Survival Outcomes of Breast-Conserving Surgery Versus Mastectomy in Locally Advanced Breast Cancer Following Neoadjuvant Chemotherapy: A Meta-Analysis

Abstract

Background

Mastectomy (MT) and breast conservation surgery (BCS) are two common surgical options for the treatment of locally advanced breast cancer (LABC). Neoadjuvant chemotherapy (NACT) is frequently administered before surgery to shrink tumors and improve surgical outcomes. However, there is a lack of consensus on the optimal surgical approach after NACT and its impact on survival outcomes.

Objective

This meta-analysis aims to compare the survival outcomes between MT and BCS in patients treated with NACT.

Method

A PRISMA selection was used to identify studies across electronic database such as PubMed, and Cochrane Library from inception until 11^th July, 2023. A total of 10 comparative studies involving a total of 5018 patients were included. Among them, 2898 patients underwent MT while 2120 underwent BCS after receiving NACT. The outcomes assessed were the 5-year overall survival (OS) and 5-year disease-free survival (DFS). The data from the included studies were pooled, and odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the differences between MT and BCS in terms of survival outcomes. Prospero: CRD42024496831.

Result

The meta-analysis revealed that patients who underwent MT after NACT had a higher 5-year OS compared to those who underwent BCS (OR 2.68, 95% CI [2.19-3.28; p < 0.00001]). Additionally, the 5-year DFS was significantly better for patients who underwent MT (OR 3.11, 95% CI [1.80-5.38; p < 0.0001]).

Conclusion

MT after NACT may be associated with better 5-year OS and DFS compared to BCS.

Keywords

chemotherapy treatment neoadjuvant surgery locally advanced breast-Conserving mastectomy breast cancer

Introduction

In spite of continuous advancements in medicine, BC is still the second most common and deadly cancer in women.¹ The number of BC cases has dramatically increased during the last forty years.² Globally, there were over 2.3 million new instances of BC in 2020. The condition also claimed the lives of about 6,85,000 people, with significant regional differences between different nations and areas.³ Interestingly, a higher proportion of BC fatalities occur in high-income countries. More than 3 million additional cases of BC and more than 1 million yearly fatalities are predicted by 2040.⁴ The effectiveness of BC treatment has significantly improved with the introduction of various modalities such as surgery, chemotherapy, radiation therapy, endocrine therapy, biotherapy, and targeted therapy.⁵

Locally advanced breast cancer (LABC) encompasses tumors that are larger than 5 cm, extend to involve the skin or underlying pectoral muscles, infiltrate axillary, supraclavicular, and/or infraclavicular lymph nodes, and may include inflammatory carcinomas. This category includes stage IIIA (T0N2M0; T1/2N2M0; T3N1/2M0), stage IIIB (T4N0-2M0), and stage IIIC (T0-4N3M0) breast cancers, without distant metastasis.^6,7In the case of LABC, NACT is considered the standard of care. Studies have demonstrated that NACT is able to downstage the disease, making BCS feasible for patients who were initially candidates for MT or were deemed inoperable. This approach is now widely accepted in clinical practice.^8–10 Preoperative chemotherapy increased the rate of BCS in the National Surgical Adjuvant Breast and Bowel Project B-18 trial in 1988, particularly in patients whose tumors were more than 5 cm. On the other hand, there was no discernible variation in OS or DFS between patients who had postoperative CT and those who did not.^11,12 Enough data was presented by several randomized studies with long-term follow-up periods to conclude that DFS and OS in BCS were superior than MT in early-stage BC.^13–17 Moreover, individuals with operable LABC who received preoperative or postoperative chemotherapy saw higher rates of BCS after preoperative chemotherapy, along with similar OS.^18,19 Additionally, patients with LABC undergoing BCS following NACT showed improved DFS and OS, according to Kuerer et al.²⁰

NACT plays a critical role in the pre-surgical treatment of LABC. With a good response to NACT, selected LABC patients may opt for BCS over MT, sparking controversy. This study aims to evaluate the survival outcomes of LABC patients undergoing BCS versus MT post-NACT, shedding light on the contentious debate surrounding the choice between these surgical approaches in neoadjuvant treatment.

Materials and Method

Protocol Registration

The protocol of this review is registered in PROSPERO (CRD42024496831), and it is noted that an ethics statement is not required in this meta-analysis as it has already been provided in each included study. The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standards.²¹

Data Sources and Searches

A literature search was conducted in PubMed, and the Cochrane Register of Clinical Trials from inception until 11^th July, 2023, with a language restriction to English. Specific search terms and MeSH headings were used to identify relevant studies: Search 1:(locally advanced breast cancer) AND (neoadjuvant therapy) AND (chemotherapy) AND (mastectomy)) OR (Breast conserving surgery). Search 2:(neoadjuvant chemotherapy) AND (surgery)) AND (mastectomy) OR (breast conserving surgery) AND (survival). Search 3: (locally advanced breast cancer) AND (neoadjuvant chemotherapy)) AND (breast conserving surgery) AND (breast conservation) AND (mastectomy).

