Oncological outcomes following extreme oncoplastic breast conserving surgery (eOPBCS) for locally advanced breast cancer (LABC): A systematic review and meta-analysis

Abstract

Introduction

Locally advanced breast cancer (LABC) accounts for 5 % of new breast cancer diagnoses in developed countries and 30–60 % in developing regions. Historically, treatment relied on mastectomy guided by the Halstedian theory. Advances in neoadjuvant chemotherapy (NACT), breast-conserving surgery (BCS), and radiation have transformed treatment into a multimodal approach. Extreme oncoplastic BCS (eOPBCS) has expanded the boundaries of BCS, enabling large-volume resections with breast reshaping. However, its oncologic outcomes compared to mastectomy remain unclear, particularly in LABC.

Methods

A systematic review and meta-analysis were conducted following PRISMA guidelines (PROSPERO: CRD42024535182). Studies involving eOPBCS for LABC were reviewed, and those comparing outcomes with mastectomy were included in the meta-analysis. The primary outcomes were overall survival (OS), disease-free survival (DFS), and local recurrence rates (LRR). Data were synthesized using a random-effects model.

Results

Of 866 identified studies, 33 were included in the systematic review and 4 in the meta-analysis, involving 2902 patients with LABC. Among them, 16.1 % underwent eOPBCS. Patients receiving eOPBCS were younger, had larger tumours, and more frequently underwent axillary clearance. The pooled hazard ratio (HR) for OS comparing mastectomy to eOPBCS was 1.72 (95% CI 1.04-2.83). Meanwhile, HRs for DFS (1.11, 95% CI 0.60-2.08) and LRR (0.67, 95% CI 0.38-1.18) showed that there were no statistically significant differences but a trend toward lower recurrence rates with mastectomy.

Conclusion

eOPBCS demonstrates comparable to superior oncological outcomes to mastectomy in LABC, offering a promising option for selected patients. However, slightly elevated local recurrence rates, though not statistically significant, highlight the importance of careful patient selection and further research. High-quality prospective studies are essential to validate these findings and refine criteria for incorporating eOPBCS into routine clinical practice.

Highlights

• •Extreme oncoplastic breast conserving surgery has expanded the boundaries of breast conserving surgery, enabling large-volume resections with breast reshaping.
• •Extreme oncoplastic breast conserving surgery demonstrates comparable to superior oncological outcomes to mastectomy in locally advanced breast cancer.
• •However, slightly elevated local recurrence rates, though not statistically significant, highlight the importance of careful patient selection and further research.

1. Introduction

Globally, locally advanced breast cancer (LABC) accounts for about 5 % of newly-diagnosed breast cancers in developed countries [1], and 30%–60 % in developing countries [2]. In a majority of patients with LABC, the mainstay surgery has been mastectomy [3], but treatment has evolved remarkably over many years, and contemporary treatment paradigms are now multimodal, involving neoadjuvant chemotherapy, surgery followed by radiation therapy and further adjuvant therapy guided by hormonal status.

Initial treatment strategies were heavily influenced by the Halstedian theory, which advocated for extensive surgical excision, including removal of the breast, pectoralis muscles, and axillary lymph nodes. The NSABP-04 Trial in the 1950s demonstrated that a Modified Radical Mastectomy (MRM) provided oncologic outcomes equivalent to those of more radical procedures, marking a pivotal shift in surgical management. Subsequent advancements, particularly the NSABP-06 trial, established that breast-conserving surgery (BCS) combined with radiation therapy was non-inferior to MRM in terms of survival outcomes, with additional benefits in terms of improved quality of life, better body image and better sexual function [4]. Concurrently, advancements in chemotherapeutic agents have facilitated significant tumour downstaging, thereby improving survival rates and expanding the applicability of BCS in LABC.

The ongoing trend toward less invasive surgical techniques, coupled with the recognized psychosocial significance of breast preservation, has driven further refinement in surgical methods. Oncoplastic breast-conserving surgery (OPBCS) emerged as a technique that combines oncologic and reconstructive principles to optimize both oncologic safety and cosmetic outcomes. Extreme OPBCS (eOPBCS) has further extended the boundaries of BCS, enabling large-volume resections and breast reshaping in cases involving tumours exceeding 50 mm, multifocal disease, extensive ductal carcinoma in situ (DCIS), and partial responses to neoadjuvant chemotherapy. Compared to mastectomy, eOPBCS is associated with reduced long-term maintenance, such as fewer implant revisions, and eliminates the need for delayed breast reconstruction [5].

