Impact of preoperative magnetic resonance imaging on surgery and eligibility for intraoperative radiotherapy in early breast cancer.

We looked at the usefulness of magnetic resonance imaging (MRI) in decision-making and surgical management of patients selected for intraoperative radiotherapy (IORT). We also compared lesion size measurements in different modalities (ultrasound (US), mammogram (MMG), MRI) against pathological size as the gold standard. 63 patients eligible for IORT based on clinical and imaging criteria over a 34-month period were enrolled. All had MMG and US, while 42 had additional preoperative MRI for locoregional preoperative staging. Imaging findings and pathological size concordances were analysed across the three modalities. MRI changed the surgical management of 5 patients (11.9%) whereby breast-conserving surgery (BCS) and IORT was cancelled due to detection of satellite lesion, tumor size exceeding 30mm and detection of axillary nodal metastases. Ten of 42 patients (23.8%) who underwent preoperative MRI were subjected to additional external beam radiotherapy (EBRT); 7 due to lymphovascular invasion (LVI), 2 due to involved margins, and 1 due to axillary lymph node metastatic carcinoma detected in the surgical specimen. Five of 21 (23.8%) patients without prior MRI were subjected to additional EBRT post-surgery; 3 had LVI and 2 had involved margins. The rest underwent BCS and IORT as planned. MRI and MMG show better imaging-pathological size correlation. Significant increase in the mean 'waiting time' were seen in the MRI group (34.1 days) compared to the conventional imaging group (24.4 days). MRI is a useful adjunct to conventional imaging and impacts decision making in IORT. It is also the best imaging modality to determine the actual tumour size.

Introduction

Although earlier studies on BCS versus mastectomy showed similar survival outcomes [1-3], the local recurrence rates in patients who underwent BCS were reportedly higher [3, 4], despite the use of conventional MMG and US for surgical planning. Recent literature, however, have shown that BCS and mastectomy had similar local recurrence and survival rates [1, 5], with local irradiation an important factor leading to reduced recurrence rate in patients who underwent BCS [2].

In patients with early breast cancer, BCS followed by fractionated EBRT is the current standard of care [6]. Increased use of BCS in the treatment of localised breast cancer is seen in the past few decades [7]. IORT, which is radiation given intraoperatively immediately upon the removal of the breast tumour, was first introduced in the 1960s and has recently regained popularity in the past two decades as an alternative to EBRT following BCS [7, 8]. Advantages of IORT include direct target tissue visualisation, lower radiation to nearby normal tissues, reduced overall cost of treatment, as well as improvement in the quality of life [8-11]. Similar rates of complications were seen in IORT and EBRT, with no significant difference in local recurrence [12]. In University Malaya Medical Centre (UMMC), IORT is used for risk-adapted patients with low-risk features (Targeted intraoperative radiotherapy [TARGIT] A criteria) while higher-risk patients are recruited under the TARGIT B trial [13].

Optimal preoperative assessment is much needed to ensure successful BCS to reduce the cost and psychosocial impact of re-operations. Conventional imaging of the breast for surgical decision making comprises of both MMG and US. MRI is not a routine assessment tool for patients with breast cancer. Indications for breast MRI include screening in high-risk patients, preoperative evaluation of multifocal-multicentric or bilateral breast cancer, assessment of treatment response of neoadjuvant chemotherapy (NAC), evaluation of patients post BCS to differentiate scar tissue from local recurrence and assessment of patients with metastatic axillary lymphadenopathy with no known primary malignancy [14]. In newly diagnosed breast cancer, MRI breast is used to define the extent of cancer, detect the presence of satellite lesions or additional disease in patients with dense breasts and identify primary cancer in patients with axillary nodal involvement [15].

In the past decade, there has been an increased use of preoperative breast MRI globally, particularly for assessment of eligibility of early breast cancer patients for BCS and IORT [16]. Promising results of breast MRI in detecting multifocal-multicentric diseases have been demonstrated with several studies reporting detection rates of secondary lesions of between 7–10% which were missed on conventional imaging in patients initially eligible for IORT, leading to change in surgical management and reduced recurrence rate, proving MRI to be a useful adjunct to conventional imaging [9, 17, 18]. Advantages of breast MRI include an accurate definition of the extent of cancer to aid in the prevention of re-excision of tumours with positive margins, assist in preoperative staging of these patients [19] as well as identify multifocal-multicentric and contralateral breast diseases [20]. It has also shown higher accuracy in determining tumour size compared to US and MMG [21-24], with the highest imaging-pathological concordance [20] and good concordance for lesions smaller than 20mm [25].

Although many recent studies favour the use of MRI in early breast cancer patients, there are some disadvantages of performing a preoperative MRI. Breast MRI has been associated with the detection of insignificant additional breast lesions, with a study reporting only 25% of biopsied lesions as malignant on histopathological examination (HPE) [26]. Due to these additional lesions detected on MRI, additional workup (imaging and biopsies) would be required to confirm their nature, leading to increase in significant added cost and ‘wait time’ as defined as the time from the diagnostic biopsy to the time of first surgical treatment, ranging from 11 to 22.4 days delay in the MRI group [27-30]. Some studies have also shown the association of MRI with an increased rate of mastectomy as the initial surgical therapy and positive margins [27, 28], with an increase in 1.8-fold in odds ratio compared to the group without MRI [27]. Two studies reported an increased rate of conversion to mastectomy post breast MRI (4.9% and 8.3%) [22, 31], while a third study did not [27]. These conversions were later deemed to be appropriate based on the HPE results [22, 31]. Given the many added benefits and limitations of adding MRI into the preoperative assessment repertoire, we sought to evaluate the usefulness of pre-operative breast MRI in detecting multifocal, multicentric, and contralateral synchronous breast cancers compared to conventional breast imaging and its impact on IORT eligibility. We also aim to correlate the accuracy of lesion size measurements on MMG, US and MRI as well as compare the ‘wait time’ between the two groups.

Materials and methods

Study design

This was a cross-sectional study involving 63 patients with early breast cancer and were deemed eligible for BCS and IORT from March 2016 to December 2019 in UMMC. The study was conducted in adherence with the approved guidelines from the Medical Ethics Committee of University of Malaya Medical Centre (MREDIC No: 2018421–6235). Written informed consent were obtained.

