The Association between Surgical Margins and Local Recurrence in Women with ductal carcinoma in situ treated with Breast Conserving Therapy: observational study

doi:10.21203/rs.3.rs-4853707/v1

Introduction

The incidence of DCIS (DCIS) constitutes 25% of the newly identified breast cancers. Approximately 35% of DCIS cases are detected in asymptomatic women during routine mammography screening. The 20-year breast-cancer-specific mortality rate was 3.3%. Breast-conserving surgery(BCS), followed by radiotherapy, is the treatment of choice. However, an adequate margin for BCS remains unclear. Therefore, we need to investigate the relationship between the margin distance and cancer recurrence.

Methods

A total of 4,355 patients with DCIS were assessed between January 1, 2010, and January 31, 2020. Of these, 4,123 patients who had invasive ductal carcinomaco-existing DCIS and who were treated with mastectomy were excluded. Thus, 232 patients with pure DCIS treated with BCS were included. All distant radial margins were measured.

Results

A total of 232 patients with DCIS underwent breast-conserving surgery,169 patients received whole breast radiotherapy, and 63 did not. Most patients received hormone therapy, and as indicated, the median follow-up was 73 months.

Recurrence was observed in seven patients. Among them, four had margins less than 2 mm, while the others had margins > 2 mm. There were no significant differences in disease-free survival (DFS) among the margin statuses.

Conclusion

Margins wider than 2 mm did not demonstrate a reduction in local recurrence for women receiving adjuvant whole-breast radiation therapy, supporting the recommendation of a negative margin threshold for surgical management of DCIS.

DCIS

Margins after BCS

Local recurrence after BCS for DCIS

The incidence of DCIS constitutes 25% of newly identified breast cancers. Approximately 35% of DCIS cases are detected in women without symptoms during routine mammography screenings. The 20-year breast cancer-specific mortality rate is 3.3%.¹ DCIS is neoplastic cells growing within ducts and considered non-obligate precursors of invasive carcinomas. Complete surgical resection is the most common treatment option. Breast-conserving surgery (BCS) stands as a treatment choice ,supported by randomized trials that reveal comparable oncological effectiveness between BCS and mastectomy.¹ Adjuvant tamoxifen at 20 mg/day was considered appropriate for the management of ER positive DCIS.¹

There are some controversial points regarding margins after BCS in both literature reviews and guidelines. 2-mm margin status is recommendation after BCS for pure DCIS and DCIS with microinvasion.²

Owing to the diversity in research, variations in defining margin distances were noted, such as grouping 2 mm margins with those ranging from 3 to 5 mm or 10 mm. The lack of clear boundary definitions for margin distances and some studies finding the importance of recurrence associated with radiation, even with margins less than 2 mm; therefore, we need to investigate the relationship between exact margin distances and cancer recurrence.

A total of 4,355 patients with histopathologic reports of DCIS from January 1, 2010, to January 31, 2020, at Ramathibodi Hospital were retrieved. Of these, 4,123 patients who had invasive ductal carcinoma co-existing DCIS and were treated by mastectomy were excluded. Thus, 232 patients with histopathologically proven pure DCIS treated with BCS were included. All distant radial margins were measured.

This study was approved by the Human Research Ethics Committee of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (approval no. COA. MURA2021/10).

All patients underwent clinical examination, ultrasonography, and mammographic evaluation. Tissue biopsy is usually performed according to the Breast Imaging Reporting and Data System (BIRADs). For instance, when the findings were classified as BI-RADS category 4 or 5, which were suspicious for malignancy, a tissue biopsy was performed. All the patients underwent standard surgical management for BCS. Moreover, the type of axillary management was considered depending on the nodal status. Indications for SLNB were microinvasive features, tumors located in the upper outer quadrant, and high-grade tumors. Adjuvant treatment was administered depending on the tumor stage, subtype, and prognostic and predictive factors. Clinical characteristics including age, menopausal status, clinical presentation, presence of mass, and screening detection were recorded (Table 1). Diagnostic and tumor characteristics, including tissue biopsy pathology, immunohistochemistry, Notthingham grade of tumor, tumor size, lymphovascular invasion(LVI), perineural invasion(PNI), clinical nodal status, pathological nodal status, and tumor margins, were recorded (Table 2). Local and systemic treatments, including type of axillary management, chemotherapy, radiation therapy, anti-hormonal therapy, and targeted therapy, and postoperative complications were recorded (Table 3). Patients underwent surveillance 1-4 times per year as clinically approximate for 5 years, then annually and mammography every 12 months, beginning 6 months or more after completion of BCT. Patients receiving tamoxifen underwent age-appropriate gynecological screening. Bone health and bone mineral density were monitored in patients treated with aromatase inhibitors. The prognosis, including overall and disease-free survival, was recorded (Table 4).

