Disease Recurrence in Patients Undergoing Mastectomy for Ductal Carcinoma In Situ

doi:10.21203/rs.3.rs-4966142/v1

PURPOSE

With DCIS incidence on the rise, up to 30% of patients undergo mastectomy for Ductal carcinoma in situ (DCIS).[1] Local recurrence rates after mastectomy for DCIS are reportedly low, but risk factors for recurrence are not known.[2] We aim to define risk factors associated with ipsilateral breast cancer recurrence in patients undergoing mastectomy for DCIS.

METHODS

We aimed to identify risk factors that may contribute to recurrence of breast cancer following mastectomy for pure DCIS. We hypothesized that close or positive mastectomy margins, age at diagnosis, extent of breast disease and mutation carriers would be associated with increased risk of recurrence. We performed a retrospective chart review of patients who underwent simple or bilateral mastectomies for pure DCIS at a single academic tertiary referral center from 2013–2023.

RESULTS

There were 165 patients who met inclusion criteria with an average length of follow-up of 39.9 months. On final surgical pathology, the average span of DCIS was 33.7mm (± 24.6mm). Hormone receptor positive disease was identified in 80.6% of the patient cohort. For margin status, 23 patients (14%) had < 1mm margins on final pathology and of those, 1 received adjuvant radiation therapy and 4 returned to the OR for re-excision. Only 1 (0.6%) patient had ipsilateral disease recurrence during the study period.

CONCLUSION

Recurrence after mastectomy for pure DCIS is a rare event and in our study sample, only one recurrence occurred. Risk factors for recurrence appear unrelated to margin status, age, extent of DCIS, or pathogenic mutation. [3]

Ductal Carcinoma In Situ

Mastectomy

Risk Factors

Local Recurrence

Ductal carcinoma in situ (DCIS) is a premalignant non-invasive lesion frequently identified by screening mammography. The incidence of DCIS has increased over the past 15–20 years, due to increased participation and improvements in screening programs.[1] The primary goal of therapy for DCIS is prevention of the progression to invasive cancer with surgery as a mainstay of therapy in the current era. Surgical management of DCIS consists of either partial mastectomy with adjuvant whole breast radiation therapy or mastectomy with immediate or delayed axillary staging. Literature estimates that almost 30% of women are electing to undergo mastectomy over breast conserving therapy for DCIS due to a variety of reasons, including but not limited to large span of calcifications on imaging, inability to undergo adjuvant radiation therapy, and personal preference.[2]

Local recurrence rates after mastectomy for DCIS are low, estimated at between 1-2.6% in the literature, and the risk factors influencing local recurrence are poorly defined.[2] While clear guidelines exist for 2mm margins for excision of DCIS via partial mastectomy, there are no such guidelines on margins for DCIS when a mastectomy is performed.[4] Previous studies provide evidence that neither margin status nor use of adjuvant radiation therapy impact local recurrence rates after mastectomy for DCIS [5]. Defining risk factors for local recurrence after mastectomy for DCIS would better identify potential targets for intervention and reduction of local recurrence for these patients. Our primary outcome was rate of local recurrence after mastectomy for pure DCIS. Secondary endpoints included recurrence risk factors including age, disease span, mutation status, and the role of pre-operative magnetic resonance imaging (MRI) during the 10-year study span.

Following Institutional Review Board approval, a retrospective chart review was performed of all patients who underwent unilateral or bilateral mastectomy for preoperative diagnosis of pure DCIS between the years of 2013–2023. Patients were excluded if an invasive cancer was identified on their surgical pathology. Clinicopathologic data including demographics, pre-operative imaging including MRI, treatment planning, genetic testing results, pathology from core needle biopsy and surgical pathology specimens were queried and analyzed using descriptive statistics. Use of pre-operative MRI imaging over the course of the study was analyzed via Chi-Squared test (Microsoft Excel, 2021).