Patient selection

Patients with a unifocal invasive ductal carcinoma of tumour size less than 30mm on conventional imaging with no lymph node or metastatic disease. All patients, except for those requiring neoadjuvant chemotherapy and with MRI contraindication, were offered MRI. Neoadjuvant chemotherapy cases were excluded. The patients were divided into two groups, those who only had pre-operative conventional imaging (MMG and US) versus those with conventional imaging plus MRI.

Equipment & techniques

All patients had full-field digital mammography (FFDM) in standard craniocaudal (CC) and mediolateral oblique (MLO) views with digital breast tomosynthesis (DBT) (Selenia Dimensions, Hologic, Bedford, Massachusetts, USA). Supplementary breast and axillary US was performed using diagnostic B-mode greyscale and colour US system (Philips iU22; Philips Healthcare, Bothell, Washington, USA) with a high frequency (12.5 MHz) linear transducer probe.

Breast MRI was performed in a 3.0 Tesla MAGNETOM Prisma® scanner (Siemens Healthcare, Munich, Germany) with a dedicated 18-channel breast coil for radiofrequency signal transmission and reception. The standard imaging protocol were T2W fast spin echo (echo time [TE] = 412ms, repetition time [TR] = 3200ms, a 256 x 256 matrix, field of view [FOV] of 250 x 250mm, slice thickness of 5mm, acquisition time of 6min 35sec), turbo inversion recovery magnitude [TIRM], diffusion-weighted imaging [DWI] (TE = 77ms, TR = 3400ms, 30 diffusion directions at b = 0s/mm2 and b = 1000s/mm2, 80 x 80 matrix, FOV of 240 x 240mm and slice thickness of 3mm, acquisition time of 5min 59sec) as well as dynamic contrast-enhanced T1W images in axial projections.

Data collection and analysis

Patients’ characteristics and HPE results were obtained from the electronic medical records (EMR). Images were retrieved from the local picture archiving and communication system (PACS) and reviewed by three board-certified radiologists (KR, MTRH, and WYC with 5–10 experience in breast imaging). Tumour size on MMG was measured by MTRH and WYC by consensus reading. Lesions on digitised external MMG images that were not measurable were excluded. The index tumour was measured in 3 dimensions on MRI. The largest dimension of the tumour in all 3 imaging modalities was taken as the tumour size, and compared to HPE.

Additional lesions detected on MRI were classified according to ACR BI-RADS 2015 lexicon into benign and suspicious masses, and non-mass enhancement (NME). For masses, these include assessment of lesions’ shape, margin and internal enhancement characteristic. NMEs were assessed according to the distribution and internal enhancement pattern.

Multifocal disease is the presence of another focus/foci of cancer (satellite lesion) in the same quadrant of the index tumour, which collectively measures <3cm, whilst multicentric disease means presence of cancer foci in more than one quadrant of the breast. The management of these additional lesions were decided in a multidisciplinary team discussion with the surgical team as per the workflow in Fig 1.

Fig 1

Workflow for patients with additional lesions detected on MRI.

A list of all the patients with accompanying data has been supplied as a S1 Data.

Pathology

On gross examination, tumours larger than 10mm were measured using a ruler, whilst a microscope was used for lesions smaller than 10mm. As per recommendation, the definition of clear margin was no ink on invasive tumours [32] and at least 2 mm away from the inked margin for ductal carcinoma in-situ (DCIS) [33]. The pathological size was taken as gold standard. Imaging measurement was compared with pathology size. Concordance between imaging and pathology was defined as size difference equal or less than 5mm. Underestimation or overestimation was defined as a discrepancy of measurement of more than 5mm.

Statistical analysis

All data were entered into IBM SPSS Statistics Data Editor Version 25 for statistical analysis. Measurable variables were analysed and summarised using means, medians, standard deviations (SD), standard error of the mean (SEM), and ranges, while categorical variables were measured in sums and percentages. The primary evaluation criterion was the incidence of satellite lesions.

The mean tumour size on US, MMG, MRI, and HPE were compared and analysed with the Paired Samples T-Test. The patients were divided into two groups (imaging size ≤ 20mm, and > 20mm) and the same test was also used for comparison of tumour sizes between these two groups.

Sensitivity and specificity was calculated with the use of true positive and false negative. True positives were satellite lesions correctly diagnosed on imaging, whereas false negatives denote satellite lesions inaccurately diagnosed as unifocal disease [34].

Results

Patient population demographics and breast MRI findings

Of the 63 patients, 21 had conventional imaging only and 42 had additional MRI. The majority had BIRADS breast density B (n = 26, 41.3%), followed by BIRADS density C (n = 23, 36.5%). 5 (7.9%) had extremely dense breast which lowers the sensitivity of MMG. 7 tumours were missed on MMG but detected on supplementary US which were performed due to either heterogeneously or extremely dense breast parenchyma.

All patient had invasive ductal carcinoma on HPE. Most (83.3%) were noted to be oestrogen receptor/progesterone receptor (ER/PR) positive. LVI was seen in 30.2% of patients with the majority of tumours classified as Grade 1 and 2 based on the Modified Bloom and Richardson score. Detailed characteristics of the tumour in our study were summarised in Table 1, as well as molecular subtyping in Table 2.

Table 1

Tumour characteristics.

Characteristics	N	n	%
Laterality
Left	30/63		47.6
Right	33/63		52.4
Hormonal receptor status *
ER+/PR+	50/60		83.3
ER+/PR-	5/60		8.3
ER-/PR+	1/60		1.7
ER-/PR-	4/60		6.7
HER-2-neu+	5/60		8.3
Lymphovascular invasion (LVI)**	19/63		30.2
Grade
1	15/63		23.8
2	36/63		57.1
3	10/63		15.9
Unknown	2/63		3.2

*2 patients had surgery done in other centres, 1 patient is still undergoing neoadjuvant chemotherapy

Table 2

Frequency of molecular subtypes in the study population.