Statistical analysis

Categorical variables were summarized as counts and percentages and compared using the chi-squared test. Continuous variables were compared using a two-sample independent t-test. Univariate analysis compared with the Cox proportional hazards model. Survival and recurrence rates were calculated using the Kaplan-Meier method. STATA version14 was used for statistical analysis. The level of significance was set at P < 0.05.

Of the 232 patients with DCIS, most were postmenopausal, with a mean age of 56 years. Of the patients, 98.28 % were asymptomatic; however, abnormal imaging findings were detected. In addition, 1.72% of patients exhibited a palpable mass. The mean tumor size was 1.05 cm. Magnetic resonance imaging (MRI) was not used to evaluate the extent of the disease. The patient had cancer in the left breast, accounting for 57.33%; see Table 1.

Table 1 The clinical characteristics

	n	%
Age
Mean ± SD	232	56.34 ± 11.23
(Min - Max)		(26 - 87)
Menopausal status
Premenopausal status	68	29.31
Perimenopausal status	82	35.34
postmenopausal status	82	35.34
Side
Left	133	57.33
Right	99	42.67
Screen detected
Yes	228	98.28
mass	4	1.72

The preoperative biopsy results mostly indicated DCIS, with the remaining results as follows: atypia in 2 patients, 5 patients were atypical ductal hyperplasia(ADH) in 1 patient, atypical lobular hyperplasia (ALH) in 1 patient, sclerosing adenosis in 1 patient, benign breast tissue (discordant lesion), fibroepithelial lesions in 2 patients, and papillary lesions in 4 patients, including papillary lesions with fibrocystic changes with focal intraductal papillomatosis, intraductal papilloma with apocrine differentiation, fibroepithelial lesion with intraductal papillomatosis, and papillary lesion with fibrocystic change. 214 patients had DCIS, while 16 had benign or borderline lesions on tissue biopsy, but required excision due to discordant lesions, upgrade rate, and risk of breast cancer. After complete excision, the pathology report showed DCIS in 16 patients, so we included them in the study.

The patient’s tumor grade distribution was as follows grade 1 (11.27%), grade 2 (60.56%) and grade 3 (28.17%). Comedonecrosis presented in 56.83 % of patients. Additionally, the tumor subtype predominantly exhibited strong positive hormonal receptor expression (ER, PR) and was negative for HER2 with a mean Ki-67 of 15.83. Lymphovascular invasion (LVI) was negative in 92.31% of cases, and perineural invasion (PNI) was negative in 100%. The mean tumor size was 1.05 cm. All patients had no lymph node metastasis. The mean margin status of the tumor was as follows, superior margin 0.8 cm, inferior margin 1 cm, anterior margin 0.6 cm, posterior margin 0.5 cm, medial margin 1 cm, lateral margin 1 cm, and margin at a nonspecific site 0.2 cm. Eighty-four patients had the nearest margin less than 2 mm, while 148 patients had a margin equal to or greater than 2 mm.; see Table 2.

