· Web viewSYSTEMATIC REVIEW AND META-ANALYSIS OF THE EFFECT OF PREOPERATIVE BREAST MRI ON THE SURGICAL MANAGEMENT OF DUCTAL CARCINOMA IN SITU. Running title: MRI versus conventional

SYSTEMATIC REVIEW AND META-ANALYSIS OF THE EFFECT OF

PREOPERATIVE BREAST MRI ON THE SURGICAL MANAGEMENT OF DUCTAL

CARCINOMA IN SITU.

Running title: MRI versus conventional preoperative assessment in DCIS of the breast

Authors:

Alessandro Fancellu1, Robin M. Turner2, J. Michael Dixon3, Antonio Pinna1, Pietrina Cottu1,

Nehmat Houssami4

1 Dept. of Clinical and Experimental Medicine, Unit of General Surgery 2, Clinica Chirurgica.

University of Sassari, Sassari, Italy.2School of Public Health and Community Medicine, The University of New South Wales, New

South Wales, Australia.3Breakthrough Breast Cancer Research Unit, Institute of Genetics and Molecular

Medicine, University of Edinburgh, UK.4 Screening and Test Evaluation Program, School of Public Health, Sydney Medical School,

University of Sydney, Sydney, Australia.  

Corresponding Author:

Dr. Alessandro Fancellu, MD, PhD,

Dept. of Clinical and Experimental Medicine, Unit of General Surgery 2, Clinica Chirurgica.

University of Sassari. V.le San Pietro, 43, 07100 Sassari, Italy

Tel: +39 079 228432

Fax: +39 079 223494

e-mail: [email protected]

Category: Systematic review

Funding: N. Houssami receives research support via a National Breast Cancer Foundation (NBCF

Australia) Practitioner Fellowship.

This paper is not based on a previous communication to a society or meeting.

1

ABSTRACT

Background: Magnetic resonance imaging (MRI) has been used increasingly in the diagnosis and

management of women with breast cancer. However, its usefulness in the preoperative assessment

of DCIS remains questionable. A meta-analysis was conducted to examine the effects of MRI on

surgical treatment of DCIS by analyzing studies comparing preoperative MRI and conventional

preoperative assessment.

Methods: Using random-effects modeling, the proportion of women with various outcomes in the

MRI versus no-MRI groups was estimated, and the odds ratio (OR) and adjusted OR (adjusted for

study-level median age) for each model were calculated.

Results: Nine eligible studies were identified that included 1 077 women with DCIS who had

preoperative MRI and 2 175 who did not. MRI significantly increased the odds of having initial

mastectomy [OR, 1.72 (P = 0.012); adjusted OR, 1.76, P = 0.010)]. There were no significant

differences in the odds of having positive margins after breast conserving surgery (BCS) between

the MRI and no-MRI groups [OR , 0.80 (P = 0.059); adjusted OR, 1.10 (P = 0.716)], nor in the

odds of having reoperation for positive margins after BCS [OR 1.06 (P = 0.759); adjusted OR 1.04

(P = 0.844)]. Overall mastectomy rates did not significantly differ according to whether or not MRI

was performed [OR 1.23, (P = 0.340); adjusted OR 0.97, (P = 0.881)].

Conclusions: Preoperative MRI in patients with DCIS is not associated with improvement in

surgical outcomes. Further studies may identify subsets of DCIS patients who might possibly

benefit from preoperative MRI.

INTRODUCTION

Ductal carcinoma in situ (DCIS) is the most common form of noninvasive cancer in the breast,

and constitutes a spectrum of proliferating malignant cells that are confined within the basement

membrane of the ductal epithelium1-3. As a consequence of widespread mammographic screening,

2

DCIS today accounts for 20-25 per cent of newly diagnosed breast cancers, with more than

63 000 cases diagnosed annually in the United States4-7.