Subtype	N	%
Luminal A	46/54	85.1
Luminal B	5/54	9.2
HER2+	2/54	3.9
Triple Negative Breast Cancer	1/54	1.8

*9 patients did not have complete hormonal information in order to fit the above subtypes

All 42 index tumours were visible on MRI. Twenty-five additional lesions were detected on MRI; 16 focal lesions, 6 non-mass enhancements (NMEs), and 3 suspicious axillary lymph nodes. Malignancy was detected in 28% of these MRIs, which comprised 5 focal lesions (DCIS), 1 NME (DCIS), and 1 axillary lymph node (metastatic disease) making up 16.7% of patients with additional malignancy in the MRI group. As a result, there were increased numbers of second-look US as well as confirmatory biopsies (5 US-guided, 2 MRI-guided breast lesion biopsies as well as 2 US-guided axillary lymph node biopsies) compared to conventional imaging group. These findings are summarised in Fig 2. There was a significant (P<0.001) increase in the mean ‘waiting time’ in the MRI group (34.1 days, 95% CI = 29.9–38.3) compared to the conventional imaging group (24.4 days, 95% CI = 19.5–29.4).

Fig 2

Additional lesions detected on MRI.

NME = Non-mass enhancement, LNs = Lymph nodes, UDH = Usual ductal hyperplasia, DCIS = Ductal carcinoma in-situ, Ix = Investigation.

Impact on surgical management

In the conventional imaging cohort (n = 21), 5 patients (23.8%) had EBRT added due to involved margins (2 patients, both had underestimated tumour size on US and LVI (3 patients). Due to the involved margins, these 2 patients (9.5% of total patients) were subjected to secondary operation for margin clearance, while the patients with LVI were subjected to post-op EBRT only.

In the MRI group (n = 42), 10 patients (23.8%) had additional EBRT due to post-surgically proven LVI (7 patients), involved margins (2 patients, both had underestimated tumour size on MRI) and metastatic axillary lymph nodes (1 patient). Both patients (4.8% of total patients) had a change in management, in which one had additional EBRT while the other proceeded with a completion mastectomy. The risk of margin involvement doubled in patients without MRI (9.5% in the conventional group versus 4.8% in the MRI group), although there was no statistical significance (Chi Square, p = 0.465). In total, 15 patients (5 in the conventional imaging and 10 in the MRI group respectively) were subjected to additional EBRT.

5 patients (11.9%) in the MRI group were not eligible for breast-conserving surgery and IORT, 2 of whom had a multifocal-multicentric disease and converted to mastectomy and 2 with tumours larger than 30mm on MRI (tumour sizes were underestimated on conventional imaging). The 5th patient with axillary lymph node metastasis only detected on MRI had additional EBRT. One patient with tumour size larger on MRI was subjected to mastectomy while the other had NAC before surgery. The remaining MRI patients (n = 27) underwent BCS and IORT as planned (Fig 3).

Fig 3

Flowchart outcome for conventional imaging only and conventional imaging plus MRI cohorts.

(BCS = Breast-Conserving Surgery, IORT = Intraoperative Radiotherapy, EBRT = External Beam Radiotherapy, LVI = Lymphovascular invasion, Ax LN = Axillary lymph node, NAC = Neoadjuvant chemotherapy).

Figs 4–7 illustrate cases in which MRI demonstrated additional tumour findings as well as tumour size estimation.

Fig 4

A 49-year-old woman with invasive carcinoma who subsequently underwent mastectomy due to imaging discordance.

Left MMG in (A) MLO and (B) CC views showing a spiculated lesion (thin arrow) in the mid outer region with foci of microcalcifications on a background of fatty breast parenchymal pattern (BIRADS density A). Corresponding US in (C) transverse view showing an ill-defined hypoechoic mass in the left 3 o’clock position, measuring 9 x 9mm with the presence of internal vascularity (D).

Fig 7

49-year-old woman with left breast invasive carcinoma who was deemed eligible for IORT based on conventional imaging but the tumour was larger than 30 mm on MRI (done 4 days apart).

Breast MRI Images maximal intensity projection (MIP) in (A) sagittal and (B) axial projections showing the index tumour (thin arrow). (C, D) Axial DCE phase 1 showing index tumour (thin arrow) with a maximal diameter (AP) of 32mm on MRI.

Breast MRI (A) Maximal intensity projection (MIP) shows the index tumour (thin arrow) and multifocal segmental clumped NME (HPE was DCIS) (arrowhead). (B, C) Axial subtracted post-contrast arterial phase 1 image shows index tumour (thin arrow) and multifocal lesion (arrowhead). (D) Colour coded intensity map of index tumour (red coloured area signifying the most intense enhancement) with type II kinetic curve (subset). (E) Colour coded intensity map of the multifocal lesion with Type III kinetic curves (subset).

Left MMG in (A) MLO and (B) CC view showing an indistinct high-density mass (thin arrow) in the left upper central region in a background of dense breast parenchyma BIRADS. (C) Corresponding ultrasound of the left breast in (C) transverse and (D) longitudinal views show irregular hypoechoic lesion with angular margins. The largest dimension on conventional imaging was 22mm.

Statistical analysis and imaging-pathological size concordance

The positive and negative findings are summarized in Table 3. A total of 60, 29, and 39 index tumours on US, MMG, and MRI respectively were included. 3 patients were excluded; 2 had surgeries in other centres and 1 was currently undergoing NAC and awaiting surgery. For MMG, only 29 patients were included as the rest had hard/soft copy external MMG images without measurement. Tumor size distribution and comparison are shown in Tables 4 and 5 and Fig 8.

Table 3

True positive (TP), true negative (TN), false positive (FP) and false negative (FN) in US and MRI.

			Satellite lesion in pathology specimen
			Yes	No
Satellite lesion in US		Yes	4 (TP)*	6 (FP)
		No	7 (FN)	43 (TN)
			Satellite lesion in pathology specimen
			Yes	No
Satellite lesion in MRI		Yes	8 (TP)*	9 (FP)
		No	3 (FN)	19 (TN)

*TP lesions seen in US and MRI were multifocal lesions adjacent to the index tumour, which were collectively <30mm. These TP lesions were HPE confirmed DCIS post-surgical excision.

Table 4

Concordances of tumour size by modality versus pathology.

	Group 1 (≤ 20mm)			Overall
	US	MMG	MRI	US	MMG	MRI
N				60	29	39
Concordant	33	12	20	34 (56.7%)	20 (69%)	27 (69.2%)
Underestimated	23	3	3	23 (38.3%)	4 (13.8%)	5 (12.8%)
Overestimated	1	1	1	3 (5.0%)	5 (17.2%)	7 (18.0%)
	Group 2 (> 20mm)
	US	MMG	MRI
Concordant	1	8	7
Underestimated	0	1	2
Overestimated	2	4	6

*Data is presented in absolute number of patients unless specified otherwise.