In the past decade, breast surgeons have sought to extend the role of oncoplastic breast conserving surgery to patients with LABC who would lose 20–50 % (level II oncoplasty) of their breast volume and who would traditionally require mastectomy [6]. Recent studies have shown comparable LRR and OS between eOPBCS and standard BCS (sBCS), while some have shown that the wider resection associated with eOPBCS has improved its oncological safety compared to sBCS and is associated with a decrease in re-excision risk by 60 %. In 2022, Sang Y et al. reported a higher 5 year OS of 96.4 % (95 % CI 94.5%–97.3 %) for the eOPBCS group versus 92.3 % (95 % CI 89.7%–93.8 %) for the MRM group with LABC. However, a slightly higher LRR was reported for patients who underwent eOPBCS compared to MRM; 5.0 % (n = 13) for the eOPBCS group compared to 3.2 % (n = 58) for the MRM group. This difference in LRR however, is not statistically significant (p = 0.115). Studies by Sarkar et al. showed that the 2-year disease-free survival (DFS) and overall survival (OS) for eOPBCS were comparable to those of mastectomy. Van dela Parra et al. further supported these findings, with a higher 5-year overall survival reported for eOPBCS compared to MRM, justifying the feasibility of eOPBCS for patients with locally advanced breast cancer.

However, eOPBCS is a technically demanding procedure that requires specialized training beyond standard BCS. The eligibility criteria for its use in women with LABC remain unclear. While some surgeons are incorporating eOPBCS techniques into their practice, it has not yet become a mainstream treatment option for LABC. Additionally, most studies on the safety of BCS focus on early-stage breast cancers, with limited data available concerning the safety, feasibility and efficacy of eOPBCS in LABC patients. This systematic review and meta-analysis thus aims to evaluate and compare the oncological outcomes of eOPBCS versus mastectomy in patients with LABC, which may provide valuable insights for surgeons and oncologists and potentially influence future guidelines and treatment options for women with LABC.

2. Materials and methods

The steps of the current systematic review and meta-analysis followed the guidelines and the recommendations offered through the Cochrane collaboration [7], and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [8] (Supplementary Table 1). The study was registered in the PROSPERO database (registration number CRD42024535182).

2.1. Inclusion and exclusion criteria

The abstracts of identified articles were first reviewed before the full-text articles were analysed. The eligibility of the papers was ensured using the inclusion and exclusion criteria. Inclusion criteria were studies where females diagnosed with LABC underwent eOPBCS as the intervention. For the meta-analysis, only studies that compared outcomes of eOPBCS with mastectomy were included in analysis, while studies lacking a comparator arm were excluded. Only studies published in English were included. Studies were independently screened by two authors (M.C and A.L.). The suitability of the full-text articles was determined by each reviewer with any discrepancies resolved by discussion with the senior author (S.G.).

3. Outcomes

The oncological outcomes of interest were local recurrence rates (LRR), disease-free survival (DFS) and overall survival (OS). Local recurrence was defined as the recurrence of breast cancer after eOPBCS or chest-wall recurrence after mastectomy. DFS was defined as the interval between the date of treatment where the disease was considered to be removed and the date of death. OS was defined as the interval between the date of diagnosis of locally advanced breast cancer and the date of death.

3.1. Risk of bias assessment

The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the papers retrieved. The NOS involves a maximum of seven points for the risk of bias. According to the NOS, a study is judged on three main categories: selection of study groups, the comparability of groups and exposure/outcome ascertainment. Each study is ranked into groups according to the NOS quality assessment: Low quality (0–3 points), medium quality (4–6 points), and high quality (7 points).

3.2. Data extraction

Using a standardized form, the source-related data, including the title, authors’ names, publication dates, study regions, study period, and study design, were extracted. The methods-related data were also extracted, including the eligibility criteria, study endpoints, and follow-up periods. Data on clinical factors were also extracted, including sample size, patients' age, pathological TNM, initial tumour size, tumour grade, previous neoadjuvant chemotherapy, type of surgery performed, and the relevant techniques used. The oncological outcomes of surgery were retrieved, including local recurrence rate, disease-free survival rate, and overall survival rate. The data reported only using graphs were extracted and converted using WebPlotDigitizer software [9].

3.3. Statistical analysis

The outcomes of interest in this study were OS, DFS and LRR, which were evaluated by hazard ratio (HR) and 95 % confidence interval (CI) of HR. The evidence of the outcomes was synthesized using a random effects model meta-analysis, as it would better account for variability both within and between studies, assuming that the selected studies are random samples drawn from a larger population. We regarded I² values of <30 % to indicate low between-study heterogeneity, 30–60 % as indicating moderate heterogeneity, and >60 % as indicating substantial heterogeneity. The analyses were performed using R version 3.3.3 and evaluated following the guidelines outlined in the Cochrane Handbook [7]. Statistical significance for the observed differences between eOPBCS and mastectomy was set at 5 %.

4. Results

4.1. Literature retrieval

A systematic search of the databases resulted in 866 studies identified. Of them, 52 of duplicates were excluded and one record was excluded as it was not written in the English language, retrieving 721 articles eligible for title and abstract screening. A total of 62 articles were included for full-text screening; 29 articles were excluded as 16 did not included oncological outcomes related to mastectomy, 10 were not specific to locally advanced breast cancer and 3 were not specific to eOPBCS. This resulted in 33 articles which were eligible for systematic review. Out of the 33 articles, 4 articles compared outcomes with traditional mastectomy and thus contained sufficient data for meta-analysis. The process of searching databases, screening, and eligibility is shown in Fig. 1.

