Introduction

Worldwide, there were approximately 2.3 million newly diagnosed female breast cancer cases in 2020 [1], accounting for almost 30% cancer cases among women [2]. The disease is the most frequently diagnosed cancer in the vast majority of countries (154 of 185) and is also the leading cause of cancer death in over 100 countries [3]. Local–regional recurrences (LRR) after breast cancer surgery is an important factor in breast cancer death and disease-free survival (DFS) has been shown to be an acceptable surrogate for overall survival at both the individual and trial levels in early [4]. Surgical treatment has evolved over the last few decades, from more extensive excision to breast conservation. Oncologists and plastic surgeons are not only working to improve oncological treatment but also striving to develop reconstructive techniques for contour correction and volume restoration [5, 6].

Autologous fat grafting (AFG) is defined as the re-implantation of adipose tissue into the breast from different body regions. After harvesting fat cells, fat is typically centrifuged to separate purified fat for breast restoration [7]. AFG for breast oncoplastic surgery following oncologic resection has reached a consensus [8, 9] and has become an increasingly common practice worldwide [10]. This is because autologous fat is biocompatible and AFG has the advantages of being a minimally invasive and simple procedure, creating a natural and soft appearance, and having a rapid recovery time with reliable efficacy. It has been proven to be superior to traditional methods of breast reconstruction [11,12,13].

AFG has been used in cosmetic plastic surgery with good results and subsequently begun to be gradually used in oncological plastic surgery as well [14,15,16,17]. However, the increase in AFG has caused oncologists and plastic surgeons to raise oncological safety concerns for breast cancer patients [18,19,20]. Some studies in vitro have shown that adipocytes and adipose-derived stem cells (ADSCs) alter the cellular microenvironment by secreting numerous cytokines and growth factors [21], causing either angiogenesis and residual quiescent malignant cells at the surgery site to proliferate [22, 23], or the antitumor immune response of breast cancer cells to change [24]. However, lots of clinical retrospective studies have reported that AFG is a safe procedure for breast reconstruction, without influencing locoregional recurrence (LRR), distant metastasis rates (DMR) and the survival of breast cancer patients [25,26,27,28,29]. As most of these studies were retrospective case series and cohort studies, however, they were unable to provide enough sufficient and strong evidence individually [30, 31].

Materials and methods

This meta-analysis was performed in accordance with the PRISMA [10] reporting guidelines for the conduct of meta-analysis for intervention trials.

Date sources were identified from January 2011 to March 2020 across the Pubmed, Medline, Web of Science, and Cochrane libraries for all published studies involving the application of autologous fat grafting in the reconstruction of breast cancer patients. The search terms were as follows: “autologous fat grafting”, “fat transfer”, “lipofilling”, and “breast cancer”. No restrictions were imposed on language. Reference lists of all eligible studies and relevant reviews were manually searched for any additional trials.

Inclusion criteria. Studies that met the following criteria were included in our meta-analysis: (1) female patients with breast conservation therapy or mastectomy, (2) AFG for breast reconstruction, (3) reported recurrence in breast cancer patients after AFG, and (4) patients with breast cancer who did not undergo AFG for breast reconstruction or who served as controls in the literature served as control groups. Data extraction and quality assessment. Data from the obtained literature were abstracted independently by Jiale Sun, He Liang, Dongcai Lin, including the author and year of publication, participants and allocation, type of surgery, number of invasive carcinomas, pathologic stage, mean time after autologous grafting, oncological follow-up period and therapy, local recurrence rates (LRR), and distant metastasis rates (Table 1).

Table 1 the characteristics of the eligible studies
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Statistical analysis. The Review Manager Software (Revman v5.3) was used to analyze the experimental data from the obtained trials, i.e., incidence rate difference (IRD) in LRR and distant metastasis between AFG and control groups. Heterogeneity among studies was estimated using the I2 statistic and substantial heterogeneity was represented by I2 > 50%. A fixed-effects model was used if the heterogeneity test did not reveal significance (I2 < 50%). Otherwise, we adopted the random-effects model. P < 0.05 was considered significant.