There were 165 patients who met inclusion criteria. The average length of follow-up was 39.9 (± 20.3) months. Average age at diagnosis was 54.5 (±11.8). Nineteen patients (11.5%) held prior diagnosis of breast cancer (64% invasive cancer, 36% DCIS). Of the 165 patients, 52 (31.5%) elected simple mastectomies, 80 (48.9%) elected skin sparing mastectomies (SSM), and 33 (20%) elected to undergo nipple sparing mastectomies (NSM). Eighty-six (52%) patients elected to undergo bilateral mastectomies (Table 1). Reconstruction was performed in114 patients (69%). Ten (8.7%) patients received immediate implant-based reconstruction, 7 (7%) received immediate tissue-based reconstruction, 16 (13%) underwent delayed tissue-based reconstruction, and 81 (71%) underwent delayed implant-based reconstruction (Table 2).

Of the 93 patients (56%) who proceeded with genetic testing, 12 pathogenic mutations were identified (13% of those tested, 7% of total cohort) with BRCA2 being the most common (Table 1). On final surgical pathology, the average span of DCIS was 33.7mm (±24.6mm). Hormone receptor positive (HR+) disease was identified in 80.6% of patients. There were 31 patients with close margins on surgical pathology: 8 patients with margins <2mm, 15 patients with margins 1mm, and 8 patients had tumor cells present at the margin.

No re-excisions, adjuvant radiation or recurrences occurred for the 8 patients with <2mm margins. Of those 15 patients with margins 1mm but not at the margin, 1 patient received adjuvant radiation therapy and 1 returned to the operating room for re-excision with negative margins. None of these 15 patients experienced disease recurrence during the study period. For the 8 patients with tumor cells present at the margin, 6 specimens were positive at the anterior margin, 1 was positive at the posterior margin, and 1 was positive in the inferolateral border. Three patients went on to re-excision with negative margins and did not experience local recurrence within the study period. One underwent re-excision with negative margins and did experience local recurrence within the study period, described in detail below.

Only 1 (0.6%) patient had disease recurrence in the ipsilateral breast during the study period. This patient underwent a unilateral SSM with sentinel lymph node biopsy (SLNB) due to extensive span of calcifications on mammography. She did not undergo preoperative MRI imaging. The patient underwent immediate deep inferior epigastric perforator (DIEP) flap reconstruction. Final surgical pathology demonstrated a 45mm span of high grade, HR+ DCIS with a positive inferolateral margin in the lower outer quadrant, lymph nodes were negative for carcinoma. Re-excision of the inferolateral margin was performed with final margins clear for DCIS. The patient did not undergo radiation therapy. The patient developed an HR+ invasive recurrence 5 years postoperatively for which they underwent partial mastectomy with repeat SLNB and adjuvant radiation therapy.

Of note, another patient included in the study did receive a diagnosis of invasive mammary carcinoma in the contralateral breast during the study follow-up period. She underwent unilateral mastectomy with SLNB for intermediate grade HR+ DCIS with negative margins and did not receive adjuvant endocrine therapy. She was then diagnosed with HR+ intermediate grade invasive mammary carcinoma five years postoperatively in the contralateral breast on surveillance imaging. She underwent mastectomy with SLNB at that time with initiation of adjuvant endocrine therapy. She did not undergo genetic testing during the study period.

Of the 165 patients, 92 (55.6%) patients underwent pre-operative MRI during the study period. Analysis of usage of pre-operative breast MRI over time did not demonstrate any notable change in utilization of MRI imaging in preoperative planning over the study period (p = 0.512) (Figure 1).