In patients with DCIS, surgical planning traditionally follows “triple assessment” with clinical

examination, mammography, and a tissue diagnosis. However, in recent years, magnetic

resonance imaging (MRI) has been used preoperatively in patients with DCIS with the aim of

better defining surgical treatment selection and reducing the need for additional surgery after

breast conserving surgery (BCS)8-10. In fact, the use of additional MRI imaging after standard

mammograpghy may theoretically help in better defining the extent of DCIS 8,11,12.

Whether the use of preoperative MRI in patients with DCIS translates into oncological

advantages in terms of local control and survival is far from clear 12-17. In this regard, two recent

studies reported no advantages for local control of DCIS in patients who underwent preoperative

MRI and BCS12,18. Furthermore, preoperative MRI has other disadvantages in that it increases the

numbers of unnecessary surgical biopsies9,10,13,19.

Thus, the effectiveness of preoperative MRI in patients with DCIS remains uncertain as recent

studies have suggested that MRI does not lead to improved rates of complete excision and may

increase rates of mastectomy9,16,20,21. Most studies of MRI in patients with DCIS have included

relatively small numbers of patients and individually studies to date may have limited statistical

power. To examine the effect of preoperative MRI in the management of biopsy-proven DCIS, a

systematic review and meta-analysis were conducted of studies comparing patients who had

preoperative MRI (MRI group) with those who had triple assessment only (no-MRI group). The

aim was to determine the effect of preoperative MRI on surgical outcomes, specifically the rates

of reoperation for positive margins and the rate of mastectomy. A secondary endpoint was to

estimate the proportion of patients who had an MRI-triggered change of treatment.

3

METHODS

Study Selection

A systematic literature search was performed using the PubMed and Cochrane databases, for

studies reporting surgical outcomes of preoperative MRI in patients diagnosed with DCIS, using

the following keywords: “ductal carcinoma in situ”, “DCIS”, “intraductal”, “MRI”, “Magnetic

Resonance Imaging” and “breast”. The “related articles” function was used to broaden the search

and all abstracts, studies, and citations scanned were reviewed as were the references of relevant

articles. The latest date for this search was March 31, 2014. No language restrictions were made.

Inclusion Criteria

For the purposes of this systematic review and meta-analysis, studies reporting on patients with

DCIS on preoperative histology were considered. To be included in this meta-analysis, studies

had to: compare outcomes of patients who had preoperative MRI (MRI group) with patients who

did not have an MRI (no-MRI group) who underwent surgery for DCIS using a controlled study

design (either randomized controlled trial or comparative cohort design); and to report on at least

one of the defined surgical outcomes (described below).

Exclusion Criteria

Studies were excluded according to the following criteria: studies that only compared MRI with

no-MRI in patients with invasive breast carcinomas; studies that compared MRI with no-MRI in

cohorts that included both invasive breast carcinoma and DCIS where it was not possible to

extract data separately for DCIS patients; studies in which the outcomes of interest (specified

below) were not reported or were not clearly reported, or if data could not be obtained or

calculated separately for each of the MRI and no-MRI groups.

Data Extraction & Quality Assessment4

One author (AF) reviewed abstracts from the literature search, and identified potentially relevant

articles. Two authors (AF, NH) extracted the following data: publication details, study population

and time-frame, number of subjects who had surgical treatment with and without preoperative

MRI, total number of DCIS cases, preoperative histology, tumour pathologic size, initial surgical

intervention (BCS or mastectomy), and final surgical outcomes. To assess the quality of studies,

the following information was also extracted: study design (whether randomisation was used; and

whether prospective or retrospective); whether consecutive subjects were included; and if a non-

randomised design was used whether the comparison group was appropriate.

Data extraction was consistent between the two reviewers. Where data on surgical outcomes were

reported but clarification was needed, study authors were contacted to confirm the data or to

obtain data clarification; this was required for 2 studies (Itakura et al, Shin et al)9,20. To avoid

overlapping patient groups, where studies reported on the same patients in more than one

publication, the most informative and/or most recent article was included.