Fig. 1.

PRISMA flow chart showing screening and selection of articles for review.

4.2. Risk of bias assessment

Out of a total of 33 papers, 7 papers were high quality, 23 were medium quality and 3 were low quality (Table S1 in Appendix).

4.3. Characteristics of all studies

A total of 33 studies were eligible for the systematic review (Table 1). The year of publication of studies ranged from 2003 to 2024 with the majority of studies (97 %, n = 32) having been published within the last 6 years. 21 (63.6 %) were retrospective studies, 11 (33.3 %) were prospective studies, and 1 (3.0 %) was a case series. Of the included studies for systematic review, total sample sizes ranged from 39 to 9861. Median age of patients ranged from 42 to 58.5 years old. Average initial tumour size ranged from 50 mm to 77 mm. The most common oncoplastic techniques used were the Round Block (30.3 %), Batwing (30.3 %), Therapeutic Mammoplasty (27.3 %) and Pedicle Reductions (27.3 %) techniques. 11 studies compared eOPBCS to standard breast conserving surgery (SBCS), 5 studies compared eOPBCS to mastectomy, whilst 20 were solely about eOPBCS. 23 studies included a mix of LABC and non-LABC patients undergoing eOPBCS, while 10 included only LABC patients undergoing eOPBCS. 5 studies compared eOPBCS to mastectomy, however, only 4 of these papers included only LABC patients. These 4 studies were hence included for meta-analysis.

Table 1.

Characteristics of all studies included in systematic review.