Table 5

Comparison of tumour size by modality versus pathology.

	Group 1 (≤ 20mm)			Overall
	US	MMG	MRI	US	MMG	MRI
N (%)	57 (95%)	16 (55.2%)	24 (61.5%)	60	29	39
Mean Difference *	-5.1 ± 1.26	-0.94 ± 1.49	-0.67 ± 1.07	-4.5 ± 1.25	1.07 ± 1.38	-0.77 ± 1.71
P value	<0.001	0.539	0.540	0.001	0.446	0.655
	Group 2 (> 20mm)
	US	MMG	MRI
N (%)	3 (5%)	13 (44.8%)	15 (38.5%)
Mean Difference *	23.3 ± 1.45	3.53 ± 2.37	-0.93 ± 4.20
P-value	0.350	0.162	0.827

*Positive value = overestimated, Negative value = underestimated

P-value ≤ 0.05 is taken as significant.

Fig 8

Bland-Altman plots of imaging (US, MMG, and MRI) and pathological size differences versus mean size differences.

Discordance was observed in larger sized tumours (>20mm) and oestrogen receptor/progesterone receptor (ER/PR) negative tumours (3 of 4 patients). Chi-Square Tests done showed no statistically significant association between LVI or breast density and size discordance.

Discussion

The increased use of BCS as a treatment of localised breast cancer created a need for optimum assessment of the extent of cancer as well as detecting multifocal-multicentric disease [35]. Failure to detect multifocal-multicentric disease, treatable by radio and chemotherapy, may lead to local recurrence [35]. Detection of contralateral cancer is also of utmost importance as these lesions will not be covered by radiotherapy [36]. MRI has been proven to be the most sensitive modality in detecting satellite lesions as well as the most accurate in determining lesion sizes and concordances.

The sensitivity of US alone in the detection of satellite lesions was 36.4%. The low sensitivity was due to the presence of many false-negative results. Our results closely correlate to the sensitivity quoted in a study which showed sensitivity of between 22.2% and 43.8% [37]. A study by Rabasco et al noted that 2D MMG alone missed 14 of 22 multifocal-multicentric lesions [34] leading to low sensitivity. Reasons for missed satellite lesions on MMG in several studies included dense breast parenchyma, technical errors, and misinterpretation of suspicious findings [37, 38]. On the other hand, MRI detected 8 out of the 11 satellite lesions, resulting in a sensitivity of 72.7%. The 3 satellite lesions that were not detected on MRI were adjacent to the index tumours and were removed together during the initial surgery. These lesions were later confirmed to be DCIS on HPE. Hence, no additional surgeries were needed in these patients. Our MRI findings correlate with Malur et al [39] and Hlawatsch et al [38] that reported 66.7% and 81% sensitivity of MRI in detecting satellite lesions respectively.

A total of 25 additional lesions were detected on MRI alone, out of which 16.7% were proven to be malignant on HPE, correlating with the figure quoted in a meta-analysis by Houssami et al of 16% additional disease detected by breast MRI [40]. Identification of these additional lesions pre-operatively will lower the recurrence rates and allow removal in the same surgical setting without the need for secondary surgery [28]. We also found that the percentages of patients requiring secondary surgeries for tumour resections due to positive margins were halved in the MRI group compared to the conventional group (4.8% on MRI versus 9.5% on conventional imaging) corresponding with findings of a study by Obdeijn et al which showed that the rates of reoperations for involved margins were approximately halved when comparing the MRI group with the control group (18.9% versus 37.4% respectively) [41]. The underestimation of the tumour size on MRI was the cause of positive margins in these patients. Recurrence rate was quoted at 5–25% in patients with positive margins [42] with the status of surgical margin being the most important factor for local recurrence prediction.

Pre-operative MRI findings impacted the surgical management of our patients. IORT was cancelled in 5 patients (11.9%) due to the presence of multifocal-multicentric diseases, tumour sizes larger than 30mm on MRI (which is incompatible with IORT) and presence of axillary lymphadenopathy, correlating with figures quoted in other studies which ranged between 5% and 12.5% [6, 17, 34]. True positive MRI findings in our study prompted the conversion of BCS to mastectomy in 3 patients (7.1% of total patients in MRI group). The subsequent surgical HPE of DCIS diseases in these patients deemed these conversions appropriate and our conversion rate is in accordance with those reported by Luciana Karla et al, 4.9% and Plana et al, 8.3% [22, 31]. Of the remaining 2 patients, one was subjected to NAC before the decision on subsequent surgery and the other was subjected to additional EBRT as a result of axillary lymph nodes involvement detected on MRI.

For lesion size, our study showed that US had the lowest concordance rate (57.6%) amongst all modalities, underestimating lesion sizes in 38.3% of patients (mean underestimation of 4.5mm). This was similarly noted in several studies which showed significant size underestimation by US [20, 43] with a mean difference of 2.5 mm [44]. Lesion sizes were underestimated in 13.8% of patients on MMG, while underestimation on MRI was seen in 12.8% of patients. Concordance rates of lesion size on MMG and MRI in this study were 69% and 69.2% respectively, which correlates with a concordance rate of 74.6% on MRI reported by Yoo EY et al [21]. Mean size differences in this study were 0.8 mm (underestimated on MRI) and 1.1 mm (overestimated on MMG) which were similar to figures quoted in a similar study which showed a mean difference of 0.6 mm (overestimated by MMG) [45]. In this study, we found that size discordances were seen in larger lesions (sizes > 20 mm) and lesions that are ER/PR negative. ER/PR negative patients made up less than 5 of this patient population. Other studies showed discordant imaging-pathological measurements as a result of tumour type (particularly invasive lobular carcinoma due to its histologic characteristics of diffuse infiltrative growth pattern and peritumoural satellite foci) [46, 47], ER negativity, lymphovascular invasion [21] and larger lesions exceeding US transducer size [48] leading to lesion size underestimation on US. Our study showed no statistically significant correlation between breast density and tumour size discordance, as reported in a study by Abu-Sinn et al [49]. Based on these findings, we concluded that MRI was the best modality in determining tumour size, which was in agreement with the findings of many studies [21, 23, 24, 43].