Outcomes of Interest

Surgical outcomes were defined as follows: initial surgery (number of patients who had

mastectomy, number who had BCS); number of patients with positive margins (or incomplete

excision due to non-negative/positive margins) after breast conservation as initial surgery;

number of patients who had reoperation after initial BCS (re-excision or conversion to

mastectomy); overall number who received mastectomy (mastectomy as initial surgery plus

mastectomy after initial BCS); MRI-triggered change of treatment (patients in which initial

surgical planning was reported to have been modified because of MRI findings). This included

both change from breast conservation to mastectomy and change from unilateral to bilateral

surgery.

5

Statistical Analysis

Descriptive statistics (median and inter-quartile range [IQR]), were used to summarise across

studies study-level age, DCIS size, and time-frame. Random effects logistic meta-regression was

used to model the proportion of subjects with the surgical outcomes in separate models defined

under ‘methods’, with odds ratios (OR) estimated for the groups that had MRI versus those that

did not have MRI (referent group: no-MRI). Random study effects were included in all models to

allow for anticipated heterogeneity between studies beyond what would arise from within study

sampling error alone; taking account of both within- and between-study variability provides valid

standard errors, confidence intervals, and P-values. Study-specific and pooled proportions (from

the meta-regressions), and 95 per cent confidence intervals (CI), were estimated (and displayed in

forest plots). Statistical significance was set at P < 0.05.

Because an earlier meta-analysis of preoperative MRI22 showed correlation between receipt of

MRI and median age, and based on the summary descriptive data for the median study-level age

between the groups being compared, a simple adjustment for age was performed. This was done

by fitting age as a binary variable, whereby the study-level median age (or mean age if median

was not reported) was categorized as younger than the median value of the study-level median

ages or older than that median value, to obtain an adjusted OR for each model 22. Because a

limited number of studies reported age an ‘unknown’ category was also included so that all

studies could be retained in the analysis when adjusted for study-level age information. It should

be noted that this represented a minimal study-level adjustment, and that more complex

adjustments (or adjustments for more variables) were avoided due to the modest number of

studies providing data on covariates. A sensitivity analysis, that excluded one study using a

historical comparison group (identified through the quality assessment of study methods), was

performed to assess whether excluding that study altered estimates of surgical outcomes.

All analyses were conducted in Stata version 13.1 (StataCorp 2009; College Station, TX).

6

RESULTS

The flow diagram summarizing the search and study identification for this systematic review is

presented in Fig. 1. Nine studies were eligible for this meta-analysis9,12,20,23-29: 7 of these were

studies that compared cohorts defined by whether or not MRI was performed 9,12,20,25,27,28,29, and 2

were randomized controlled trials of preoperative MRI 23,26. Four studies included patients with

both DCIS and invasive breast cancer20,23,26,29, whereas 5 studies included patients with DCIS

only9,12,25,27,28. Four studies included patients undergoing BCS as primary surgery 12,20,23,27, whereas

5 studies evaluated preoperative MRI in patients scheduled for either mastectomy or breast

conservation as initial surgery9,25,26,28,29. The histological diagnosis of DCIS was obtained

preoperatively in most cases by using core-biopsy.

Overall, 3 252 subjects with DCIS were analyzed; of those, 1 077 had preoperative MRI and

2 175 did not. Characteristics of each study including quality assessment are summarized in Table

1; heterogeneity between studies for various patient and tumour characteristics was present. In all

the included studies, patients in the MRI and no-MRI groups were from the same time-frame,

except for one study29 that used a historical comparison group. The study-level median age for the

patients in the MRI and no-MRI groups was 54.2 years (IQR 51.7 to 57.7) and 60.7 years (IQR

59.2 to 63.0), respectively. The study-level median DCIS size for the MRI and no-MRI groups

was 2.6 cm (IQR 1.8 to 3.2) and 2.2 cm (IQR 1.6 to 2.5), respectively. The median study time-

frame (using mid-point of timeframe) was 2005 (IQR 2 003.75 to 2 007.5).