Reference	Study Type/Year of Study	Groups Included	No. of Patients	No. of LABC	Median Age	Median Size (cm)	Nodal Status	Hormonal Status	NACT (%)	Oncoplastic Technique	Axillary Clearance	Margin Involvement (%)	Pathological Complete Response (%)	Follow-Up (months)	Local Recurrence Rate (%)	Disease-Free Survival (%)	Overall Survival (%)
1. Sang Y et al.	Retrospective cohort/2022	1. MRM 2. O-BCS 3. S-BCS	2080	91	ND	ND	ER+: 50 PR+: 41 Her2+: 37	ER+: 50 PR+: 41 Her2+: 37	100	VDA	1. 91.4 2. 60.4 3. 60.0	ND	MRM: 465 (25.6) BCS: 107 (41.0)	55.1	1. 18.1 2. 3.6 3. 7.6	5 year: 1. 92.3 2. 92.2 3. 92.4	5 year: 1. 88.1 2. 96.4 3. 96.4
2. Koppiker C et al.	Retrospective cohort/2023	1. O-BCS	205	61	49	2.5	ER/PR+: 99 Her2+: 55 TNBC: 40	ER/PR+: 99 Her2+: 55 TNBC: 40	27.3	Simple TM, Complex TM, Extreme TM	41.3	Positive: 1.4	16 (28.6)	39	7.0	5 year: 92.2	5 year: 95.9
3. Dr L V et al.	Prospective cohort/2023	1. O-BCS	311	66	ND	5.0	ND	ND	ND	SWPR	ND	Close: 12.2 Positive: 7.4 MRM: 1.6	ND	24	1.5	ND	ND
4. Ali O et al.	Retrospective cohort/2023	1. O-BCS	250	52	42	5.5	ER+: 21 PR+: 34 Her2+: 21	ER+: 21 PR+: 34 Her2+: 21	100	EB, LM, PL, FM, BTD, GF, JM, BM, SPR, IPR, LDF, LTF	100.0	Positive: 0	10 (19.2)	53	2	3 year: 92.9 5 year: 82.2	ND
5. Di Leone A et al.	Retrospective cohort/2022	1. O-BCS 2. MRM	297	87	ND	1. 4.4 2. 4.1	ER+: 44 PR+: 31	ER+: 44 PR+: 31	10	ETM, JM, RB, BM	ND	Positive: 1. 1.1 2. 1.4	87 (29.3)	39.5	1. 3.4 2. 6.1	3 year: 1. 95.1 2. 96.2 p = 0.286	3 year: 1. 95.7 2. 95.0 P = 0.394
6. Koppiker C et al.	Case series/2021	1. O-BCS	207	12	49	ND	ND	ND	9.2	Simple TM, Complex TM, Extreme TM, SPWPR	44.9	Positive: 0	ND	25	1.0	ND	ND
7. Khan S et al. DOI: 10.1245/s10434-021-10068-0	Prospective cohort/2021	1. O-BCS 2. S-BCS	891	223	58.4	1. 7.4 2. 2.1	ND	ND	ND	SPWPR, SWPR	ND	Close: 1. 25.6 2. 8.8	ND	43	5 year: 1. 3.6 2. 2.3 (p = 0.80)	5 year: 1. 92.2 2. 98.3 (p < 0.01)	5 year: 1. 97.9 2. 99.2 (p = 0.79)
8. Gulcelik M A et al.	Prospective cohort/2021	1. O-BCS	1043	951	46	ND	Lum A/B: 685 TNBC: 168 Her2+: 190	Lum A/B: 685 TNBC: 168 Her2+: 190	15.8	RAT, IPR, SPR, CM, FM, RB, BM	39.0	Close/Positive: 10.0 MRM: 4.5	16 (10.6)	60	7.0	5 year: 91.7	5 year: 94.0
9. Gulcelik M A et al.	Retrospective cohort/2021	1. MRM 2. O-BCS	565	225	47.2	ND	N0: 62 N1/2/3: 163	Lum A/B: 119 TNBC: 49 Her2+: 55	40.0	RAT, FM, VM, IPR, SPR, BM, RB, RM	1. 79 2. 74.7	Close/Positive: 1. ND 2. 11.1 MRM: 1. ND 2. 6.2	(9.4)	43	1. 7.9 2. 10.2	6 year: 1. 93.0 2. 90.7	5 year: 1. 89.8 2. 91.2
10. Resende Paulinell R et al.	Retrospective cohort/2020	1. O-BCS	73	20	53.5	3.9	ND	ND	30.1	Geometric compensation: SPR, IPR, SLPR, SMPR	36	Positive: 2.7 Re-excision: 2.7	2 (9.09)	35.3	4.29	5 year: 88.8	ND
11. Koppiker C et al.	Retrospective cohort/2019	1. O-BCS	39	12	47.2	7.5	ND	ND	43.6	TM	ND	Positive: 0	ND	12	0	ND	ND
12. Kilic B et al.	Retrospective cohort/2023	1. O-BCS	86	56	51.0	5.8	N0: 31 N1: 37 N2: 12 N3: 6	ER+: 71 PR+: 67 Her2+: 17 TNBC: 8	40.7	RDM, RB, RAT, GF, VM	ND	Positive: 3.5 MRM: 1.2	0 (0)	75	3.4	5 year: 96.0 7 year: 94.4	5 year: 90.0 10 year: 68.0
13. Sarkar D K et al.	Prospective cohort/2022	1. O-BCS	43	35	ND	ND	ND	Lum A/B: 15 TNBC: 42 Her2+: 18	ND	LDMF, VRAM, TM, CWPF	ND	Positive: 2.3	42 (97.6)	24	4.6	ND	ND
14. Almeida N R et al.	Retrospective cohort/2021	1. O-BCS 2. S-BCS	866	54	ND	ND	N0: 72 N1/2/3:26	Lum A/B: 56 Her2+: 14 TNBC: 10	1. 77.6 (76) 2. 90.2 (693)	SWPR, PM, flaps	1. ND 2. ND	Positive: 1. 6.2 2. 10.3 MRM: 1. 4.1 2. 4.3	ND	50.4	1. 6.1 2. 3.9	ND	ND
15. Kaviani A et al.	Prospective cohort/2020	1. O-BCS	937	218	48.1	2.5	N0: 447 N1: 201 N2: 84 N3: 31	ER+: 575 PR+: 550 Her2+: 144	7.4 (69)	BM, RB, RDM, JM, LM, ITR, MM, Holmstrom, “Cross”, SSM	25.1	Positive: 52 MRM: 21	ND	26.4	5.4	94.6	98.7
16. Sparavigna M et al.	Retrospective cohort/2023	1. O-BCS	109	5	57.8	ND	N0: 75 N1: 24 N1mic: 4 N2/3: 6	ER+: 66 PR+: 65 Her2+: 23 TNBC: 15	32.0	SPR, IPR	27.5	Positive: 2.7 MRM: 1.8	ND	36.0	6.4	5 year: 94 (95%CI)	5 year: 97 (95%CI)
17. Gulcelik M et al.	Retrospective cohort/2022	1. O-BCS	1074	220	51.1	2.3	N0: 744 N1: 266 N2: 64	ER+: 805 ER-: 269 PR+: 612 PR+: 462 Her2+: 204 Her2+: 870	ND	RAT, IPR, VM, SPR, FM, RM, RB, BM	ND	Positive: 8.9 MRM: 4.0	ND	61.0	3.6	5 year: 88.0 10 year: 72.0	5 year: 96.0 10 year: 90.2