Although US had the lowest sensitivity in detection of satellite lesions and had significant size underestimation compared to pathological findings, US was still an useful tool in decision-making of surgery and IORT. Studies have shown that US as an adjunct to MMG improves breast cancer diagnostic yield especially in women with dense breast [50, 51]. Adding US to MMG was found to be significantly more sensitive in cancer detection compared to MMG alone with no significant difference in specificity [52]. Most of the initial breast biopsy in our patients are via US guided and all the additional lesions detected on MRI in this study were reassess by second look US and some underwent US guided biopsies.

Although we observed an increase in the mean ‘wait time’ of 10 days in the MRI group compared to the conventional imaging group, this was shorter than the delay quoted by Bleicher et al [27] and Zhang et al [30] which showed an average of 22.4-day delay in their patients as a result of MRI due to the additional imaging and biopsies preformed post breast MRI. The delay observed in our study was due to 1–2 week average MRI appointment waiting time in our centre. Li Y et al [53] noted no significant decrease in patients’ disease free survival with delay of more than 90 day, However, on the other hand Richards et al [54] showed a 12% lower 5-year survival with delay of more than 90 days. The delay encountered in our study likely have no impact on patients’ disease free survival. The majority (85%) of patients in this population also were of Luminal A subtype (ER/PR positive, HER2-negative) which has demonstrated slower growth and lower grade in past literature, thus strengthening this belief [55].

Small sample size was the major limiting factor in this study. Although there were lesser patients with involved margins in the MRI group, there was no statistical significance which may be due to small cohort. There were only limited numbers of patients with ER and PR negativity (4 in total) for a more representative analysis. Thus it is difficult to discuss the role of ER/PR negativity in the selection of patients for preoperative MRI in this population.

Conclusion

In our study, MRI was proven to be a useful adjunct to conventional imaging in patients with early breast cancer due to its high sensitivity, negative predictive value, high imaging-pathological size concordance, and ability to detect satellite lesions which may be missed by conventional imaging. The use of MRI reduced the risk of involved margins by two-folds. However, a larger sample size would be required to determine its significance. MRI also impacted the surgical management in a fraction of our patients.

Although our findings concluded that MRI had a definitive role as an adjunct to conventional imaging in the pre-operative assessment of patients planning for BCS and IORT, the value of routine use of pre-operative MRI in the work-up of patients for BCS and IORT remains controversial. For now, until long-term data on clinical outcomes and cost-effectiveness are available, it may be more beneficial to use pre-operative MRI in selective patients.

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Additional Editor Comments:

This is a study that addresses an important and current issue, the indication of preoperative magnetic resonance imaging in breast cancer and its eventual impact on eligibility for intraoperative radiotherapy.

Secondarily, the study evaluated the accuracy of different imaging modalities in defining the dimensions of breast cancer using the surgical specimen as a reference standard, this is a data already well evaluated in studies with a larger number of patients and greater methodological rigor.

The reviewers raised important questions that I ask the authors to address and I emphasize the importance of describing the criteria for indicating MRI in this study in detail and the characteristics of patients in both study groups, with and without preoperative MR. Some pathological charateristics are described but there are some known criteria that favor the use of preoperative MRI due to the chance of impact on the conduct, I can mention Triple negative/HER-2/luminal B, High grade DCIS, Invasive lobular histology, dense breasts and young patients` tumors. Some of these characteristics of the population and subgroups were not provided and may influence the results.

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**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript titled 'Impact of preoperative MRI on surgery and eligibility for intraoperative radiotherapy

(IORT) in early breast cancer' by Chan et al examined the impact of pre-operative MRI on decision-making of surgery and IORT for 63 breast cancer patients randomized into two groups. Their findings are interesting and will have a positive effect on clinical practice if published. There are some minor concerns regarding the manuscript.

1. Since MRI and mammogram have better correlation with pathological findings, is ultrasound still an useful tool in decision-making of surgery and IORT? Please discuss the issue in the discussion section.

2. Since sample size is small in this study, statistical power of the analysis is limited. Does the authors have a plan to collect more patients to increase their sample size and make stronger conclusion?

3. BCS was not explained the first time when the abbreviation appeared in the 'abstract' although it was explained in the 'Introduction'.

Reviewer #2: Dear Authors,

About the article "IMPACT OF PREOPERATIVE MRI ON SURGERY AND ELIGIBILITY FOR INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER", please consider the following aspects:

1- In the title, avoid using abbreviations, unless you also indicate their meaning. For example, MRI (Magnetic Resonance Imaging);

2- In the abstract, consider including the abbreviation of some keywords such as magnetic resonance imaging, ultrasound and mammography, and use this standardization throughout the text, since sometimes these words are abbreviated and sometimes not throughout the text. Or don’t abbreviate them in the abstract and start using the abbreviations, after properly signaling them, starting the introduction.

3- Match the objective of the abstract with that of the introduction. There is an objetive a correlation between the “waiting time” and the study groups in relation to the methods to which they are submitted, not informed to the reader in the abstract of the article;

4- Regarding the study population, consider whether it is interesting to know how many patients were excluded from the analysis, perhaps in relation to the number of MRI scans done in the same period. Consider using a flow diagram.

5- Regarding the study population, consider inserting in the flow diagram (Figure 3) all the patients elected for the study and not only those who underwent MRI, in order to better systematize the data.

6- In the methods, please provide more information regarding tumor characteristics and the identification of satellite and metastatic lesions (multifocal-multicentric disease), reported in the results, such as those included in tables 1 and 2.

7- In the methods, clearly describe the variables related to patients and tumor characteristics, such as breast parenchyma density, as these are potential confounding factors and effect modifiers.

8- Consider standardizing breast lesions dimensions in "mm or cm" in the methods and results.

9- In the results, consider performing the following analyses in order to rule out possible biases regarding the evaluation of tumor size in relation to the different methods:

- breast density x study groups (MMG and US x MRI).

10- In the discussion, an interesting reflection would be the impact that the result of this work brings to clinical practice.

Other observations:

Page 2, line 44 - Include the term referring to the abbreviation MRI.

Page 2, line 51 – Include the term referring to the abbreviation BCS.

Page 3, line 80 - Include the expression referring to the abbreviation UMMC.

Page 3, lines 80 to 82 - What is the bibliographic reference based for the classification of IORT indications in UMMC?