Four studies reported data for MRI-triggered changes of treatment 9,25,28,29: the proportion of

patients who had changes to initial surgical treatment (mostly conversion from a planned initial

BCS to initial mastectomy) based on preoperative MRI findings was estimated as 15.7 per cent

(95 per cent CI 6.1-35.0).

Modeled Estimates

7

The results of the models are summarized in Table 2. The number of subjects and studies

contributing to each model are shown: subject numbers vary according to the number of studies

reporting the specific surgical outcome and according to whether the analysis applied to all

subjects or only those who received initial BCS. In Table 2 are also shown the estimated pooled

proportions with each surgical outcome for the MRI vs no-MRI groups, as well as the OR

estimated from each model.

In the present meta-analysis, there was evidence that preoperative MRI increased the odds of

having mastectomy as initial surgery [OR, 1.72 (P = 0.012)]; this finding did not change after

adjustment for study-level age [adjusted OR, 1.76, P = 0.010)]. Conversely, the odds of receiving

breast conservation were much higher for women not having MRI [OR, 0.55 ( P = 0.006);

adjusted OR, 0.53 (P = 0.004)]. There were no statistical differences in the odds of having

positive margins or incomplete excision after BCS as initial surgery between the MRI and no-

MRI groups [OR , 0.80 (P = 0.059); OR from sensitivity analysis, 0.82 (P= 0.082); adjusted OR,

1.10 (P = 0.716)]. There were no statistical differences in the odds of having reoperation for

positive margins after BCS [OR 1.06 (P = 0.759); OR from sensitivity analysis, 1.16 (P = 0.475);

adjusted OR 1.04 (P = 0.844)]. The overall mastectomy rate (initial mastectomy plus mastectomy

for positive margins after BCS), however did not significantly differ according to whether or not

MRI was performed [OR 1.23, (P = 0.340); adjusted OR 0.97, (P = 0.881)].

Fig. 2 and Fig. 3 show study-specific and estimated pooled proportions for each surgical

outcome, the OR and the age-adjusted OR.

DISCUSSION

The use of MRI in breast practice has progressively increased over the last decade. In particular,

MRI has been used increasingly in the preoperative assessment of patients with both invasive and

non-invasive breast cancer. However, its value remains controversial given that it has not been

shown to be useful in improving surgical outcomes15,16,22,30 or longer term outcomes17. A recent 8

meta-analysis from Houssami et al, indicated an unfavorable harm-benefit ratio for surgical

outcomes from the routine use of preoperative MRI with evidence that it increased mastectomy

rates; however, meta-analytic studies have focused mainly on invasive breast cancer 22. The

application and potential value of MRI in patients with pure DCIS has been less well studied with

much fewer published reports. Hence, the aim of this work was to evaluate preoperative MRI for

patients with biopsy-proven DCIS through a systematic review and meta-analysis of studies that

have compared surgical outcomes for patients who did and did not have preoperative MRI. DCIS

differs in many respects from invasive cancer, in biological behavior, mammographic appearance,

surgical perspectives, adjuvant treatments, and even MRI imaging patterns 1,11,13,31,32. Some studies

have suggested in patients with biopsy-proven DCIS that MRI provides potentially a more

accurate assessment than mammography of the presence of multicentricity and may provide better

evaluation of disease extent31,33,34. From a surgical perspective, the potential advantages of

preoperative MRI in DCIS include fewer re-excisions for positive margins and detection of

multifocal or multicentric disease if MRI does indeed provide a better assessment than

mammography of disease extent that also leads to fewer reoperations. It is therefore plausible that

MRI could assist in surgical planning of patients with DCIS of the breast. However, data from the

current meta-analysis show no evidence that preoperative MRI does improve surgical outcomes

(collective data in Table 2). As in invasive cancer, in practice preoperative MRI in DCIS patients

appears to have some potential harms, such as increased mastectomies and increased surgical

biopsies13,16,19,20,22. One reason for this is that MRI has limited specificity in patients with DCIS

(ranging in the literature between 58 and 89 per cent) and variable positive predictive value

(ranging between 25 and 84 per cent)35.