18. DiPasquale A et al.	Retrospective cohort/2022	1. O-BCS	340	41	60.0	1.8	ND	ER+/PR+: 265 ER+/PR-: 37 ER-/PR-: 31 Her2+: 27 Her2-: 273	ND	BRB, LAF, SWPR, SPWPR, MM, LM, GF	5.3	Positive: 9.4 MRM: 4.7	ND	ND	ND	ND	ND
19. Van la Parra et al.	Retrospective cohort/2021	1. O-BCS 2. S-BCS 3. MRM	195	13	51.0	1. 4.6 2. 4.4 3. 4.3	ND	1. Lum A: 14 Lum B, high Ki-67: 25 Lum B, HER2 type: 2 HER2+/triple+: 7 TNBC: 17 2. Lum A: 13 Lum B, high Ki-67: 28 Lum B, HER2 type: 2 HER2+/triple+: 3 TNBC: 19 3. Lum A: 12 Lum B, high Ki-67: 28 Lum B, HER2 type: 1 HER2+/triple+: 6 TNBC: 18	100.0	LM, SPR, JM, VM, IPR, RB	1. ND 2. ND 3. ND	Positive: 1. 10.8 2. 26.1 3. ND	1. 24.6 2. 33.8 3. 23.1	59.0	1. 4.1 2. 0 3. 19.4	5y: 1. 67.4 (95%CI) 2. 86.1 (95%CI) 3. 66.2 (95%CI)	1. 5y: 85.3 (95%CI) 2. 5y: 94.1 (95%CI) 3. 79.9 (95%CI)
20. Tabary M et al.	Prospective cohort/2021	1. O-BCS	675	179	48	2.2	N0: 335 + 18 N1: 142 + 10 N2: 72 + 2 N3: 20 + 4	ER+: 456 + 18 PR+: 435 + 17 Her2+: 113 + 12	8.15	BM, RB, LM, MM, JM, LM, ITM	27.7	Clear: 88.1 Positive: 6.7	ND	30.5	5.5	6 year: 91.0	5 year: 98.7
21. Savioli F et al.	Retrospective cohort/2021	O-BCS	50	50	55	5.3	N0: 36 N1/2/3: 14	ER+: 33 PR+: 28 Her2+: 5 TNBC: 3	6.00	SWPR, Mastopexy, RAT, LICAP, Fish-tail Mammoplasty, MS, BM, CBS, TDAP	ND	Positive: 18.0 MRM: 12.0	ND	56	10.0	91.5	ND
22. Oh M Y et al.	Retrospective cohort/2021	1. O-BCS 2. S-BCS	742	12	48.9	3.0	N0: 209 N1: 127 N2: 29 N3: 6	ER+/PR+: 274 Her2+: 68	25.3	VDA, GM, SNR, RB, BM, Mini LDF, OM	1. ND 2. ND	Close: 7.0 Positive: 5.1	ND	1. 84.4 (O-BCS) 2. 87.9 (S-BCS)	ND	1. 5 year: 92.9 (95 % CI) 2. 5 year: 94.5 (95 % CI)	1. 5 year: 96.9 (95 % CI) 2. 5 year: 98.6 (95 % CI)
23. Atallah D et al.	Retrospective cohort/2021	1. O-BCS 2. S-BCS	277	1	53.6	1.9	N0: 106 N1/2/3: 61	ER+: 140 PR+: 136 Her2+: 10	0	LRA, RF, RDM	1. ND 2. ND	Close: 4.7 Positive: 11.0	ND	72	0	ND	ND
24. Andre C et al.	Retrospective cohort/2020	1. O-BCS 2. S-BCS	4178	19	58.5	2.0	N0: 295 N1/2/3: 163	ER+: 379 PR+: 309 Her2+: 75	0.02	Simple excision, IR, inverted T incisions, RB, DM, TM	1. ND 2. ND	Positive: 5.9	ND	64	1. 0.9 2. 1.5	1. 5 year: 99.1 2. 5 year: 98.4	1. 5 year: 92.9 2. 5 year: 94.7
25. Kelemen P et al.	Retrospective cohort/2019	1. O-BCS 2. S-BCS	700	3	58	ND	N0: 237 N1: 67 N2: 16 N3: 3	ER+: 271 PR+: 119 Her2+: 19 TNBC: 38	ND	TM, (SPR, IPR, CPR), MM, LM, Periareolar OBCS	1. 20.6 2. 5.1	Close/Positive: 8.0 MRM: 2.6	1. 4.9 2. 0	51	1. 1.1	1. 5 year: 88.5 2. 5 year: 78.2	1. 5 year: 100.0 2. 5 year: 97.3
26. Rodriguez G et al.	Retrospective cohort/2018	O-BCS	146	19	ND	ND	N0: 107 N1: 32 N2: 6 N3: 1	Her2+: 12 TNBC: 13	19.1	BRB, VM, Lateral with RNAC, BM, Centralectomy, GF, Adipofascial RF, CBS, LIQVF, Symmetrisation	24	Positive: 6.8	7.4	ND	0.7	5 year: 96.6	5 year: 97.9
27. Broecker J et al.	Retrospective cohort/2017	1. O-BCS 2. S-BCS	87	13	57	4.4	N0: 20 N1: 23 N2: 3 N3: 1	ER+/PR+: 26 Her-2+: 17 TNBC: 9	71.3	VDA	ND	Positive: 7.0	1. 36 2. 38	44	1. 5.0	1. 5 year: 95.0	1. 5 year: 91.0
28. Acea-Nebril B et al.	Retrospective cohort/2017	1. O-BCS 2. S-BCS	801	27	58.0	1. 1.7 2. 1.3	N0: 107 N1: 48 N2: 13 N3: 2	Her2+: 11 TNBC: 19	ND	RM	1. 43.5 2. 29.8	ND	ND	84	1. 9.8 2. 5.1	1. 10 year: 75.4 2. 10 year: 82.2	1. 10 year: 90.4 2. 10 year: 83.0
29. Crown A et al.	Prospective cohort/2018	O-BCS	111	111	58.5	7.3	N0: 73 N1/2/3: 38	ER+: 94 PR+: 72 Her2+: 16 TNBC: 8	5.4	RE, Mastopexy, RM, CBS, RAT	ND	Close: 37.8 Positive: 51.4 MRM: 26.3	ND	36	2.7	ND	ND
30. Youssef M M G et al.	Prospective cohort/2018	O-BCS	70	70	46	ND	N0: 17 N1: 44 N2: 9	ER+: 53 PR+: 53 Her2+: 9	100	TM, VDA, GF, SPR, IPR, LDF	75.7	MRM: 4.2	27.5	42	4.2	3 year: 90.2	5 year: 100.0
31. Khan S et al.	Prospective cohort/2018	O-BCS	311	66	ND	7.7	ND	ND	ND	RDM, SWPR, SPWPR, CBS	ND	Close: 28.8 Positive: 9.1 MRM: 6.1	ND	24	1.5	ND	ND
32. Youssef M et al.	Prospective cohort/2017	O-BCS	40	40	44.5	ND	ND	ND	100	VRPA, LDF	ND	MRM: 7.5	ND	42	7.5	3 year: 90.2	3 year: 100.0
33. Carter S A et al.	Retrospective cohort/2016	1. O-BCS 2. S-BCS 3. MRM	9861	76	57	ND	N0: 943 N1: 164 N2: 15 N3: 38	ER+: 963 PR+: 797 Her2+: 126 TNBC: 128	23.6	ND	ND	Close/Positive: 1. 8.3 2. 5.8 3. 2.4	ND	40.8	5.2	1. 3 year: 94.6 2. 3 year: 96.1 3. 3 year: 88.8	1. 3 year: 95.8 2. 3 years: 96.8 3. 98.5