Mastectomy for DCIS continues be either recommended by physicians or chosen by patients for a variety of reasons. Patient preference, large span of calcifications on mammogram, or large span of enhancement on MRI were cited as the most common reasons for pursuing mastectomy in our study sample. Over half of the patients in our study elected to undergo bilateral mastectomies for diagnoses of unilateral DCIS and many proceeded on to autologous or implant-based reconstruction. This may be due to several factors, including anxiety at developing future cancer in the contralateral breast, desire to avoid radiation with breast conservation, interest in avoiding endocrine therapy for prevention of contralateral breast cancer and a desire for bilateral reconstruction to maximize cosmetic symmetry. These trends are in line with previously published literature noting that more women who may be candidates for breast conserving therapy are electing to undergo unilateral or bilateral mastectomies, including those with node negative or in-situ disease.[5, 6]

Over half (56%) of the patients in our study underwent preoperative serum genetic testing and 13% of those who were tested had a pathogenic mutation. BRCA2 mutation was the most commonly identified mutation (5 total). These genetic test results played a significant role in patients’ decisions to ultimately undergo mastectomy rather than breast conserving therapy as well as decisions to pursue bilateral as opposed to unilateral mastectomy.

Only one patient in this series experienced local recurrence during the study follow-up period. This makes meaningful statistical analysis of recurrence rates difficult. This patient underwent a skin-sparing unilateral mastectomy with immediate autologous tissue reconstruction with DIEP flap. Her final surgical pathology was notable for high grade HR + DCIS with micropapillary & solid architectural patterns. The specimen was noted to have a positive margin approximately 10mm medial and 40mm inferior to the lateral marking suture. This patient did not undergo preoperative breast MRI. The patient returned to the operating room for revision of her reconstruction and a 2.5cm margin re-excision of the interior and lateral margins including the anterior skin. Per the operative report: “We designed a lateral excision of skin approximately 2.5-3 cm wide that tapered inferiorly towards the 8 o'clock position. All soft tissue below this down to the DIEP flap was removed to encompass the entire area of concern of a positive margin.” The margin re-excision was negative for any residual DCIS on final surgical pathology. Five years later, the patient was diagnosed with high grade, HR + invasive ductal carcinoma identified on surveillance mammogram. The ductal carcinoma was in a similar location to her prior area of margin positivity. Whether this represents a true local recurrence versus incomplete excision and progression of the patients’ initial disease is unclear.

Seventeen patients in our cohort underwent immediate reconstruction following either unilateral or bilateral mastectomies. Ten underwent direct to implant reconstruction and seven underwent autologous tissue reconstruction with the majority undergoing DIEP flaps (4 patients). The single individual who experienced local disease recurrence in this study underwent immediate DIEP flap reconstruction. This significantly complicated her return to the operating room for re-excision. Per the operative note it appears to have been difficult to clearly identify prior margins and a wider section of tissue was excised than perhaps would have been required had the patient undergone delayed reconstruction. While we do not believe it is essential for all patients who undergo mastectomy for DCIS to await final surgical pathology and undergo staged reconstruction with tissue expander placement, it may be worthwhile to consider in those patients with large spans of calcifications or non-mass enhancement on MRI who may be at higher risk of close or positive margins.

Many women in this series elected to undergo SSM or NSM as opposed to non-skin sparing mastectomy. This appears to be in line with current trends. [7] There have been retrospective studies demonstrating the safety of SSM with similar disease-free survival and overall survival compared to non-skin sparing mastectomy.[8, 9]. Previous small studies have also evaluated the safety of NSM for DCIS and found similar oncologic outcomes compared to SSM and non-skin sparing mastectomies [10–13]. There is also ample evidence in the literature of the oncologic safety of NSM and SSM for invasive cancer.[14] Our cohort included women pursuing both SSM and NSM. Only one patient (who elected to undergo SSM) experienced local recurrence during the study.