One of the most important findings the present meta-analysis was that preoperative MRI

increased the odds that the initial surgery was mastectomy (27.6 per cent in the MRI group vs

18.2 per cent in the no-MRI patients). Conversely, the odds of having breast conservation were

9

significantly higher for women who did not have preoperative MRI (82.0 per cent vs 71.5 in the

MRI patients). These findings probably reflect MRI’s capacity for detecting multifocal and

multicentric disease and so results in more patients being considered unsuitable for BCS, and

based on the MRI assessment of disease these patients are considered as being better treated by

mastectomy. In this regard, whether mastectomy is justified in lower risk patients even if there is

extensive DCIS is far from clear. Although MRI identifies more disease than conventional

mammography and ultrasound there is no evidence either in invasive breast cancer or DCIS that

treating this MRI-detected disease with more radical surgery improves outcome. In contrast, it can

be argued that MRI does harm because mastectomy is usually advised if occult and

multicentric MRI-only detected foci are identified through preoperative MRI 27,30,36,.

In our the present study, the proportion of patients who had a change in their surgical treatment

based on preoperative MRI findings was estimated to be 15.7 per cent. Interestingly, this

proportion is similar to the studies on preoperative MRI in invasive breast cancer. A meta-

analysis from Houssami et al estimated that a median of 16 per cent of breast cancer patients had

additional disease identified on preoperative MRI leading to a change in surgical treatment 14.

Fancellu et al, also found that 16.5 per cent of patients eligible for breast conservation had MRI-

triggered change of initial surgical treatment13. Based on very limited information on conversion

from initial BCS to mastectomy due to MRI findings with description of correlation with final

pathology, it has been assumed that such conversion to mastectomy was appropriate because in

most cases (22 from 23 patients for the 3 studies) there was more extensive disease, either larger

tumour, or multifocal or multicentric disease9,25,28. Although this would seem a fair assumption, it

remains unclear whether for some of these patients breast conservation would have led to the

same prognostic outcomes had MR not been performed, as suggested in recent IPD meta-

analysis17, and this constitutes part of the ongoing controversy on MRI staging of the breast.

Furthermore, although again based on limited data, there was indication that MRI did not

correlate well with exact tumour size measurement at pathology25,27 suggesting that the above-10

mentioned assumed ‘appropriate’ conversion to mastectomy may represent unnecessary radical

surgery for at least some of the cases converted to mastectomy on the basis of MRI.  Thus, it

should be acknowledged that the issue of what is ‘necessary’ versus ‘unnecessary’ mastectomy in

patients with DCIS is open to debate and interpretation. The presumed justified conversion from

BCS to mastectomy (i.e. based on pathologically-proven more extensive or multicentric disease)

may not necessarily translate into patient benefit. Studies have reported that only 30 to 50 percent

of DCIS evolve to invasive disease if left untreated8,37. Given that much DCIS will not evolve to

invasive carcinoma, it could be argued that most of the patients with DCIS treated with

mastectomy receive an overtreatment. Besides, patients with higher risk DCIS receive radiation

after BCS and patients with estrogen positive DCIS often receive adjuvant endocrine treatment38.

These treatments are effective because they treat occult disease in the breast and so if MRI detects

disease that would otherwise have been effectively treated by radiotherapy or endocrine treatment

it is unlikely to improve outcomes12,13,39. In this context, it is possible that the role of MRI in DCIS

will become better defined when there is better understanding of DCIS biology.