The Risk of Bias. Publication bias was assessed by both Egger's linear regression statistical test and visual inference of funnel plot for the primary outcome. Publication bias was not assessed for the subgroups, as the number of studies was insufficient. For all statistical analyses, the 95% confidence interval was displayed, and P < 0.05 was considered significant.

Results

Systematic review and characteristics

A total of 4596 publications were retrieved through the initial literature search and 3398 studies remained after duplications were excluded. After the title and abstract review, 3325 publications were excluded because the topics were irrelevant, the articles were reviews, the studies were nonrandomized controlled trials, or no usable data were reported. Seventy-three potentially relevant articles were identified for detailed review.

After a full-text review, 29 duplicate studies were removed, and 25 of 44 studies were excluded due to a lack of comparability based on the mirror principle. Following this process, 11 clinical trials involving 5886 patients were identified as eligible to be included in the meta-analysis. The articles were published between 2010 and 2020. The main features of the eligible studies are summarized in Table 1 and flowchart. The surgery types of AFG, invasive carcinoma, the rates of chemotherapy, radiotherapy and hormonal therapy are summarized in Table 1. And the outcomes of 11 clinical trials were LRR and DFS (Table 1).

figure a

AFG effect on LRR in patients

The HR and 95% CI from eight studies (including 4578 patients) were combined to compare the LRR rate between patients who had AFG and corresponding controls from cohort studies. The pooled HR indicated that AFG was not associated with a significantly increased risk of LRR when compared with corresponding controls (HR = 1.26, 95%, CI 0.90, 1.76; Fig. 1). As shown in Fig. 1, there was no significant heterogeneity across the included studies (I2 = 0.0%; P = 0.99), hence, a fixed‐effect model was applied. Publication bias was assessed using funnel plots and Egger’s test, which indicated no asymmetry in the included literature. Sensitivity analysis confirmed the stability across the included studies.

Fig. 1
figure 1

AFG effect on LRR

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Disease-free survival

The HR and 95% CI from five studies (including 3186 patients) were combined to compare the DFS rate between patients who had AFG and corresponding controls from cohort studies. The P value of the heterogeneity test was 0.81 and a fixed-effect model was used. The pooled HR for DFS showed that there was no significant difference between AFG and corresponding controls (HR = 1.27, 95% CI 0.96, 1.69; Fig. 2).

Fig. 2
figure 2

AFG effect on DFS

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Discussion

AFG is an increasingly common form of plastic surgery used to improve the morphologic results of breast reconstruction after cancer. Concerns surrounding the oncological safety of AFG in patients with breast cancer have been highly controversial over the past decade. The conflicting evidence from molecular and clinical arenas has engendered divergent and even polarized opinions among plastic surgeons and oncologists on whether the clinical benefits of AFG outweigh its potential risks [32,33,34,35,36,37]. Despite the large number of publications on this topic, studies have been unable to provide convincing evidence. We conducted this meta‐analysis accordingly to evaluate the oncological safety of AFG for breast reconstruction.

A number of previous systematic reviews and one small meta-analysis have attempted to evaluate the oncological safety of AFG. These studies, however, were hindered by the low quality and the small number of studies reviewed [38,39,40,41,42,43]. Studies of this nature typically involve time-to-event (survival-type) data, and the most appropriate statistics to use are the log hazard ratio and its variance. However, in most cases, the current meta-analysis of survival data only estimated the number of events included in the study at a certain point in time and described it by calculating the ratio of event incidence among different groups, that is, using relative risk (RR) or odds ratio (OR). As such, we cannot describe the whole picture resulting from this data simply using the ratio of the survival number of the two groups at a fixed time point, without considering all the factors. Consequently, incomplete data may lead to inappropriate conclusions.