4.4. Characteristics of studies in the meta-analysis

Four studies contained sufficient data for meta-analysis of outcomes. Within these studies, 16.1 % (468) women with LABC received eOPBCS over MRM. A total number of 2902 patients with LABC were included in our meta-analysis. The mean age of these patients ranged from 43 to 51 years of age. Mean initial tumour size ranged from 4.4 cm to 4.6 cm for eOPBCS patients and 4.1 cm–4.3 cm for MRM patients. 29.5 % (119) of patients had a nodal status of N0 and 70.5 % (284) were nodal positive or N1/2/3. 70.7 % (331) of patients undergoing eOPBCS were hormone positive. 62.5 % of LABC patients underwent NACT. Follow-up duration ranged from 39.5 to 59 months. 7.9 % of patients undergoing MRM underwent axillary clearance, while 42.8 % of patients undergoing eOPBCS underwent axillary clearance.

5. Outcomes

The forest plots are shown in Fig. 2. Using a random effects model, the pooled HR for OS after mastectomy versus eOPBCS was 1.72 (95 % CI 1.04 to 2.83), indicating a higher risk of mortality associated with mastectomy, though the 95 % CIs were wide. (Fig. 2). The pooled HR for DFS after mastectomy versus eOPBCS was 1.11 (95% CI 0.60-2.08) showed that there was no statistically significant difference between the two surgical approaches. (Fig. 2). The pooled HR for LRR after mastectomy versus eOPBCS was 0.67 (95 % CI 0.38 to 1.18), indicating a trend toward lower recurrence rates with mastectomy, though this was not statistically significant. (Fig. 2).

Fig. 2.

Forest plots showing pooled HR for OS, DFS and LRR following mastectomy versus ePOBCS for LABC.

5.1. Publication bias

Funnel plots were used to analyse the three outcome variables: overall survival, disease free survival and local recurrence rates (Fig. 3). There was minimal asymmetry, indicating a low potential for publication bias for all three outcomes.

Fig. 3.

Funnel plots for studies reporting overall survival, disease free survival and local recurrence rates after mastectomy versus eOPBCS.

6. Discussion

The results of the meta-analysis suggest that eOPBCS is associated with higher pooled overall survival rates as compared to mastectomy. In terms of overall survival, eOPBCS demonstrated consistently higher 3-year and 5-year overall survival rates across all 4 papers. The 5-year disease-free survival rate was comparable between eOPBCS and mastectomy, with eOPBCS showing a trend towards higher local recurrence rates than mastectomy but not statistically significant. This supports the growing body of evidence indicating that less radical, breast-conserving surgeries can be oncologically safe for selected patients with LABC.

eOPBCS could be a viable alternative to mastectomy for selected patients with LABC, providing cancer control with potentially superior survival outcomes and cosmetic benefits. The slightly higher LRR observed in eOPBCS, while not statistically significant, highlights the need for careful patient selection and meticulous surgical technique. This trend parallels earlier studies on SBCS, where local recurrence rates were slightly higher than those for mastectomy, yet overall survival remained comparable. The ability of eOPBCS to achieve low margin positivity, despite being performed in patients with larger tumours, is particularly noteworthy. This suggests that eOPBCS allows for wider excision margins, which may contribute to its oncological safety, even in cases where traditional SBCS might fall short.