Given only one patient in this study experienced any form of recurrence during the study prior, we are unable to identify definitive risk factors for recurrence after mastectomy for DCIS. Prior published literature has not found any association with either margin status or use of adjuvant radiation therapy in local recurrence after mastectomy for DCIS. In our study, 31 underwent mastectomy with inadequate (< 2mm) margins. Only one patient elected to undergo adjuvant radiation therapy and 4 patients returned for re-excision of previously close or positive margins. Of the other 26, none experienced local recurrence during the study period. This may indicate the use of adjuvant radiation or re-excision may not necessarily be indicated in cases of DCIS given the risk of recurrence is so low.[3]

Over half of the patients in our study underwent pre-operative breast MRI imaging. We previously posited there would be an increase in MRI use over time as trends have shifted towards increased use of SSM and NSM. Pre-operative MRI provides additional information when attempting to predict disease involvement of the dermis or nipple-areolar complex.[15] However, our data demonstrate relatively stable usage of preoperative MRI usage over time. This may be explained by the fact that the increase in performance of SSM and NSM pre-dates the year 2018, when the bulk of our data collection began.[7]

This study has several notable limitations. First, the average follow-up during the study period was only 3 years. As such we were only able to identify very early recurrence, which may explain why only one patient experienced disease recurrence within the study period. Secondly, the study size is relatively small, including 165 patients. A larger study with longer follow-up must be performed to more precisely evaluate local recurrence rates of DCIS or invasive cancer after mastectomy. In addition, data analysis was limited by the fact that only one patient experienced the primary outcome in this study. Recurrence after DCIS is rare; more data from larger samples and longer follow-up periods must be gathered to adequately power a study to examine this rare occurrence.

In line with previously published literature, we found that recurrence of DCIS or invasive cancer after mastectomy for pure DCIS is a rare occurrence. Prior studies provide evidence that neither margin status nor use of adjuvant radiation therapy impact local recurrence rates after mastectomy for DCIS.[3] We did not find any indications within our analysis to refute these claims. The need for adjuvant radiation or return to the operating room for re-excision in the setting of positive margins continues to be determined on an individual patient basis through multidisciplinary tumor board discussion.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.

Author Contribution

MCK and RLM wrote the main text and prepared figures. All authors were involved in project conception and reviewed results and analysis.

Data Availability

Data is provided within the manuscript and is readily available by request from the corresponding author.

ACKNOWLEDGEMENTS & FUNDING INFORMATION

The data herein was presented at the 2024 American Society of Breast Surgeons Annual Meeting in Orlando, FL. This work did not receive any sources of funding.