Petit et al. [44] showed that AFG was not conducive to the oncologic safety. In this study, the risk of local recurrence was increased in the fat grafting group, but most patients in this study were followed up for about 40 months, with a short follow-up time. However, later, Petit et al. [45] showed that there was no significant difference in tumor recurrence rate between groups with the increase of follow-up time. Several publications suggest that a follow-up period of at least 5 years or longer is required to investigate the relationship between fat grafting and oncologic safety The study by Krastev et al. [46] had a small sample size and after the subsequent study by Krastev et al. [28] had an increased sample size, the results showed that there was no significant difference between the two groups of fat grafted subjects and control subjects. Silva-Vergara et al. [47] also showed that there no significant differences in recurrence were observed in 205 patients who had lipofilling compared with controls. Sorrentino et al. [48] and Stumpf et al. [49] showed that there was no difference in LRR or distant recurrence of breast cancer between AFG and those who underwent breast-conserving surgery alone. Kronowitz et al. [27] found that the 5-year cumulative locoregional recurrence rate and systemic recurrence rate were not significantly different between the case and control group, and there was no primary breast cancer in healthy breasts reconstructed with lipofilling. Tukiama et al. [50] performed a meta-analysis and got a similar conclusion as ours, AFG did not affect tumor recurrence, but they did not analyze the effect of AFG on DFS in the study.

Some reports have investigated the oncological safety of AFG from other aspects. Fertsch et al. [51] showed that there was no increased recurrence risk was observed between DIEP-flap reconstruction and control group. And, Gale et al. [52] also found that no significant excess oncologic events were observed in patients underwent fat grafting using different surgical types. Klinger et al. [53] reported that there was non-inferiority of the AFG procedure for LRFS and LRR among different biological subtypes (luminal-like group, HER2 enriched-like group and triple negative breast cancer group). Silva-Vergara et al. [47] also found that AFG at both stages does not affect the rate of locoregional recurrence.

We performed a systematic assessment of LRR data for 4578 patients who underwent AFG after breast cancer. As shown in Figs. 1 and 2, there was no significant difference in LRR and DFS between the AFG and control groups. The results provide strong evidence that AFG does not increase the risk of LRR in breast cancer patients. A total of eight studies on the oncological safety of autologous fat transplantation for breast reconstruction were included in this study, all of which were cohort studies. The LRR and DFS of the autologous fat transplantation group and surgery alone group were analyzed and compared. The results showed that the comparison results between the AFG group and the control group in terms of local tumor recurrence and disease-free survival rate were similar, with no statistically significant differences. A study by Biazus et al. [54] showed that postoperative tumor recurrence was significantly correlated with the number of metastatic axillary lymph nodes and less correlated with fat grafting, indicating that autologous fat is relatively safe for breast reconstruction [55, 56]. Overall, our study further supports previous data on the safety of AFG, which does not affect LRR and DFS of breast cancer patients after surgery. Our data support that AFG can be used for breast restoration in breast cancer patients after surgery, but also hope that AFG can benefit more breast cancer patients.

However, some limitations from this meta-analysis must be highlighted. First, more high-quality clinical studies are needed to refine the analysis, including tumor size, lymph node status, and different breast cancer types, to provide certain criteria for the application of AFG. Second, this meta-analysis included a variety of surgical types of AFG. Overall, AFG did not affect the LRR and DFS of breast cancer patients, but more subsequent reports are still needed to refine whether different surgical types of AFG will have an effect on the LRR and DFS of breast cancer, which needs to be supported by more literature reports. Finally, there are similar limitations in other reviews, is that rigorous statistical analysis could not be done given the lack of standardization of the outcomes measured.

Conclusion

Autologous fat grafting has now achieved widespread acceptance among plastic surgeons. A total of 11 studies and 5886 patients were included, this meta-analysis of all included studies about survival outcomes showed AFG did not significantly increase LRR and DFS. Based on this review and our meta-analyses, AFG can be performed safely in breast reconstruction after breast cancer surgery. However, to properly assess the oncological risk of AFG after breast cancer surgery, more prospective and randomized studies are needed with a sufficient follow-up time (5 years at least) and the proper analysis of critical factors.