Reoperation for tumor-involved margins or incomplete excision after BCS remains a primary

concern for breast surgeons and patients. In fact, although DCIS is a non-obligate precursor of

invasive carcinoma, it can locally recur as in situ or invasive disease and positive margins are one

of the most important risk factors for local recurrences 8,40,41. In the literature, the rate of

reoperation ranges between 10 per cent and 68 per cent and depends on multiple variables,

including differences in selection criteria for breast conservation, surgeons’ expertise, definition

of positive margins, surgical techniques, and tumor histotype 42,43. The rates of reoperation after

BCS are, in general, higher for patients undergoing surgery for DCIS than in patients with

invasive carcinoma. In a retrospective study, it has been reported that 29.5 per cent of the women

with DCIS in England had at least one reoperation after primary BCS within 3 months42. In the

present analysis, the rates of positive margins or incomplete excision after BCS, as well as the 11

reoperation rates, did not statistically differ between the MRI and no-MRI patients, despite the

fact that MRI should theoretically have provided a more accurate assessment of the tumor extent

compared to conventional imaging. These data may be explained by the possibility of

discrepancy between the MRI estimate of DCIS size and pathology size (as known to also occur

with mammography) as observed in MRI-specific studies44,45 studies, and by possible difficulty

in translating MRI images into surgical procedures (although there are no data to support the

latter possibility).

The present meta-analysis showed that the overall mastectomy rate did not statistically differ

between those who had and those who did not have MRI, even though the odds of having initial

mastectomy were higher in the MRI patients. The reoperation rates (including conversion to

mastectomy) were also not statistically different between the two groups. This partly reflects that

different studies contributed to the different models in the statistical analysis. There was the

suggestion of slightly higher reoperation rates in the MRI group, but the lack of significant

differences probably also reflect the limited power in some of the models that are based on only a

few studies. The model for ‘positive margins or incomplete excision’ included the largest dataset

in this meta-analysis, and indicated the lack of an effect from preoperative MRI for this important

surgical endpoint. It is also possible that at re-operation more of the MRI-group had wider

excisions whereas more of the no-MRI group had mastectomy, which would have the effect of

rendering similar final overall mastectomy rates for both groups despite the initially higher

mastectomy rate for the MRI group.

Histological studies have shown that most DCIS is unicentric. Much of the multifocal disease

identified by MRI may be in continuity rather than truly a second focus 46,47. Multifocality is not in

itself a contraindication to BCS in either DCIS or invasive breast cancer and satisfactory rates of

local control are possible with BCS48,49 assuming that the appropriateness of BCS is determined

by the ability to excise all of the disease with a good cosmetic result 50. 12

Some authors discuss a possible role of MRI in patients with particular subsets of DCIS 21,27,51.

Unfortunately, only three studies eligible for this meta-analysis reported data on preoperative

MRI according to tumour characteristics9,25,27; hence, there were limited outcomes data suitable

for subgroup analyses. Recent literature suggests that DCIS is a heterogeneous disease also from a

molecular perspective, including different subtypes with different biological behaviour 52-56.

Identification of subsets of DCIS patients who might benefit from MRI, if any, awaits further

definition of the biology associated with progression to invasive disease or recurrence.

The costs of MRI are of concerns in the current era of spending accountability, and the increased

time usually taken for obtaining MRI images and results is an important aspect when considering

routine use of preoperative MRI. Many have raised concerns also about possible delay in surgical

treatment due to the time implications of preoperative MRI13,17,57.

These issues are particularly relevant when dealing with a disease typically with an excellent life-

time prognosis such as DCIS of the breast.

A limitation of this work is the small number of studies that were available for inclusion in this

analysis, and that not all outcomes data were available for all studies. Furthermore, as identified

in the quality assessment (Table 1), only two studies were randomized trials and most studies

used a comparison group rather than randomization, therefore selection bias may have affected

the results of the primary studies and also the meta-analysis. The use of a historical comparison

group in one study29 was of concern from a methodology perspective to us , hence we its effect on

estimated OR’s was explored by including/excluding that study through a sensitivity analysis (as

shown in Table 2, its exclusion did not substantially change results). Despite these acknowledged

limitations, this work represents the largest comparative analysis of pre-operative MRI in DCIS 13

patients to date, and our the analyses were adjusted for observed imbalances in study-level age

between MRI and no-MRI groups, as identified in previous preoperative MRI research 22. When

interpreting the age-adjusted estimates, it is important to recognize that a study-level adjustment

does not entirely account for the potential effect of age, and further adjustment (either more

complex statistically, or including more variables) is not appropriate given that so few studies

were available.