Page 4, line 85 - Leave only the abbreviations for mammography and ultrasound, since they were indicated on lines 68 and 69, respectively.

Page 4, line 96 and 97 - Leave only the abbreviation BCS.

**********

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Reviewer #1: No

Reviewer #2: No

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10 Apr 2022

To

PLOS ONE Editorial Office

Dear Sir/Dr,

Response to Reviewer’s Comments.

Ms. No.: PONE-D-21-32579

Title: IMPACT OF PREOPERATIVE MRI ON SURGERY AND ELIGIBILITY FOR INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER

Thank you very much for your comments to the above referenced manuscript and for consideration for publication in your respected journal. We highly appreciate the reviewers’ comments and have revised the manuscript according to the reviewer’s recommendation (see point-by-point reply enclosed herewith). We thank the reviewers for their valuable suggestions in improving the paper. The substantive changes have been addressed below with regards to each reviewers questions.

Below is the corrections/point-by-point reply to your comments.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Authors’ reply: Thank you for the comments. We have followed the PLOS ONE’s style requirement and file naming as per template.

2. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Authors’ reply: Thank you for the comments. The ethics statement is in the Materials and Methods section under Study Design subsection as highlighted. We have deleted the statement that was previously in the Acknowledgements section.

Additional Editor Comments:

This is a study that addresses an important and current issue, the indication of preoperative magnetic resonance imaging in breast cancer and its eventual impact on eligibility for intraoperative radiotherapy.

Secondarily, the study evaluated the accuracy of different imaging modalities in defining the dimensions of breast cancer using the surgical specimen as a reference standard, this is a data already well evaluated in studies with a larger number of patients and greater methodological rigor.

The reviewers raised important questions that I ask the authors to address and I emphasize the importance of describing the criteria for indicating MRI in this study in detail and the characteristics of patients in both study groups, with and without preoperative MR. Some pathological charateristics are described but there are some known criteria that favor the use of preoperative MRI due to the chance of impact on the conduct, I can mention Triple negative/HER-2/luminal B, High grade DCIS, Invasive lobular histology, dense breasts and young patients` tumors. Some of these characteristics of the population and subgroups were not provided and may influence the results.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Authors’ reply: Thank you for the favourable response.

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Authors’ reply: Thank you for the favourable response.

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Authors’ reply: Thank you for the favourable response.

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Authors’ reply: Thank you for the favourable response.

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript titled 'Impact of preoperative MRI on surgery and eligibility for intraoperative radiotherapy

(IORT) in early breast cancer' by Chan et al examined the impact of pre-operative MRI on decision-making of surgery and IORT for 63 breast cancer patients randomized into two groups. Their findings are interesting and will have a positive effect on clinical practice if published. There are some minor concerns regarding the manuscript.

1. Since MRI and mammogram have better correlation with pathological findings, is ultrasound still an useful tool in decision-making of surgery and IORT? Please discuss the issue in the discussion section.

Authors’ reply: Thank you for your comments. Although MRI and MMG have better correlation with pathological findings, initial imaging assessment of early breast cancer patients for eligibility for BCS and IORT are done with MMG and US. Breast MRI is not a routine assessment tool for patients with breast cancer. Studies (1,2,3) have shown that US as an adjunct to MMG improves breast cancer diagnostic yield especially in women with dense breast. Adding US to MMG was found to be significantly more sensitive in cancer detection compared to MMG alone (80.8% vs 56.6%) with no significant difference in specificity. Most of the initial biopsy in patients presenting with suspicious breast related symptoms are via US guided. All the additional lesions detected on MRI in this study were reassess by second look US and some lesions underwent US guided biopsies. We have included this in the discussion section from line 400 – 405 of the manuscript.

1. Corsetti V, Houssami N, Ferrari A, Ghirardi M, Bellarosa S, Angelini O, et al. Breast screening with ultrasound in women with mammography-negative dense breasts: evidence on incremental cancer detection and false positives, and associated cost. European journal of cancer. 2008;44(4):539-44.

2. McCavert M, O’Donnell M, Aroori S, Badger S, Sharif M, Crothers J, et al. Ultrasound is a useful adjunct to mammography in the assessment of breast tumours in all patients. International journal of clinical practice. 2009;63(11):1589-94.

3. Yip CH, Pathy NB, Teo SH. A review of breast cancer research in Malaysia. Med J Malaysia. 2014;69(August):8–22.

2. Since sample size is small in this study, statistical power of the analysis is limited. Does the authors have a plan to collect more patients to increase their sample size and make stronger conclusion?

Authors’ reply: Thank you for your comments. Increment of the sample size is beyond the scope of the current study.

3. BCS was not explained the first time when the abbreviation appeared in the 'abstract' although it was explained in the 'Introduction'.

Authors’ reply: Thank you for your comments. We have edited and included the full term/form of BCS which is Breast-Conserving Surgery in the abstract.

Reviewer #2: Dear Authors,

About the article "IMPACT OF PREOPERATIVE MRI ON SURGERY AND ELIGIBILITY FOR INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER", please consider the following aspects:

1- In the title, avoid using abbreviations, unless you also indicate their meaning. For example, MRI (Magnetic Resonance Imaging);

Authors’ reply: Thank you for your comments. We have edited and included only the full term/form of MRI which is Magnetic Resonance Imaging in the title and also remove IORT abbreviation in the title.

2- In the abstract, consider including the abbreviation of some keywords such as magnetic resonance imaging, ultrasound and mammography, and use this standardization throughout the text, since sometimes these words are abbreviated and sometimes not throughout the text. Or don’t abbreviate them in the abstract and start using the abbreviations, after properly signaling them, starting the introduction.

Authors’ reply: Thank you for your comments. We have standardized our manuscript with regards to the use of abbreviations. We have used the full term with abbreviation in the abstract and started using these abbreviations from the introduction section.

3- Match the objective of the abstract with that of the introduction. There is an objetive a correlation between the “waiting time” and the study groups in relation to the methods to which they are submitted, not informed to the reader in the abstract of the article;

Authors’ reply: Thank you for your comments. We have included the results of the wait time for surgical management in the abstract in line 60 and 61 as per below:

“Significant increase in the mean ‘waiting time’ were seen in the MRI group (34.1 days) compared to the conventional imaging group (24.4 days)”

The results and the discussion on the “waiting time” were included in the Results section under the subheading of Patient population demographics and breast MRI findings from line 200 to 204 and in the Discussion section from line 408-416.