Table 2 Diagnostic and tumor characteristics

	n			%(median, IQR)
Preoperative tissue biopsy pathology
DCIS		214	93.04
Atypia		2	0.87
Atypical ductal hyperplasia(ADH)		5	2.17
Atypical lobular hyperplasia (ALH)		1	0.43
Sclerosing adenosis		1	0.43
Benign breast tissue (discordant lesion)		1	0.43
Fibroepithelial lesion		2	0.87
Papillary lesion (discordant lesion)		4	1.74
Grade
Grade1	24			11.27
Grade2	129			60.56
Grade3	60			28.17
Comedonecrosis
No	98			43.17
Yes	129			56.83
ER (%)
Mean ± SD	225			63.45 ± 37.97
Median (IQR)				80 (20 - 90)
PR (%)
Mean ± SD	224			40.22 ± 36.08
Median (IQR)				40 (1 - 72.5)
HER2
Neg	86			43.43
1+	25			12.63
2+	45			22.73
3+	42			21.21
Ki-67 (%)
Mean ± SD	170			15.83 ± 12.63
Median (IQR)				10 (8 - 20)
LVI
Negative	24			92.31
Positive	2			7.69
PNI
Negative	11			100.00
Positive	0			0
cN
Mean ± SD	228			0
Median (IQR)				0
Tumor size (cm)
Mean ± SD	200			1.05 ± 0.83
Median (IQR)				0.9 (0.4 - 1.5)
pN
Mean ± SD	229			0
Median (IQR)				0
Margins of tumor(cm) Superior margin	132			0.8 (0.45 - 1.4)
Inferior margin	130			1 (0.4 - 1.3)
anterior Margin	127			0.6 (0.1 - 1.1)
posterior Margin	131			0.5 (0.1 - 1)
medial margin	129			1 (0.6 - 1.6)
lateral margin	130			1 (0.6 - 1.8)
margin not specific site	80			0.2 (0.1 - 0.3)

The nearest margin margin
< 0.2 cm 148
≥ 0.2 cm 84

Abbreviations : ER, Estrogen receptor ; PR, Progesterone receptor; HER2, human epidermal growth factor receptor-2; cN , clinical node, pN, pathological node

Among the 230 patients, 66 (28.70%) underwent sentinel lymph node biopsy(SLNB) due to these patients had indications for SLNB includings microinvasive features in 32 patients, tumor located at the upper outer quadrant in 5 patients, and high-grade tumors in 27 patients. Nine patients underwent reresection due to positive or close margin status. After reresection, 2 out of 9 patients still had remaining DCIS and obtained clear margin, while the others were no residual disease. The majority of patients (84.78%) underwent a 5-year course of adjuvant anti-hormonal therapy. A total of 124 patients received radiation therapy, with an average radiation dose of 42.5 Gy and a boost at tumor bed of 10 Gy in 88 patients. The average time from surgery to the start of radiation was 39 days, and all patients showed no major complications after treatment; see Table 3.

Table 3 Local and systemic treatment

	n	% \| Median (IQR)
SL NB
No	164	71.30
Yes	66	28.70
Indication for SLNB
Microinvasive	32	50.00
Upper outer quadrant	5	7.81
High grade	27	42.19
SLNB result
SLN negative	66	100.00
Number of all retrived SLN	64	3 (2 - 5)
ALND
No	122	100.00
Yes	0	0
Reresection
No	222	96.10
Yes	9	3.90
Pathology after reresection
No residual	4	66.67
DCIS	2	33.33
Radiation dose (Gy)	124	42.5 (42.5 - 50)
Radiation boost	88	10 (10 - 10)
Date from operation to radiation (day)	169	39 (32 - 49)
Complication
No	231	100
Yes	0	0
Duration of endocrine treatment (years)	231	5 (3 - 5)
Type of Endocrine treatment
No	35	15.22
Tamoxifen	190	82.61
Aromatase inhibitor	5	2.17

Abbreviations : SLNB, sentinel lymph node biopsy ; ALND, axillary lymph node dissection, Gy, Gray

The median follow-up period was 73 months, during which we identified seven cases of recurrence. One of them had systemic recurrence. Additionally, All patients who had local recurrence were all survived. There was no significant difference in DFS among margin status, with a rate of 93.61%; see table 4,5, figure1.