Multiple factors could have affected the oncological outcomes observed such as the distribution of cancer stage, hormonal status, pathological complete response (pCR) rates, management of nodal metastases, systemic therapy or radiotherapy regimen and compliance. These factors have been described by majority of the studies but detailed chemotherapy agents and radiotherapy fields or fractions were not routinely reported. There were no stark differences in proportions in the demographics and tumour characteristics however there seemed to be slight differences in the pathologic complete response (pCR) rates, which is a pseudo-marker for overall survival. There were higher pCR rates in the MRM groups in two studies (difference of 10.6 % and 2.4 %) [10,11] and higher pCR rates in the eOPBCS group by 1.5 % in one study [12]. Despite having more pCR in the MRM group, the overall survival rates remained higher for the eOPBCS group. In addition, the slightly higher but not statistically significant local recurrence rates were not surprising for eOPBCS compared to MRM. Similar to BCS trials, BCS + RT has slightly higher local recurrence rates but comparable survival with MRM and hence both are being offered as first-line options for breast cancer ever since.

The role of NACT in facilitating breast conservation cannot be overstated. Studies included in our review indicated that NACT led to significant tumour downstaging, thereby increasing the feasibility of eOPBCS. Moreover, the variation in pathological complete response (pCR) rates between eOPBCS and mastectomy groups did not translate into differences in OS, reinforcing the potential of eOPBCS to achieve excellent outcomes even in the absence of complete tumour response to chemotherapy. The response to neoadjuvant chemotherapy is a vital consideration prior to offering eOPBCS as it has been shown to down-stage breast tumours and hence increase the rate of breast-conserving surgery. Man et al. reported that after initiation of neoadjuvant chemotherapy, the mean tumour size of the patients studied reduced from 4 cm to <2 cm. This was especially so in HER-2 positive tumours, where the HER2-positive group showed a relatively more significant tumour size reduction to around 75 %. Before commencement of neoadjuvant chemotherapy, 25 % of patients were scheduled to undergo breast-conserving surgery and 75 % for mastectomy. After chemotherapy, one third of the patients initially scheduled for mastectomy switched to breast-conserving surgery [13]. Sang et al. noted that over almost a decade of follow up, the proportion of patients undergoing breast-conserving surgery steadily increased in patients after NAC. Notably, the percentage of patients undergoing eOPBCS increased from 0.43 % to 7.60 % throughout the 9 years [14]. The feasibility and effectiveness of eOPBCS for patients with LABC post-neoadjuvant chemotherapy (post-NACT) also depends on the understanding of tumour shrinkage patterns as this affects subsequent surgical planning. Tumour shrinkage patterns can be broadly classified into the following groups: concentric shrinkage, diffuse decrease, decrease of intensity only, stable disease and mosaic shrinkage [15]. In some cases, the tumour may also shrink completely. In cases where there is complete clinical response and the tumour shrinks completely, patients will require pre-NACT tumour marking, otherwise surgery will be complicated as lesions are no longer visible. A study conducted by Minella C et al. showed that the use of breast or lymph node clips is an effective method to augment breast-conserving management of breast cancer patients after NACT [16]. However, for tumours that fail to shrink completely, there is limited evidence to suggest that pre-NACT tumour marking will improve accuracy of resection margins and affect outcomes [17]. Post-NACT tumour markings are sometimes done for tumours that do not shrink completely to facilitate tumour resection during eOPBCS, allowing for accurate resection margins and better oncological outcomes. Concentric responses also use post-NACT residual tumour marking as the basis for surgery. Mosaic patterns necessitate detailed post-NACT marking to ensure all tumour nodules are addressed. Techniques such as guide wire localization and skin tattooing are effective for this purpose, making the absence of pre-NACT marking not an absolute contraindication for eOPBCS.

Regardless of type of surgery, clear margins are fundamental in ensuring complete tumour resection and good oncological outcomes. Margin positivity is a known independent predictor of local recurrence in BCS and the risk increases with tumour size [18]. However, margin positivity reported in the studies were considered low (1.1¹⁶ to 11.1¹⁷) as compared to those traditionally described for SBCS in early breast cancer trials of 10–20 % [19]. This corroborates with a study by Van La Parra et al., which found that eOPBCS had a lower involved margin rate compared to standard breast-conserving surgery (BCS), and both eOPBCS and standard BCS had a lower local recurrence rate compared to mastectomy. This might be attributed to the broader resections that are possible in eOBCS. Instead of the conventional teaching where surgeons should remove the cancer while leaving as much normal tissue as possible in SBCS, eOPBCS enables the surgeon to employ a strategy akin to a robber who “steals from the bank before being caught.” In this context, it means the surgeon can remove the cancer with wide margins of normal tissue (i.e., “steal”) before it becomes impossible for oncoplastic techniques to adequately fill the defect, thereby avoiding visible postoperative deformities (i.e., “being caught”).