4- Regarding the study population, consider whether it is interesting to know how many patients were excluded from the analysis, perhaps in relation to the number of MRI scans done in the same period. Consider using a flow diagram.

Authors’ reply: Thank you for your comments. The inclusion criteria for this study are all patients with early breast cancer that are deemed to be eligible for BCS and IORT on conventional imaging. This include patients with unifocal disease with breast tumour size ≤ 3cm with no lymph node involvement or metastasis. Patients requiring neoadjuvant chemotherapy and those with MRI contraindication were excluded. These were mentioned under patient selection subheading from line 136 to 141. Unfortunately however, we do not have the data on the no of patients excluded from the analysis in relation to the total no of MRI done in the same period of time.

5- Regarding the study population, consider inserting in the flow diagram (Figure 3) all the patients elected for the study and not only those who underwent MRI, in order to better systematize the data.

Authors’ reply: Thank you for your comments. Figure 3 flowchart has already included the outcome for all 63 early breast cancer patients deemed eligible for this study. The patients were divided into two arms: those with conventional imaging (MMG and US) (n=21) alone and those with MRI as adjunct to conventional imaging (n=42).

6- In the methods, please provide more information regarding tumour characteristics and the identification of satellite and metastatic lesions (multifocal-multicentric disease), reported in the results, such as those included in tables 1 and 2.

Authors’ reply: Thank you for your comments. This study included 63 patients with early breast cancer (unifocal invasive ductal carcinoma with tumour size ≤ 3cm with no lymph node involvement or metastasis) that are deemed to be eligible for BCS and IORT on conventional imaging. Except for patients requiring neoadjuvant chemotherapy and those with MRI contraindication, the rest of the patients included in the study were offered MRI. This was mentioned under patient selection subheading from line 136 to 141. Table 1 summarised the detailed characteristics of the tumour included in our study.

Additional lesions detected on MRI were classified according to ACR BI-RADS 2015 lexicon into benign and suspicious masses, and non-mass enhancement (NME). For masses, these include assessment of lesions’ shape, margin and internal enhancement characteristic. NMEs were assessed according to the distribution and internal enhancement pattern. Multifocal disease is the presence of another focus/foci of cancer (satellite lesion) in the same quadrant of the index tumour , which collectively measures <3cm, whilst multicentric disease means presence of cancer foci in more than one quadrant of the breast. The management of these additional lesions were decided in a multidisciplinary team discussion with the surgical team. This was mentioned under data collection and analysis subheading from line 159 to 174.

7- In the methods, clearly describe the variables related to patients and tumor characteristics, such as breast parenchyma density, as these are potential confounding factors and effect modifiers.

Authors’ reply: Thank you for your comments. The table below summarizes the risk factors attributable to breast cancer in all the 63 patients involved in this our study. Many of these data were not documented in detail in the Electronic Medical Records (EMR)

Risk factors of patients with breast cancer (N=63)

Risk factors N %

Early menarche (age <12)

Late onset menopause (age ≥ 55)

Smoking

Alcohol intake

Hormonal therapy (HRT, OCP)

Para

Nulliparous

Multiparous

Breastfeeding

Family history of breast cancer 6/63

6/51*

2/63

6/63

21/63

4

59

54/59**

17/63 9.5

11.8

3.2

9.5

33.3

6.3

93.7

91.5

27.0

*51 patients had attained menopause, 12 were still premenopausal.

**59 patients were multiparous, 4 patients were nulliparous.

As for breast parenchymal density, out of the 63 patients, the majority of patients in this study have BIRADS breast density B. 5 (7.9%) have extremely dense breast which would lower the sensitivity of mammography. Seven (7) tumours were missed on mammography but detected on supplementary US which were performed due to either heterogeneously or extremely dense breast parenchyma. The table below summarizes the breast density of all patients involved in this study.

Mammographic breast density (N=63)

Breast Density N %

A

B

C

D 9

26

23

5 14.3

41.3

36.5

7.9

These were mentioned in results section under subheading patient population demographics and breast MRI findings from line 200 to 204

In view of the limited number and incomplete EMR documentation, the assessment and statistical analysis of variables related to patients eg breast parenchyma density, as potential confounding factors and effect modifiers with tumour characteristics are beyond the scope of this study.

8- Consider standardizing breast lesions dimensions in "mm or cm" in the methods and results.

Authors’ reply: Thank you for your comments. We have standardized our manuscript and have used “mm” instead of “cm” throughout.

9- In the results, consider performing the following analyses in order to rule out possible biases regarding the evaluation of tumor size in relation to the different methods:

- breast density x study groups (MMG and US x MRI).

Authors’ reply: Thank you for your comments. Unfortunately, these analyses are beyond the scope of our study

10- In the discussion, an interesting reflection would be the impact that the result of this work brings to clinical practice.

Authors’ reply: Thank you for your comments. We have included the impact of the results of this study in the conclusion section.

Other observations:

Page 2, line 44 - Include the term referring to the abbreviation MRI.

Authors’ reply: Thank you for your comments. We have edited and included the full term/form of MRI which is Magnetic Resonance Imaging in the abstract.

Page 2, line 51 – Include the term referring to the abbreviation BCS.

Authors’ reply: Thank you for your comments. We have edited and included the full term/form of BCS which is Breast-Conserving Surgery in the abstract.

Page 3, line 80 - Include the expression referring to the abbreviation UMMC.

Authors’ reply: Thank you for your comments. We have edited and included the full term/form of UMMC which is University Malaya Medical Centre in the introduction section.

Page 3, lines 80 to 82 - What is the bibliographic reference based for the classification of IORT indications in UMMC?

Authors’ reply: Thank you for your comments. We have added the he bibliographic reference for IORT classifications in UMMC as per below.

Esposito E, Douek M. Update on intraoperative radiotherapy: new challenges and issues. Ecancermedicalscience. 2018;12:793. Published 2018 Jan 10. doi:10.3332/ecancer.2018.793

Page 4, line 85 - Leave only the abbreviations for mammography and ultrasound, since they were indicated on lines 68 and 69, respectively.

Authors’ reply: Thank you for your comments. We have standardized our manuscript with regards to the use of abbreviations. We have used the full term with abbreviation in the abstract and started using these abbreviations from the introduction section.