Table 4 Prognosis (overall survival/disease free survival)

	n	% \| Median (IQR)
Recurrence
No	216	96.86
Locoregional	6	2.69
Systemic	1	0.45
Type of recurrence
DCIS	3	1.30
IDC(invasive ductal carcinoma)	3	1.30
Site of recurrence
Old site	3	100.00
New site	0	0
Management after recurrence
No surgery	1	14.28
Breast conserving surgery	0	0
Mastectomy	6	85.71

Table 5 The nearest margin factors associated recurrence

	Total	no (n = 225)	recurrence (n = 7)	p-value
		n (%)	n (%)
Margin (mm)				0.999
0 - 0.5	22	22 (9.77)	0 (0)
>0.5 - 1.0	82	79 (35.11)	3 (42.86)
>1.0 - 1.5	44	44 (19.55)	0 (0)
>1.5 - 2.0	10	9 (4)	1 (14.29)
>2.0	74	71 (31.55)	3 (42.86)

A total of 232 patients with DCIS who underwent breast-conserving surgery, mostly receiving radiation and hormone therapy as indicated, the median follow-up was 73 months.

Recurrence was observed in seven patients see, table 6. Among them, four had margin less than 2 mm, while the others had margin more than 2 mm. Three of them had negative or low-positive estrogen receptor. One patient had HER2 overexpression. There was no significant difference in DFS among margin status. Our results same as those of studies. ^7,5,8

Out of 232 patients, 87 patients had nearest margins less than 2 millimeters, and 26 out of 87 patients had more than one site with margin less than 2 millimeters. However, none of them developed local recurrence.

The retrospective study by Macdonald³ on a population of 445 individuals with DCIS, followed by excision alone, identified the margin status as a significant factor in local recurrence. The cut off margin was 1 millimeter.

The meta-analysis by Clive Dunne⁴ on a population of 4,660 individuals with DCIS followed BCS revealed that if the postoperative margin distance was less than 2 millimeters, there was an increased of ipsilateral breast cancer recurrence compared to more than 2-millimeter margin. Moreover, no significant difference was observed between margins greater than 2 to 5 millimeters or greater than 5 millimeters.

The retrospective study by Van Zee⁵, which reviewed a database of 2,996 cases from 1978 to 2010 with a follow-up period of 0-30 years, DCIS treated with breast-conserving surgery. The study found that a greater postoperative margin distance was significantly associated with a reduction in ipsilateral breast cancer recurrence, particularly in the group that did not receive radiation therapy (P < .0001). However, there was no significant difference observed in the group underwent radiation therapy (P = .95).

Based on the study by Monica Morrow ⁶, summarizing recommendations from the SSO/ASTRO/ASCO 2016 consensus, utilizing meta-analysis of 20 studies involving a population of 7,883 individuals, suggested that postoperative margin distance of at least 2 millimeters in treating DCIS with breast-conserving surgery.

From the meta-analysis conducted by M. Luke Marinovich⁷, reviewing 20 studies involving a population of 7,883 individuals with 865 cases of breast cancer recurrence, two studies were prospective, while 18 were retrospective, data collection from 1968 to 2010. The analysis revealed that a postoperative margin distance of at least 2 millimeters did not significantly reduce the recurrence risk statistically, especially in cases underwent radiation therapy. Due to the research diversity, variations in the definition of margin distance, such as some studies combining the 2-millimeter group with the 3 to 5 millimeters group or 10 millimeters and above, led to inconclusive effects of increased margin distance on recurrence. In conclusion, the study suggested that negative margins in treating DCIS (DCIS) with breast-conserving surgery can potentially reduce the recurrence rate.

From the study by Henry M. Kuerer⁸ at MD Anderson Cancer Center, which reviewed practice guidelines and outcomes of DCIS after BCS in a population of 1,261 individuals, they were found that the ipsilateral recurrence rate at a 5-year follow-up was 3.7% when the postoperative margin distance was greater than or equal to 2 millimeters, and 2.2% when the margin was close or positive. Approximately 80% of patients received radiation therapy. Therefore, the study concludes that there was no significant difference in recurrence rates between groups that received radiation therapy, comparing postoperative margin distances less than 2 millimeters to those greater than or equal to 2 millimeters.