Advantages of eOPBCS compared to mastectomy include improved cosmesis, improved breast skin sensation, less chest pain. eOPBCS provides an alternative surgical option to mastectomy with reconstruction for women with LABC who will require radiotherapy regardless of surgical type. Other than surgical factors such as post-operative recovery and tumour recurrence, patient factors, such as cosmesis, are important to consider as well. Patients who undergo eOPBCS enjoy normal-appearing breasts, as well as good breast sensitivity, improving their quality of life [20,21]. Nonetheless, there are also challenges associated with eOPBCS for women with LABC. The extensive rearrangement of breast tissue could affect interpretation of future mammographic studies. Youssef et al. described that tumour bed displacement during wide glandular flap mobilization posed a challenge later on in radiation therapy, and that the difficulty in calculating target and boost volume raised concerns about local recurrence. However, radiotherapy studies showed that if a cavity has been marked by at least 3 metallic clips on the tumour bed after glandular displacement, the tumour bed can still receive a sufficient booster dose. In addition, compared to traditional breast-conserving surgery, Almeida et al. showed that patients undergoing eOPBCS had a higher frequency of postoperative complications such as wound dehiscence, without the need of reoperation, due to use of broader incisions. The mean weight of the resections in eOPBCS was also three times greater, leading to increased tissue mobilization, which can lead to seroma and necrosis. To date, there are limited studies suggesting a delay to adjuvant therapy when eOPBCS was used as compared to traditional mastectomy. A study by Klit et al., of 1798 patients showed that eOPBCS was not associated with a significant delay in the time interval from biopsy to surgery or in the time interval from surgery to adjuvant chemotherapy compared to patients undergoing other forms of breast surgery, such as the traditional mastectomy [22]. Since eOPBCS is a more complex surgery, specialized training with high case volume would be needed in order to ensure its efficacy and viability as an alternative to mastectomy. Patients also need to be carefully selected, to achieve successful oncologic and cosmetic outcomes [23].

Although this review is a significant step forward in evaluating the oncological outcomes of extreme oncoplastic breast-conserving surgery for women with LABC, there are several limitations that should be considered when interpreting the results. First, it is essential to consider the possibility of selection bias. Selection bias occurs when the participants included in the studies are not representative of the general population, leading to potential differences in outcomes based on the characteristics of those selected for specific interventions (e.g., patients who underwent eOPBCS vs. mastectomy). This is particularly relevant in retrospective studies where the choice of surgical intervention might be influenced by factors such as tumour characteristics or patient preferences, which could skew the results. Second, there was considerable variability in the definitions and reporting of key outcomes, such as local recurrence rates and pathological complete response, which could affect the comparability of results across studies. The heterogeneity in study designs, patient populations, and surgical techniques also introduces variability in the meta-analysis. Third, most of the studies included were conducted in Western countries, where differences in breast size and surgical practices may limit the generalizability of the findings to other populations, particularly those with smaller breast sizes. This is particularly relevant when considering the feasibility of eOPBCS in women with LABC but have smaller breast sizes, for whom mastectomy may still be required ultimately. The lack of randomized controlled trials on eOPBCS for LABC highlights the need for more rigorous research to confirm the findings and establish clear guidelines for its clinical application.

7. Conclusion

eOPBCS offers comparable, and in some cases superior, oncological outcomes compared to mastectomy for patients with LABC. However, the slightly elevated, though not statistically significant, local recurrence rates observed with eOPBCS underscore the need for careful patient selection and further research. The predominance of retrospective studies and the lack of randomized controlled trials highlight the need for more high-quality, prospective research to confirm these findings and refine the criteria for eOPBCS in clinical practice. As surgical techniques and oncologic care continue to evolve, eOPBCS may play an increasingly important role in the management of LABC, offering patients a balance between effective cancer control and quality of life.

Sources of support

Nil.

CRediT authorship contribution statement

Megan Chua Wern Ee: Writing – review & editing, Writing – original draft, Visualization, Data curation. Ashley Lee Shi Hui: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Wong Hung Chew: Data curation. Emmeline Elaine Cua-Delos Santos: Writing – review & editing, Writing – original draft. Sean Li Siwei: Writing – review & editing, Writing – original draft, Data curation. Sng Ming Xian: Writing – review & editing, Writing – original draft, Data curation. Qin Xiang Ng: Data curation. Serene Goh Si Ning: Writing – review & editing, Writing – original draft, Visualization, Supervision, Methodology, Formal analysis, Data curation, Conceptualization.

Data availability

The datasets that support the findings of this study are available from the corresponding author (A.M.) upon reasonable request.

Funding

No specific funding was received for the conduct of this study.

Dr Serene Goh Si Ning is supported by the NUHS Clinician Scientist Program 2.0 (NCSP 2.0) under Department of Surgery, National University Hospital.

Conflict of interest

Nil.

Appendix A. Supplementary data

The following is the Supplementary data to this article: