Oncological safety of nipple-sparing mastectomy after neoadjuvant chemotherapy: a systematic review

ABSTRACT Background: the use of nipple-sparing mastectomy (NSM) in local advanced breast cancer after neoadjuvant chemotherapy (NQT) is increasing, despite few studies on the subject. The aim of this systematic review was to determine the safety of NSM after neoadjuvant chemotherapy. Methods: for this systematic review we searched MEDLINE; Cochrane; Scientific Electronic Library Online (SciELO); Embase and Scopus. A literature search of all original studies including randomized controlled trials, cohort studies and case-control studies comparing women undergoing NSM after neoadjuvant chemotherapy for breast cancer was undertaken. Outcomes were locoregional recurrence (LRR), nipple recurrence and distant recurrence (DR). Data analysis was undertaken to explore the safety of NSM after NQT. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on PROSPERO, number CRD42021276778. Findings: a total of 437 articles were identified. Four articles were included with 1466 patients all of which had a high to serious risk of overall bias. Local recurrence in the NSM after the NQT group ranged from zero to 9.8%. Nippleareolar complex (NAC) recurrence ranged from zero to 2.1%. The distant recurrence rate ranged from 6.5% to 16%. Due to the lack of pattern among the control groups, it was not possible to perform a meta-analysis. Interpretation: this review provides information for decision making in performing NSM after NQT. Despite the low rates of local recurrence and patients should be counseled about limited oncological information.


INTRODUCTION
B reast cancer is the most common cancer in the world.According to the Global Cancer Observatory, there were an estimated 2.26 million new cases in 2020 and 684,996 deaths 1 .
Breast cancer treatment is constantly changing.Surgery is the main one, and its aesthetic results have been improving, even in advanced diseases, without compromising oncological safety.
Breast-conserving surgery is the standard treatment nowadays; however, mastectomy is still required in some cases.

Radical mastectomies have been increasingly
replaced by less aggressive procedures, which allow for better immediate breast reconstruction results.Skin-sparing mastectomy (SSM) was first described by Toth and Lappert and consists of removing the glandular tissue of the breast and the nipple-areola complex (NAC), preserving the skin 2 .Skin and NAC-sparing mastectomy, also known as nipple sparing mastectomy (NSM), preserves the cutaneous envelope and NAC, further improving aesthetic results and patients' quality of life 3 .NSM has been increasingly used, and its safety is well established in the treatment of earlystage breast cancer, as well as risk-reducing surgeries due to germline mutations.However, there are few studies that have evaluated the oncological safety of this technique in higher-risk patients, who are usually submitted to neoadjuvant chemotherapy 4 .Neoadjuvant chemotherapy (NQT) is currently a major pillar of Nissen Oncological safety of nipple-sparing mastectomy after neoadjuvant chemotherapy: a systematic review the glandular tissue with preservation of the cutaneous envelope and the NAC.SSM consists of the removal of the glandular tissue and the NAC, with preservation of the cutaneous envelope.Total mastectomy consists of removing glandular tissue, NAC, and the skin, without immediate breast reconstruction.

Outcome Measures
The primary outcome was the local recurrence rate during the follow-up interval, including NAC recurrence.The secondary outcome was the distant recurrence rate during the follow-up interval.

Research Methods
We searched the following electronic databases, with no defined start date, until September  S1 (additional information).Queries have been translated into the appropriate syntax for other databases.There was no language and date limitation for the search.
Selected studies were imported into Rayyan ®7 .
Duplicate articles were excluded.The selected articles were included in two stages.In the first step, two authors (LN and IS) examined all titles and abstracts, and articles with discrepancies were resolved by consensus or proceeded to the next step.In the second stage, the articles were evaluated in full.After the second stage, a senior author (IR) analyzed all remaining discrepancies.

Data extraction, collection, and management
Two researchers (LN and IS) were responsible for extracting data from the selected studies and entering them into an Excel ® 2011 database.Discrepancies were discussed with a senior author (IR).

Studies and Participants
We included studies with levels of evidence 1-3 according to the Oxford Center for Evidence-Based Medicines (RCTs, cohort, and case-control studies) 6 .We did not include single-group cohorts in the analysis, but results were collected and presented separately.We excluded case reports, case series, expert opinion, or conference abstracts.
We included women undergoing NSM after NQT for invasive breast carcinoma.We excluded studies that did not determine the relapse rate exclusively for the NSM group after NQT, as well as studies that performed neoadjuvant hormone therapy.We did not restrict minimum follow-up time or language.

Interventions and Comparators
The intervention of interest was NSM, the comparator was SSM or total mastectomy after neoadjuvant chemotherapy.NSM consists of removing

Risk of bias assessment
We used the ROBINS-I tool (Risk of Bias for Assessing Non-Randomized Trials of Interventions) to assess the risk of bias and quality of each eligible trial (Table 1) 8 .