Page 4, line 96 and 97 - Leave only the abbreviation BCS.

Authors’ reply: Thank you for your comments. We have standardized our manuscript with regards to the use of abbreviations. We have used the full term with abbreviation in the abstract and started using these abbreviations from the introduction section.

Submitted filename: response to reviewers.docx

Click here for additional data file.

19 May 2022

14 Jun 2022

To

PLOS ONE Editorial Office

Dear Sir/Dr,

Response to Reviewer’s Comments.

Ms. No.: PONE-D-21-32579

Title: IMPACT OF PREOPERATIVE MRI ON SURGERY AND ELIGIBILITY FOR INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER

Thank you very much for your comments to the above referenced manuscript and for consideration for publication in your respected journal. We highly appreciate the reviewers’ comments and have revised the manuscript according to the reviewer’s recommendation (see point-by-point reply enclosed herewith). We thank the reviewers for their valuable suggestions in improving the paper. The substantive changes have been addressed below with regards to each reviewers questions.

Below is the corrections/point-by-point reply to your comments.

Journal Requirements:

Additional Editor Comments:

The reviewers raised important questions that I ask the authors to address and I emphasize the importance of describing the criteria for indicating MRI in this study in detail and the characteristics of patients in both study groups, with and without preoperative MR. Some pathological charateristics are described but there are some known criteria that favor the use of preoperative MRI due to the chance of impact on the conduct, I can mention Triple negative/HER-2/luminal B, High grade DCIS, Invasive lobular histology, dense breasts and young patients` tumors. Some of these characteristics of the population and subgroups were not provided and may influence the results.

Author’s reply:

Thank you for your constructive comment. In this study we did observe patients who were ER-/PR- as well as HER-2 negative and included them in the results particularly in Table 1. We have now added Table 2 which lists the Molecular Subtypes more clearly. We also noted that the majority of patients were in the category of BIRADS density B. We did not look at invasive lobular histology or DCIS in these patients as our focus as mentioned in methodology was on patients who had invasive ductal carcinoma. However, we did detect DCIS in some of the satellite lesions that were excised and this was discussed in the Discussion section. In addition, majority of our patients were in the 40-60 ages range, therefore to improve readability of this manuscript, we did not emphasise the younger age group. I hope that this addresses your comments and concerns.

Below is Table 2, which is located just after Table 1 in the manuscript.

Table 2. Frequency of Molecular Subtypes in the study population

Subtype N %

Luminal A 46/54 85.1

Luminal B 5/54 9.2

HER2+ 2/54 3.9

Triple Negative Breast Cancer 1/54 1.8

Submitted filename: Response to reviewers 13.6.docx

Click here for additional data file.

12 Jul 2022

15 Aug 2022

To

PLOS ONE Editorial Office

Dear Sir/Dr,

Response to Reviewer’s Comments.

Ms. No.: PONE-D-21-32579

Title: IMPACT OF PREOPERATIVE MRI ON SURGERY AND ELIGIBILITY FOR INTRAOPERATIVE RADIOTHERAPY (IORT) IN EARLY BREAST CANCER

Thank you very much for your comments to the above referenced manuscript and for consideration for publication in your respected journal. We highly appreciate the reviewers’ comments and have revised the manuscript according to the reviewer’s recommendation (see point-by-point reply enclosed herewith). We thank the reviewers for their valuable suggestions in improving the paper. The substantive changes have been addressed below with regards to each reviewers questions.

Below is the corrections/point-by-point reply to your comments.

Journal Requirements:

Additional Editor Comments:

Thank you for providing additional tumor/patient characteristics in Table 2. You were previously asked to address and emphasize the importance of these data as they may influence the results. We would like to invite you to add a paragraph in your results or discussion section to address this concern.

Author’s reply:

Thank you Editor for your constructive comments. We have now added several lines in the discussion to allude to the data in Table 2:

Line 394, 419 and 425.

I hope that these will be sufficient to address your concerns which we much appreciate.

We noticed that you provide the patient list with data as supplementary file. This should be mentioned in the material and methods section.

Author’s reply:

Thank you for your comment. We have now added a sentence within Materials and Methods: Data Collection and Analysis; Line 171.

Below is the response to the previous revision that we had done:

The reviewers raised important questions that I ask the authors to address and I emphasize the importance of describing the criteria for indicating MRI in this study in detail and the characteristics of patients in both study groups, with and without preoperative MR. Some pathological charateristics are described but there are some known criteria that favor the use of preoperative MRI due to the chance of impact on the conduct, I can mention Triple negative/HER-2/luminal B, High grade DCIS, Invasive lobular histology, dense breasts and young patients` tumors. Some of these characteristics of the population and subgroups were not provided and may influence the results.

Author’s reply:

Thank you for your constructive comment. In this study we did observe patients who were ER-/PR- as well as HER-2 negative and included them in the results particularly in Table 1. We have now added Table 2 which lists the Molecular Subtypes more clearly. We also noted that the majority of patients were in the category of BIRADS density B. We did not look at invasive lobular histology or DCIS in these patients as our focus as mentioned in methodology was on patients who had invasive ductal carcinoma. However, we did detect DCIS in some of the satellite lesions that were excised and this was discussed in the Discussion section. In addition, majority of our patients were in the 40-60 ages range, therefore to improve readability of this manuscript, we did not emphasise the younger age group. I hope that this addresses your comments and concerns.

Below is Table 2, which is located just after Table 1 in the manuscript.

Table 2. Frequency of Molecular Subtypes in the study population

Subtype N %

Luminal A 46/54 85.1

Luminal B 5/54 9.2

HER2+ 2/54 3.9

Triple Negative Breast Cancer 1/54 1.8

Submitted filename: Response to reviewers 15.8.docx

Click here for additional data file.

28 Aug 2022

Impact of preoperative magnetic resonance imaging on surgery and eligibility for intraoperative radiotherapy in early breast cancer

PONE-D-21-32579R3

Dear Dr. Ramli Hamid,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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George Vousden

Staff Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

6 Oct 2022

PONE-D-21-32579R3

Impact of preoperative magnetic resonance imaging on surgery and eligibility for intraoperative radiotherapy in early breast cancer

Dear Dr. Ramli Hamid:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. George Vousden

Staff Editor

PLOS ONE