Study Selection

Inclusion Criteria

Only full published article in English

Woman diagnosed with LABC

Stage I, II or III

Patients treated with chemotherapeutic agents

Comparative studies (BCS and MT)

Outcomes such as 5 years OS and DFS

Exclusion Criteria

Review articles, case reports, letter to the editor, abstracts and comments.

Studies with conflicting result and unavailable postoperative outcomes and complications.

Single arm studies BCS or MT.

Stage IV or with inflammatory breast cancer

Treated with other neoadjuvant therapy before surgery

Original studies lacking available data.

Data Extraction

We used Endnote 20 program to remove duplicate entries. The titles and abstracts of the articles that were found were vetted by two separate co-authors. By conferring with a third reviewer, disagreements were settled. As shown in Table 1, information on first author name, nationality, study type and definition of LABC the number of patients who underwent BCS and MT, the kind of neoadjuvant chemotherapy, and survival outcomes like 5-year OS and DFS were obtained. In each of the included studies, the survival outcomes were defined as follows: DFS in the NACT groups was measured from the initiation of systemic therapy to the occurrence of the first locoregional or systemic recurrence or death before any relapse. OS in the NACT groups was calculated from the start of the initial treatment to the date of the last follow-up or the event of death from any cause.

Table 1.

Characteristics of Included Studies.

Author	year	Country	Age, year	Study type	Definition of LABC	NACT	BCS/MT	5 year- OS	5 year-DFS
Schwartz et al²²	1994	USA	55	RS	Stage III (T2,N2; T3,NO; T3,Nl/N2; T4, NO/Nl/N2) disease	Cyclophosphamide, Methotrexate, and Fluorouracil	55/103	44/69	42/55
Sweeting et al²³	2011	USA	39 /40	RS	Stage II to III	Anthracycline, Taxane	54/68	48/41	44/39
Cho et al²⁴	2013	Korea	49	RS	Stage I, II and IV	Anthracycline, Taxane	124/307	110/258	101/49
Levy et al²⁵	2014	France	49 / 49 (23–84)	RS	Stage II to III	Anthracycline, Taxane	111/173	100/131	-
Barranger et al²⁶	2015	France	49.6	RS	-	Anthracyclines, Cyclophosphamide, and 5-fluorouracil, Taxanes	86/33	66/25	64/20
Parmer et al²⁷	2006	India	47.6	RS	locally advanced disease: skin involvement (peau d’orange, ulceration, skin infiltration, satellite nodules), matted or fixed axillary lymph nodes, ipsilateral supraclavicular or internal mammary lymph nodes, fixity to chest wall, arm oedema, and no evidence of distant metastasis	Cyclophosphamide, Anthracycline, Adriamycin, Epirubicin, 5-Fluorouracil, Tamoxifen	188/476	-	117/176
Simons et al²⁸	2020	Netherlands	50.65 /49.99	RS	Stage I, II and IV	-	362/199	345/171	329/165
Fitzal et al²⁹	2010	Austria	-	RS	-	Cyclophosphamide, Methotrexate, and Fluorouracil	197/111	181/82	-
Gwark et al³⁰	2022	Korea	-	RS	-	-	839/802	770/650	751/618
Song et al³¹	2023	China	<50 >50	RS	cT1-3N0-2M0 stage and ypT0-2N0-2M0	Anthracycline, Taxane	104/626	103/564	87/490

Quality Assessment

The Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1 risk of bias test was used to evaluate the quality of the included studies. Evaluations were conducted to see whether there was bias in sequence formation, allocation concealment, blinding, inadequate data, or selective reporting. As seen in Figures 1 and 2, trials were classified as high risk, low risk, or unknown risk or unclear bias. In Table 2, the bias risk is displayed.

Figure 1.

Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Table 2.

The Assessment of the Risk of Bias in Based on the Cochrane Risk of Bias Tool.