In summary, the present meta-analysis has shown that preoperative MRI in patients with DCIS is

not associated with an improvement in surgical outcomes. MRI increases the initial rate of

mastectomy, although the overall mastectomy rate was not significantly increased from MRI.

Importantly, this meta-analysis shows that preoperative MRI does not reduce the odds of having

negative margins after BCS nor does it reduce the odds of patients requiring reoperation for

positive margins. On the basis of the collective evidence summarized in this meta-analysis,

preoperative MRI does not improve the surgical treatment of women with DCIS of the breast.

Further studies may be warranted for the identification of subsets of DCIS patients who might

potentially benefit from preoperative MRI.

AKNOWLEDGEMENTS

N. Houssami receives research support via a National Breast Cancer Foundation (NBCF

Australia) Practitioner Fellowship.

Disclosure: The authors declare no conflict of interest.

14

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21

FIGURE LEGENDS

Figure 1: Systematic search and selection strategy.

Figure 2 : Study-specific and estimated pooled proportions with each surgical outcome for MRI

versus no-MRI groups. Study-specific proportions are shown as circles, and pooled proportions

are shown as squares; lines represent 95% CI with solid lines for MRI group and dashed lines for

no-MRI.

Figure 3 : Estimates of the effect of preoperative MRI on surgical outcomes in DCIS. Number in

each model shown in square brackets; adjusted OR is based on study-level age adjustment (see

methods)

22

Full-text articles of potentially eligible publications evaluated against defined inclusion criteria:n=41

Publications excluded based on pre-defined eligibility criteria: n = 32Reported data only in subjects who had MRI (no comparison group), n=21Reported only on invasive carcinoma, n= 5Did not report specified surgical outcomes, n=3It was not possible to extrapolate data relative to DCIS patients: n=2Reported data also presented in a subsequent article for the same group included in this meta-analysis: n=1

Studies examining surgical outcomes for patients with DCIS receiving preoperative MRI, using a controlled study design: n=9 (7 RCC and 2 RCT)

Figure 1: Systematic search and selection strategy

Papers excluded if not eligible based

on screening of abstract:

n = 739

Potentially relevant publications were identified by searching PubMed & Cochrane

databases, from 1983 to March 2014, by combining the following keywords: “ductal

carcinoma in situ”, “ DCIS”, “intraductal”, “breast”, “magnetic resonance”, ”MRI”.

Potential relevant publications identified based on above search strategy: n=780

23

24

25

Table 1: Characteristics of Studies in the Meta-Analysis reporting on Preoperative MRI in DCIS

Author/

year of

publication

No. of DCIS

patientsEligible subjects Characteristics of the study & quality appraisal

Design

Was randomisation

used to assign to

intervention?

Were consecutive

subjects with DCIS

included or recruited?

If not a RCT, was

comparison group

appropriate?

Turnbull

(COMICE) 23,

2010

91

Patients with biopsy-

proven primary breast

cancer scheduled for

wide local excision

RCT Yes Yes

Not applicable, a RCT,

patients randomized within

same time-frame (2002-2007)

Allen25, 2010 98 Patients with DCIS who

underwent core biopsy

RCC No Yes Yes, same time-frame (2007)

Itakura9, 2010 149 Patients with DCIS who

underwent core biopsy

RCC No YesYes, same time-frame (2000-

2007)

Peters

(MONET)26,

2011

80

Patients with non-

palpable DCIS and IC

who underwent core

biopsy

RCT Yes Yes

Not applicable, a RCT,

patients randomized within

same time-frame (2006-2010)