From the study by Melissa Pilewskie and Monica Morrow⁹, a current review recommends a margin status cutoff of 2 millimeters.

The researcher conducted a literature review on Pubmed and Cochrane, searching for the terms "margin" and "DCIS" published since 2016. We have found a total of 1,142 articles on Pubmed and 141 on Cochrane. Subsequently, we have reviewed literature and identified five related studies:

Talha Shaikh's retrospective study¹⁰ on 498 individuals with DCIS treated by BCS and followed for 8.3 years. They defined positive margins as ≤2 mm. Positive margins less than or equal to 2 mm were identified as a significant factor reducing the risk of recurrence.

Piero Fregatti's retrospective study¹¹ on 388 individuals with DCIS treated by BCS found that margins less than 1 mm were a significant factor in local recurrence compared to margins greater than or equal to 1 mm.

Audree B's retrospective study¹² on 1,491 individuals with DCIS treated by BCS found that radiation was a significant factor in recurrence, regardless of margins less than 2 mm. No significant difference was observed for recurrences when comparing margins less than 2 mm followed by radiation to margins greater than 2 mm.

Gregory E. Ekatah's retrospective study¹³ on 466 individuals with DCIS treated by BCS identified margins less than 1 mm as a significant factor in recurrence compared to margins greater than or equal to 1 mm.

Sadia Khan's retrospective study¹⁴ on 720 individuals with DCIS treated by BCS found that margins less than 1 mm were a significant factor in recurrence compared to margins greater than or equal to 1 mm.

The meta-analyses⁷ the study suggested that negative margins in treating DCIS (DCIS) with breast-conserving surgery can potentially reduce the recurrence rate.

Due to the diversity in research, variations in defining margin distances were noted. So, This research try to investigate the exact margin and the recurrence of cancer.

This study had some limitations, including short-term follow-up, retrospective analysis, a small number of patients in comparison to the period examined, and an inability to explain the prognostic factors associated with recurrence due to the low number of recurrences in DCIS.

Table 6 Summary of patients who have recurrence.

Number	Age	Grade	ER (%)	PR (%)	HER2	Ki67 (%)	Nearest margin(mm)	Endocrine treatment	RT	Recurrence	DFS(months)
1	46	1	98	98	-	-	1	Yes	Yes	Local	69
2	64	2	95	80	0	5	1	Yes	Yes	Systemic	41
3	54	2	0	0	-	0	4	No	Yes	Local	73
4	54	3	0	0	3+	60	3	no	Yes	Local	39
5	38	2	80	90	0	10	1	Yes	Yes	Local	102
6	40	2	10	0	0	20	7	Yes	Yes	Local	69
7	49	2	80	20	3+	5	2	Yes	Yes	Local	46

Margin wider than 2mm did not demonstrate reduction in local recurrence for women receiving adjuvant whole breast radiation therapy, supporting a recommendation of a negative margin threshold for surgical management of DCIS. Longer duration of follow-up period in larger study could lead to more robust data.

ER

Estrogen receptor

PR

Progesterone receptor

HER2

human epidermal growth factor receptor-2

cN

clinical node,pN,pathological node

Conflicts of interest

The authors have no conflict of interest to declare. None of the authors received financial support or had any institutional or other relationships that might lead to bias.

Source of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability statement (DAS)

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The need for informed consent was waived by the ethics committee/IRB (The Faculty of Medicine, Ramathibodi Hospital, Mahidol University, approval no. COA. MURA2021/10), it is a retrospective research article performed according to relevant guidelines and regulations to report the clinical characteristics, outcome, and the incidence of recurrence from January 2010 till January 2020. We collected statistical data from the files of the patients who had written consent to follow the survivorship program. We confirm that all experiments on humans and/or the use of human tissue samples were performed according to relevant guidelines and regulations.

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No competing interests reported.

The Association between Surgical Margins and Local Recurrence in Women with ductal carcinoma in situ treated with Breast Conserving Therapy: observational study

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Abstract

Figures

Introduction

Materials and methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

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