Author	Random sequence generation	Allocation concealment	BlindingOf participant	Blinding of outcome data	Incomplete data addressed	Selecting reporting	Other bias
Schwartz et al²²	low	low	low	low	low	low	Unclear
Sweeting et al²³	low	low	low	low	low	low	unclear
Cho et al²⁴	low	low	unclear	low	low	low	low
Levy et al²⁵	low	low	low	low	low	high	low
Barranger et al²⁶	low	low	low	low	low	low	low
Parmer et al²⁷	low	low	low	low	low	low	unclear
Simons et al²⁸	low	low	low	high	high	low	unclear
Fitzal et al²⁹	low	low	low	high	high	high	unclear
Gwark et al³⁰	low	high	low	high	low	high	unclear
Song et al³¹	low	low	low	low	low	low	unclear

Statistical Analysis

Review Manager (RevMan) 5.4.1 was used to carry out the statistical analysis. We calculated 95% confidence intervals (CI) and odds ratios (ORs) for dichotomous data. Depending on the level of heterogeneity, either a fixed effects model or a random effects model was employed to obtain pooled estimates of the outcome. The χ2 tests were employed to assess the homogeneity of effects, with a p-value of less than 0.05 signifying substantial heterogeneity. The fixed effects model was used to estimate the pooled effect of outcomes when the hypothesis of homogeneity was not rejected; the random effects model was also computed when the opposite was true.

Results

We found 860 studies using our first search strategy; 110 of those were screened. After the title and abstracts were reviewed, there were still 69 papers. The eligibility of 41 articles was fully assessed. After 31 publications were eliminated for various reasons, including reviews, case reports, non-English language, and insufficiently relevant data. Ten papers in all, as indicated by Figure 3, satisfied the inclusion and exclusion criteria. The analysis included 5018 individuals with a diagnosis of LABC. 2120 patients received BCS and 2898 patients had MT. Table 1 lists the types of NACT agent used such as Cyclophosphamide, Methotrexate, Fluorouracil, Anthracycline, Taxane, and Epirubicin. A five years survival outcome (OS and DFS) was calculated.

Figure 3.

Prisma flow of selected studies.

Nine studies^{22–26,28–31} were collected for 5-year OS for BCS (n = 1932) and MT(n = 2422). The meta-analysis revealed a significant difference between the two groups. The patients who underwent MT had higher 5-year OS as compared to BCS (OR 2.68,95% CI [2.19-3.28; p < 0.00001] as depicted in Figure 4.

Figure 4.

Forest plot of OS (BCS vsMT).

Eight studies^{22–24,26–28,30,31} were retrieved for 5-year DFS for BCS(n = 1812) and MT(n = 2614). The analysis demonstrated a statistically significant between BCS and MT. Five-year DFS was better after MT than BCS (OR 3.11[1.80-5.38; p < 0.0001] as shown in Figure 5.

Figure 5.

Forest plot of DFS (BCS vsMT).

Publication Bias

Figure 6 and 7 depict OS and DFS between MT and BCS after NACT funnel plot by log hazard ratio for the above-mentioned comparisons. These funnel plots show that the majority of the analyzed studies are centered on the median axis and that all of the studies fall within the funnel, indicating that there is no significant publication bias.

Figure 6.

Funnel plot of OS (BCS vsMT).

Figure 7.

Funnel plot of DFS (BCS vsMT).

Discussion

Systemic treatment is the standard of care for women with LABC. NACT has been shown to be equivalent to adjuvant chemotherapy in terms of OS and DFS rates.^19,32,33 NACT has also been successful in downsizing large tumors, allowing for BCS instead of MT.^34,35

Despite a previously conducted meta-analyses that attempted to address the limitations associated with small-scale studies and yielded results which is contrary to our current meta-analysis, our study was still essential. This is because there has been a gap since the last meta-analyses (2016 and 2017), and numerous cohort studies included in our analysis were not considered in the previous study. Specifically, our meta-analysis encompassed 5018 patients with LABC who underwent MT and BCS, whereas the previous analysis included less or more than half of our sample size.^5,36

When comparing BCS to MT in patients who received NACT, multiple studies have consistently shown no significant differences in OS.^5,37–43 However, the findings of this meta-analysis suggest that MT after NACT may be associated with 5-year OS (OR 2.68, 95% CI [2.19-3.28; p < 0.00001]) and DFS (OR 3.11, 95% CI [1.80-5.38; p < 0.0001]) compared to BCS. Several factors may contribute to these findings. One potential reason is that MT involves the complete removal of breast tissue, which can reduce the risk of residual or recurrent disease. On the other hand, BCS aims to preserve the breast tissue but may have limitations in completely clearing the tumor. The administration of NACT before surgery is intended to shrink the tumor and eliminate any remaining cancer cells. MT may prove more effective in removing all residual disease compared to BCS. It is worth noting that patients who underwent MT may have had more advanced tumors compared to those who had BCS, which could have influenced the observed survival outcomes due to selection bias. Additionally, the use of different chemotherapeutic agents in the study could also explain why the findings suggest that these medicines impact the survival rate of MT in LABC. Furthermore, treatment decisions, including the choice between MT and BCS, are often influenced by patient preferences and surgeon recommendations. It is possible that patients with more favorable tumor characteristics or personal considerations may be more likely to opt for BCS, which could have influenced the observed survival outcomes. Radiotherapy, a crucial adjuvant treatment in reducing the risk of local recurrences in breast cancer patients, particularly those who have undergone BCS, may have played a role in the outcomes. Four included studies^23,25,27,30 that received radiotherapy may have introduced a potential confounding factors that could have influenced the interpretation of the results. Careful evaluation of these studies characteristics and treatment protocols is essential to understand their impact on the outcomes. However, it is important to approach these results with caution due to variations in tumor size, grade, and nodal status between the two groups. Further analysis and data are necessary to provide more conclusive findings.