Kropcho27,

2011158

Patients with DCIS

undergoing breast

conserving surgery

RCC No YesYes, same time-frame (2002-

2009)

Shin20, 2012 87Patients with DCIS

scheduled for breast

conserving surgery

RCC No YesYes, same time-frame (2003-

2005)

Davis28, 2012 218 Patients with DCIS who

underwent core biopsy

RCC No UnclearYes, same time-frame (2007-

2011)

Obdeijn29, 50 RCC No Unclear (consecutive for No, a historical comparison:

26

2013

Patients with DCIS and

IC suitable for breast

conserving surgery

two different time-

periods)

MRI group 2007-2010, no-

MRI group 2005-2006

Pilewskie12,

20142321

Patients with DCIS who

underwent breast

conserving surgery

RCC No YesYes, same time-frame (1997-

2010)

RCC, Retrospective Comparative Cohorts of DCIS patients; RCT, Randomized Controlled Trial; DCIS, Ductal Carcinoma In

Situ; IC, Invasive Carcinoma; NR, not reported

Table 2

Models Comparing Surgical Outcomes In Subjects with DCIS Who Had Preoperative MRI vs

Those Who Did Not Have MRI

Model Comparing Outcomes in Those

Who Had MRI vs Those Who Did Not

Have MRI [No. Had MRI vs No MRI in

Each Model]*

Estimated Pooled

Proportion With Outcome

(95% CI)

MRI No MRI

Model OR [Referent: no-MRI]

OR 95% CI

P for

Model¥

OR Adjusted for Age§

[Referent: no-MRI]

OR 95% CI

P for

Model¥

Studies of all subjects with DCIS (9

studies)

Initial surgery: mastectomy [316 vs 279;

5 studies]9,25,26,28,29

27.6%(21.8-34.3) 18.2%(13.6-24.0) 1.72 1.13-2.61 0.012 1.76 1.15-2.69 0.010

Initial surgery: BCS [316 vs 279;

5 studies]9,25,26,28,29

71.5%(64.5-77.6) 82.0(76.1-86.7) 0.55 0.36-0.84 0.006 0.53 0.35-0.82 0.004

Positive margins or

incomplete excision after BCS as initial

surgery [762 vs 1906; 4 studies]23,25,27,29

21.3%(15.6-28.5) 25.0%(18.6-33.0)0.80

(0.82)†

0.64-1.01

(0.65-1.03)†

0.059

(0.082)†1.10 0.64-1.89 0.716

Reoperation: re-excision or conversion

to mastectomy after BCS as initial

surgery [356 vs 276; 5 studies]20,23,25,28,29

37.9%(29.5-47.0) 34.5%(26.1-44.0)

1.06 (1.16)†

0.72-1.57

(0.78-1.72)†

0.759 (0.475)†

1.04 0.70-1.55 0.844

27

Overall mastectomy rate: Initial

mastectomies plus mastectomies for

positive margins after BCS [378 vs 263;

5 studies]20,25,26,27,28

13.86%(3.4-42.1) 11.5%(2.7-37.4) 1.23 0.80-1.9 0.340 0.97 0.61-1.53 0.881

DCIS, Ductal Carcinoma in Situ; BCS, Breast Conserving Surgery; OR, Odds Ratio; CI, Confidence Interval* Subject numbers vary according to the number of studies reporting the specific surgical outcome and according to whether the analysis applied to all subjects or only those who received initial breast conserving surgery.¥ P value for model comparing estimates of each surgical outcome in those who had MRI relative to those who did not have MRI

(referent group).

§ OR adjusted for model outcomes using study-level median age (see methods).

† For these outcomes (‘Positive margins or incomplete excision after BCS as initial surgery’ and ‘Reoperation: re-excision or

conversion to mastectomy after BCS as initial surgery’) the actual OR is reported based on all studies reporting data; in brackets

we also report the OR from sensitivity analysis that excluded one study using a historical comparison group.

28