Nash AL, Hwang ES (2023) The Landmark Series-Ductal Carcinoma in Situ: The Evolution of Treatment. Ann Surg Oncol 30(6):3206–3214
Kim D, Ki Y, Kim W, Park D, Joo J, Jeon H, Nam J (2020) Comparison of local recurrence after mastectomy for pure ductal carcinoma in situ with close or positive margins: A meta-analysis. J Cancer Res Ther 16(6):1197–1202
ElSherif A, Freyvogel Ramirez M, Moore EC, Dietz JR, Tu C, Valente SA (2023) Mastectomy margins for ductal carcinoma-in-situ (DCIS): 18 Years of follow-up. Am J Surg 226(5):646–651
ASBrS (2017) Consensus Guideline on Breast Cancer Lumpectomy Margins In
Kummerow KL, Du L, Penson DF, Shyr Y, Hooks MA (2015) Nationwide trends in mastectomy for early-stage breast cancer. JAMA Surg 150(1):9–16
Ward EM, DeSantis CE, Lin CC, Kramer JL, Jemal A, Kohler B, Brawley OW, Gansler T (2015) Cancer statistics: Breast cancer in situ. CA Cancer J Clin 65(6):481–495
Lago V, Maisto V, Gimenez-Climent J, Vila J, Vazquez C, Estevan R (2018) Nipple-sparing mastectomy as treatment for patients with ductal carcinoma in situ: A 10-year follow-up study. Breast J 24(3):298–303
Mota BS, Bevilacqua JLB, Barrett J, Ricci MD, Munhoz AM, Filassi JR, Baracat EC, Riera R (2023) Skin-sparing mastectomy for the treatment of breast cancer. Cochrane Database Syst Rev 3(3):Cd010993
Skjerven HK, Myklebust EM, Korvald C, Porojnicu AC, Kaaresen R, Hofvind S, Schlicting E, Sahlberg KK (2023) Oncological outcomes after simple and skin-sparing mastectomy of ductal carcinoma in situ: A register-based cohort study of 576 Norwegian women. Eur J Surg Oncol 49(3):575–582
Nashimoto M, Asano Y, Matsui H, Machida Y, Hoshi K, Kurosumi M, Fukuma E (2024) Comparison of locoregional recurrence risk among nipple-sparing mastectomy, skin-sparing mastectomy, and simple mastectomy in patients with ductal carcinoma in situ: a single-center study. Breast Cancer
Shaffer K, Harris L, Ng S, Tjoe JA (2024) Nipple-Sparing Mastectomy and Adequate Margins for Patients With Ductal Carcinoma In Situ. Am Surg :31348241246179
Wu ZY, Kim HJ, Lee J, Chung IY, Kim JS, Lee SB, Son BH, Eom JS, Kim SB, Gong GY et al (2020) Recurrence Outcomes After Nipple-Sparing Mastectomy and Immediate Breast Reconstruction in Patients with Pure Ductal Carcinoma In Situ. Ann Surg Oncol 27(5):1627–1635
Woodward S, Willis A, Lazar M, Berger AC, Tsangaris T (2020) Nipple-sparing mastectomy: A review of outcomes at a single institution. Breast J 26(11):2183–2187
Elmore LC, Dietz JR, Myckatyn TM, Margenthaler JA (2021) The Landmark Series: Mastectomy Trials (Skin-Sparing and Nipple-Sparing and Reconstruction Landmark Trials). Ann Surg Oncol 28(1):273–280
Healy NA, Parag Y, Soppelsa G, Wignarajah P, Benson JR, Agrawal A, Forouhi P, Kilburn-Toppin F, Gilbert FJ (2022) Does pre-operative breast MRI have an impact on surgical outcomes in high-grade DCIS? Br J Radiol 95(1138):20220306

Table 1. Demographic information of study cohort and summary of surgical outcomes following mastectomy for ductal carcinoma in situ. DCIS = ductal carcinoma in situ. VUS = variant of unknown significance. HR = hormone receptor

Demographics
Total Patients	165
Age at Diagnosis	54.5 years (±11.8)
Prior diagnosis of breast cancer	19 (11.5%)
DCIS	7 (36%)
Invasive cancer	12 (64%)
Underwent pre-operative genetic testing	93 (56%)
VUS identified	55 (59%)
Pathogenic mutation identified	12 (13%)
BRCA2	6
PTEN	2
BRCA1	1
MUTHR	1
RAD51D	1
CHEK2	1
Average length of follow-up	39.9 months (±20.3)
Surgical Pathology
Average span of DCIS	33.7mm
HR positive	80.6%
< 1 mm margins	23 (14%)

Table 2. Cohort operative (mastectomy type and reconstruction) data

Surgical Details	# Patients
Laterality
Unilateral mastectomy	86	52.12%
Bilateral mastectomy	79	47.88%
Mastectomy Type
Non-skin sparing	52	31.52%
Skin-sparing	80	48.48%
Nipple-sparing	33	20.00%
Reconstruction
Underwent reconstruction	114	69.09%
No Reconstruction	51	30.91%
Reconstruction Type
Immediate implant based	10	8.77%
Immediate tissue based	7	7.02%
Delayed tissue	16	13.16%
Delayed implant	81	71.05%

No competing interests reported.

Disease Recurrence in Patients Undergoing Mastectomy for Ductal Carcinoma In Situ

Status:

Journal Publication

Version 1

Abstract

Figures

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

Declarations

Author Contribution

Data Availability

ACKNOWLEDGEMENTS & FUNDING INFORMATION

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1