RESULTS
We identified 437 studies across all search platforms and, after removing duplicate articles, 301 remained.After applying the eligibility criteria, were included four articles in the analysis of results (Figure 1).
The four articles were of level 3 evidence, and included 1,466 patients, of whom 466 were in study groups; however, only 312 were classified as of interest for this study.One hundred and fifty-four patients had been included in the study groups without having undergone NSM mastectomy and were excluded from the analysis.A total of 1,055 participants underwent SSM, upfront NSM, or conventional mastectomy as a control group.The follow-up time ranged from 35 to 68 months.Table 2 shows the summary of the included studies.Four single cohort articles had data collected separately, for simple description (Table 4).In these studies, the maximum local recurrence was 12%.NAC recurrence ranged from zero to 1.9%.Locoregional recurrence showed a significant difference in the study by Santoro et al. 3 .However, the study group is composed of patients with more advanced clinical stages (stages II and III correspond to 96% in the study group and only 50% in the control group -SSM after NQT).Agresti et al. 11 paired groups with propensity score matching and in pairing 1, which compared post-NQT NSM and post-NQT TM, there was no significant difference.Finally, in the NSM group (no NQT in the pairing 3 group), the local recurrence rate was significantly higher in patients with T2-T3 than T1 (0.8% and 6.3%, respectively, p=0.050).This data agrees with McBain et al. 12 , who have demonstrated a higher rate of local recurrence in more advanced tumors, as well as in younger patients, depending on the incision margins.

DISCUSSION
The study that showed a significant difference in local recurrence was from Santoro et al. 3 .However, the characteristics of participants in the study and control groups were different, with a higher clinical stage, a higher incidence of lymph node positive, and

R E S U M O R E S U M O
2022: MEDLINE via PubMed; Cochrane Library (including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials); Online Scientific Electronic Library (SciELO); Embase; and Scopus.We also examined the references of included articles.One of the authors (LN) conducted the search, using appropriate keywords in English and Boolean logical operations.The MEDLINE search strategy is shown in Table breast cancer treatment, particularly in more aggressive molecular subtypes, such as triple negative and HER2positive diseases, as well as locally advanced disease.As in the situations described above there is a greater risk of local recurrence, and since NSM is a recent technique in the treatment of breast cancer, there are concerns, mainly regarding the remaining retroareolar tissue and the possibility of recurrence in the NAC.The aim of this study was to perform a systematic review of the oncological safety of NSM for patients treated with neoadjuvant chemotherapy and to compare it with other mastectomy techniques.METHODS This review is reported in accordance with PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) standards5.We registered the protocol in PROSPERO (International Perspective Register of Systematic Reviews) under number CRD42021276778, available at https:// w w w .c r d .y o r k .a c .u k / p r o s p e r o / d i s p l a y _ r e c o r d .php?ID=CRD42021276778 .

Figure 1 .
Figure 1.PRISMA flowchart for selection of studies.
11 performed propensity score matching to obtain balanced subgroups in many observed covariates.Three subgroups were created to assess local disease-free survival (LDFS): • Group 1 included post-NQT NSM in the study group and post-NQT total mastectomy (post-NQT TM) to assess locoregional recurrence.The 4-year LDFS of the post-NQT NSM and post-NQT TM cohorts was 0.89 (95% CI 0.77-0.95) and 0.93 (95% CI 0.83-0.97),respectively (HR = 1.31, 95% CI 0.40-4.35), the difference not being significant (p=0.655).• Group 2 included post-NQT NSM in the study group and NSM (without NQT) to assess the role of tumor size before NQT in locoregional recurrence (tumor size before NQT as an equilibrium covariate).The risks of local recurrence were comparable between the two matched groups (HR = 1.23, 95% CI 0.37-4.04,p=0.739).• Group 3 included post-NQT NSM in the study group and NSM (without NQT), to assess the role of tumor size after NQT in locoregional recurrence (tumor size after NQT as an equilibrium covariate).The size of the pathologic tumor after NQT was taken as the basis for comparing local recurrence, there being a significant difference: the 4-year LDFS was 0.89 (95% CI 0.77-0.95) in the group NSM post-NQT and 0.98 (95% CI 0.94-0.99) in the NSM (HR = 3.60, 95% CI 1.10-11.80,p=0.035).Agresti et al. 11 conclude that in patients undergoing chemotherapy, the risk of local recurrences after NSM is significantly associated with the stage of breast cancer at diagnosis before chemotherapy.It is not associated with the type of surgical procedure.

Table 1 -
Methodological bias of included studies using ROBINS-I.
NissenOncological safety of nipple-sparing mastectomy after neoadjuvant chemotherapy: a systematic review 1: Confusion bias; 2: Bias due to participant selection; 3: Bias in the classification of interventions; 4: Bias due to deviations from intended interventions; 5: Bias due to lack of data; 6: Bias in the measurement of results; 7: Bias in the reported result.

Table S1 -
Search strategy for MEDLINE.

Table 3
shows the oncological results.Local recurrence in the NSM group after NQT ranged from zero to 9.8%.Recurrence in NAC ranged from zero to 2.1%.The distant recurrence rate ranged from 6.5% to 16% in the study groups and from 7% to 28.2% in the control groups.

Table 2 -
Summary of included studies.
NSM: skin and nipple-areolar complex sparing mastectomy; TM: total mastectomy; NQT: neoadjuvant chemotherapy; Upfront: surgery before neoadjuvant chemotherapy; SG: study group.*The study group included 13 patients undergoing NSM and 18 patients undergoing SSM after neoadjuvant chemotherapy.**balancing of the two groups in clinical and/or radiological tumor size at diagnosis.***balancing the two groups with pathological tumor size.&: The study group included 187 patients undergoing NSM and 136 patients undergoing SSM after neoadjuvant chemotherapy.

Table 4 -
Oncological results in single cohort articles.