disease based on the final pathological analysis of surgical specimens. Of the 152 patients, 53 (35%), 90 (59%), 24 (16%) and 34 (22%) met the eligibility criteria for the LORIS, COMET, LORD and LORETTA trial, respectively. Among patients with low-risk ductal carcinoma in situ, 10 (19%), 14 (16%), 6 (25%) and 4 (12%) patients were upstaged to invasive disease in LORIS, COMET, LORD and LORETTA, respectively. The upstaging to pT1b or higher rates were 2% (1/53), 3% (3/90), 0% (0/24) and 3% (1/34) in LORIS, COMET, LORD and LORETTA, respectively. Conclusions The upstaging rate in patients eligible for the clinical active surveillance trials was 12-25%. Although the rate of upstaging to pT1b or higher was low, further studies are required to determine the rates of upstaging to invasive cancer and the risk factors among patients with low-risk ductal carcinoma in situ.

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Topics: Ductal carcinoma (53%)

Open accessJournal ArticleDOI: 10.1038/S41416-021-01496-6
Maartje van Seijen1, Esther H. Lips1, Liping Fu1, Daniele Giardiello1  +13 moreInstitutions (5)
Abstract: BACKGROUND Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort. METHODS The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989-2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models. RESULTS The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9-32.6) after BCS compared to 18.2% (95% CI 16.3-20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)age < 50 3.2 (95% CI 1.6-6.6); HRage ≥ 50 3.6 (95% CI 2.6-4.8) and for iIBC: HRage<50 2.1 (95% CI 1.4-3.2); HRage ≥ 50 4.3 (95% CI 3.0-6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HRage < 50 0.7 (95% CI 0.3-1.5); HRage ≥ 50 0.7 (95% CI 0.4-1.3) and for iIBC: HRage < 50 0.6 (95% CI 0.4-0.9); HRage ≥ 50 1.2 (95% CI 0.9-1.6)). CONCLUSION RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

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Topics: Population (50%)


37 results found

Open accessJournal ArticleDOI: 10.1136/JNNP.2.4.335
Abstract: AFFECTIONS of the nervous system which result from inadequate nutrition have assumed an increasingly important position through the rapid accumulation of clinical, experimental, and pathological data. The artificial synthesis of a number of the components of the vitamin B complex has made available pure crystalline material in large amounts for clinical research, and thus a milestone in the history of these affections has been passed. It now seems appropriate to review and summarize the knowledge of these important substances. To evaluate the status of a nutritional deficiency in man is difficult. As a rule the patient induces his own disease and provides a deficiency that is not quantitatively measurable, but frequently clinical and laboratory evaluations are attempted. Both the laboratory method and the clinical method have certain advantages. Mice are not yet men and until they are the work coming -from the study of human beings is essential. Since the experience of investigators working with animals may often point the way for clinical research, we have interspersed in this review a few of the pertinent studies on the effect of nutritional deficiency on the nervous system of animals. A scheme for illustrating the multiple factors of the vitamin B complex is given in Fig. 1. To date the following portions of the vitamin B complex have been isolated and synthesized in amounts sufficient to allow for clinical trial: thiamin hydrochloride, nicotinic acid, riboflavin, and 2-methyl, 3-hydroxy, 4, 5-di (hydroxymethyl) pyridine. The deficiencies of these substances as they apply to the nervous system of man will be discussed briefly.

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2,604 Citations

Open accessJournal ArticleDOI: 10.1016/S0140-6736(12)61611-0
Michael Marmot1, Douglas G. Altman2, David Cameron3, John Dewar4  +2 moreInstitutions (5)
17 Nov 2012-The Lancet
Abstract: © 2013 Cancer Research UK. All rights reserved. 1.1 Introduction: The breast cancer screening programmes in the United Kingdom currently invite women aged 50-70 years for screening mammography every 3 years. Since the time the screening programmes were established, there has been debate, at times sharply polarised, over the magnitude of their benefit and harm, and the balance between them. The expected major benefit is reduction in mortality from breast cancer. The major harm is overdiagnosis and its consequences; overdiagnosis refers to the detection of cancers on screening, which would not have become clinically apparent in the woman's lifetime in the absence of screening. Professor Sir Mike Richards, National Cancer Director, England, and Dr Harpal Kumar, Chief Executive Officer of Cancer Research UK, asked Professor Sir Michael Marmot to convene and chair an independent panel to review the evidence on benefits and harms of breast screening in the context of the UK breast screening programmes. The panel, authors of this report, reviewed the extensive literature and heard testimony from experts in the field who were the main contributors to the debate. The nature of information communicated to the public, which too has sparked debate, was not part of the terms of reference of the panel, which are listed in Appendix 1. 1.2 Relative mortality benefit: The purpose of screening is to advance the time of diagnosis so that prognosis can be improved by earlier intervention. A consequence of earlier diagnosis is that it increases the apparent incidence of breast cancer in a screened population and extends the average time from diagnosis to death, even if screening were to confer no benefit. The appropriate measure of benefit, therefore, is reduction in mortality from breast cancer in women offered screening compared with women not offered screening. In the panel's judgement, the best evidence for the relative benefit of screening on mortality reduction comes from 11 randomised controlled trials (RCTs) of breast screening. Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality in women invited for screening. The relative reduction in mortality will be higher for women actually attending screening, but by how much is difficult to say because women who do not attend are likely to have a different background risk. Three types of uncertainties surround this estimate of 20% reduction in breast cancer mortality. The first is statistical: the 95% confidence interval (CI) around the relative risk (RR) reduction of 20% was 11-27%. The second is bias: there are a number of potential sources of distortion in the trials that have been widely discussed in the literature ranging from suboptimal randomisation to problems in adjudicating cause of death. The third is the relevance of these old trials to the current screening programmes. The panel acknowledged these uncertainties, but concluded that a 20% reduction is still the most reasonable estimate of the effect of the current UK screening programmes on breast cancer mortality. Most other reviews of the RCTs have yielded similar estimates of relative benefit. The RCTs were all conducted at least 20-30 years ago. More contemporary estimates of the benefit of breast cancer screening come from observational studies. The panel reviewed three types of observational studies. The first were ecological studies comparing areas, or time periods, when screening programmes were and were not in place. These have generated diverse findings, partly because of the major advances in treatment of breast cancer, which have a demonstrably larger influence on mortality trends than does screening, and partly because of the difficulty of excluding imbalances in other factors that could affect breast cancer mortality. The panel did not consider these studies helpful in estimating the effect of screening on mortality. The other two types of studies, case-control studies and incidence-based mortality studies, showed breast screening to confer a greater benefit than did the trials. Although these studies, in general, attempted to control for non-comparability of screened and unscreened women, the panel was concerned that residual bias could inflate the estimate of benefit. However, the panel notes that these studies' findings are in the same direction as the trials. 1.3 Absolute mortality benefit: Estimates of absolute benefit of screening have varied from one breast cancer death avoided for 2000 women invited to screening to 1 avoided for about 100 women screened, about a 20-fold difference. Major determinants of that large variation are the age of women screened, and the durations of screening and follow-up. The age of the women invited is important, as mortality from breast cancer increases markedly with age. The panel therefore applied the relative mortality reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality over the ages 55-79 years for women in the United Kingdom, assuming that women who began screening at 50 years would gain no benefit in the first 5 years, but that the mortality reduction would continue for 10 years after screening ended. This yielded the estimate that for every 235 women invited to screening, one breast cancer death would be prevented; correspondingly 180 women would need to be screened to prevent one breast cancer death. Uncertainties in the figure of a 20% RR reduction would carry through to these estimates of absolute mortality benefit. Nonetheless, the panel's estimate of benefit is in the range of one breast cancer death prevented for B250 women invited, rather than the range of 1 in 2000. 1.4 Overdiagnosis: The major harm of screening considered by the panel was that of overdiagnosis. Given the definition of an overdiagnosed cancer, either invasive or non-invasive, as one diagnosed by screening, which would not otherwise have come to attention in the woman's lifetime, there is need for a long follow-up to assess the frequency of overdiagnosis. In the view of the panel, some cancers detected by screening will be overdiagnosed, but the uncertainty surrounding the extent of overdiagnosis is greater than that for the estimate of mortality benefit because there are few sources of reliable data. The issue for the UK screening programmes is the magnitude of overdiagnosis in women who have been in a screening programme from age 50 to 70, then followed for the rest of their lives. There are no data to answer this question directly. Any estimate will therefore be, at best, provisional. Although the definition of an overdiagnosed case, and thus the numerator in a ratio, is clear, the choice of denominator has been the source of further variability in published estimates. Different studies have used: only the cancers found by screening; cancers found during the whole screening period, both screen-detected and interval; cancers diagnosed during the screening period and for the remainder of the women's lifetime. The panel focused on two estimates: the first from a population perspective using as the denominator the number of breast cancers, both invasive and ductal carcinoma in situ (DCIS), diagnosed throughout the rest of a woman's lifetime after the age that screening begins, and the second from the perspective of a woman invited to screening using the total number of breast cancers diagnosed during the screening period as the denominator. The panel thought that the best evidence came from three RCTs that did not systematically screen the control group at the end of the screening period and followed these women for several more years. The frequency of overdiagnosis was of the order of 11% from a population perspective, and about 19% from the perspective of a woman invited to screening. Trials that included systematic screening of the control group at the end of the active part of the trial were not considered to provide informative estimates of the frequency of overdiagnosis. Information from observational studies was also considered. One method that has been used is investigation of time trends in incidence rates of breast cancer for different age groups over the period that population screening was introduced. The published results of these studies varied greatly and have been interpreted as providing either reassurance or cause for alarm. So great was the variation in results that the panel conducted an exercise by varying the assumptions and statistical methods underlying these studies, using the same data sets; estimates of overdiagnosis rates were found to vary across the range of 0-36% of invasive breast cancers diagnosed during the screening period. The panel had no reason to favour one set of estimates over another, and concluded that this method could give no reliable estimate of the extent of overdiagnosis. Were it possible to distinguish at screening those cancers that would not otherwise have come to attention from those that, untreated, would lead to death, the overdiagnosis problem could be much reduced, at least in terms of unnecessary worry and treatment. Currently this is not possible, so neither the woman nor her doctor can know whether a screen-detected cancer is an 'overdiagnosed' case or not. In particular, DCIS, most often diagnosed at screening, does not inevitably equate to overdiagnosis - screen-detected DCIS, after wide local excision (WLE) only, is associated with subsequent development of invasive breast cancer in 10% of women within 10 years. The consequences of overdiagnosis matter, women are turned into patients unnecessarily, surgery and other forms of cancer treatment are undertaken, and quality of life and psychological well being are adversely affected.

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Topics: Overdiagnosis (72%), Breast cancer screening (69%), Mass screening (66%) ... show more

1,231 Citations

Journal ArticleDOI: 10.1016/0140-6736(90)90747-S
03 Mar 1990-The Lancet
Abstract: To assess the potential of breast-conserving treatment for ductal carcinoma in situ (DCIS), 82 mastectomy specimens were studied by Egan's serial subgross method. 42 (51%) of the tumours were larger than 50 mm and only 12 (15%) were smaller than 20 mm; the size distribution was not affected by the mode of detection (mammography 52 cases, clinical examination 30). All but 1 case showed only 1 region of tumour. 66% of tumours involved one breast quadrant, 23% extended over more than one quadrant, and 11% were centrally located. Mammographic estimates, based on the extent of microcalcifications, frequently underestimated the histological size of tumours, the extent of the discrepancy being related to the histological type—8/50 predominantly comedo DCIS showed a discrepancy greater than 20 mm compared with 15/32 predominantly micropapillary/cribriform. In view of the frequently large size, adequate excision of many DCIS will require a wide excision involving up to a whole quadrant.

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Topics: Ductal carcinoma (54%)

554 Citations

Open accessJournal ArticleDOI: 10.1093/JNCIMONOGRAPHS/LGQ039
C Correa, Paul McGale, Carolyn W. Taylor, Yaochen Wang  +6 moreInstitutions (1)
Abstract: Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages ≥ 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10-year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.

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Topics: Breast cancer (60%), Ductal carcinoma (50%)

500 Citations

Open accessJournal ArticleDOI: 10.1016/S1470-2045(10)70266-7
Jack Cuzick1, Ivana Sestak1, Sarah E Pinder2, Ian O. Ellis3  +6 moreInstitutions (8)
01 Jan 2011-Lancet Oncology
Abstract: Summary Background Initial results of the UK/ANZ DCIS (UK, Australia, and New Zealand ductal carcinoma in situ) trial suggested that radiotherapy reduced new breast events of ipsilateral invasive and ductal carcinoma in situ (DCIS) compared with no radiotherapy, but no significant effects were noted with tamoxifen. Here, we report long-term results of this trial. Methods Women with completely locally excised DCIS were recruited into a randomised 2×2 factorial trial of radiotherapy, tamoxifen, or both. Randomisation was independently done for each of the two treatments (radiotherapy and tamoxifen), stratified by screening assessment centre, and blocked in groups of four. The recommended dose for radiation was 50 Gy in 25 fractions over 5 weeks (2 Gy per day on weekdays), and tamoxifen was prescribed at a dose of 20 mg daily for 5 years. Elective decision to withhold or provide one of the treatments was permitted. The endpoints of primary interest were invasive ipsilateral new breast events for the radiotherapy comparison and any new breast event, including contralateral disease and DCIS, for tamoxifen. Analysis of each of the two treatment comparisons was restricted to patients who were randomly assigned to that treatment. Analyses were by intention to treat. All trial drugs have been completed and this study is in long-term follow-up. This study is registered, number ISRCTN99513870. Findings Between May, 1990, and August, 1998, 1701 women were randomly assigned to radiotherapy and tamoxifen, radiotherapy alone, tamoxifen alone, or to no adjuvant treatment. Seven patients had protocol violations and thus 1694 patients were available for analysis. After a median follow-up of 12·7 years (IQR 10·9–14·7), 376 (163 invasive [122 ipsilateral vs 39 contralateral], 197 DCIS [174 ipsilateral vs 17 contralateral], and 16 of unknown invasiveness or laterality) breast cancers were diagnosed. Radiotherapy reduced the incidence of all new breast events (hazard ratio [HR] 0·41, 95% CI 0·30–0·56; p Interpretation This updated analysis confirms the long-term beneficial effect of radiotherapy and reports a benefit for tamoxifen in reducing local and contralateral new breast events for women with DCIS treated by complete local excision. Funding Cancer Research UK and the Australian National Health and Medical Research Council.

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Topics: Tamoxifen (53%)

419 Citations

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