However, other studies have shown no statistically significant differences in OS between the BCS and MT groups.^25,26 Some studies have reported the oncological safety of BCS after NACT, with no effect on OS compared to MT. These studies suggest that being a candidate for BCS after NACT may be an indication of favorable tumor biology.³⁶ A few other neoadjuvant cohort studies reported on the oncological safety of BCS. All reported that BCS did not affect survival compared to MT.^24,44,45But, another meta-analysis indicated that BCS was a safe surgical approach after NACT for LABC and was associated with improved OS (OR 2.12; 95% CI 1.51-2.98, p < 0.01) compared to the MT group.⁵Emmanuel and colleagues also demonstrate that NACT allows equivalent OS and DFS in a comparison of patients who received BCS with the ones who received MT. Five-year OS after BCS and MT were equivalent (77%). Five-year DFS after BCS and MT were respectively 74% and 59% (not significant). With a 5-year DFS of 62% for the BCS group and 37% in the MT group (P < .001).²⁶ The results of Parmar et al were in favor of BCS in the NACT setting.²⁷ Similarly, the meta-analysis of Mauri et al found no difference in the OS and DFS between neoadjuvant and adjuvant groups of patients who underwent BCS.⁴⁶ Van der Hage et al have published the results of the European Organization for Research and Treatment of Cancer Trial 10,902, which contradicts the reports mentioned above. They demonstrate that patients who were initially scheduled to receive MT but underwent BCS due to tumor downstaging had a worse OS (hazard ratio, 2.53; 95% CI, 1.02-6.25) than those who received BCS initially.¹⁹

Limitation

Potential biases in patient selection, outcome evaluation, and other research-related variables could impact the validity and generalizability of the study results. Additionally, the inclusion of studies with diverse patient characteristics, treatment plans, and follow-up durations may introduce heterogeneity and influence the final outcomes. It is important to note that the lack of randomization in these trials means that patient assignment was influenced by several factors such as tumor stage, responses to treatment, receptor status, and the use of radiotherapy.

Moreover, limited number of investigations, affected the accuracy of outcomes and statistical power. There is also a possibility of publication bias, where positive studies are more likely to be published compared to those with conflicting, potentially skewing the overall findings. Therefore, it is crucial to interpret the results of the meta-analysis while considering these limitations. Further research may be necessary to address these issues and to provide more robust evidence to support the conclusions drawn from the study.

Conclusion

In summary, this meta-analysis indicates that MT following NACT may lead to better 5-year OS and DFS outcomes compared to BCS for individuals with LABC. Thus, we concluded that for patients who show positive responses to NACT, MT may be a suitable and effective surgical approach, providing a potentially beneficial treatment option for those with advanced-stage BC. It is crucial to emphasize the significance of tailoring the choice of surgical procedure to each patient's unique preferences and clinical circumstances. Furthermore, there is a clear need for additional research to delve into various factors that could impact survival rates in patients undergoing NACT, such as breast cancer molecular subtypes and responses to chemotherapy. Long-term follow-up studies are essential to fully understand the impact of these surgical approaches on late recurrence rates and OS beyond the conventional 5-year timeframe. These findings underscore the importance of individualized treatment decisions and ongoing research efforts to enhance outcomes for individuals with LABC.

Footnotes

Abbreviation

Acknowledgment

We express our gratitude to each and every author for their contributions that helped us finish this article.

Authors’ contributions

All authors participated in the study's conception and design. Specifically, RQ, LY, XQ, and DL, made substantial contributions to the reporting of the work. All authors were actively involved in reviewing relevant literature, drafting the manuscript, and revising the final draft. Material preparation, data collection, and data analysis were carried out by RQ, XC, ZS, XW, PC, and DW. RQ authored the initial draft of the manuscript, while XC, DL and DS revised and proofread it. All authors provided feedback on earlier versions, and the final manuscript has been reviewed and approved by all.

Availability of data and materials

All data analyze during this study is included in this article.

Consent for publication

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

This article does not contain any studies with human participants or animals performed by any authors.

Funding

This study was supported Jiangsu Province Maternal and Child Health Research Project (F202322), Project of Zhenjiang City Social Development (SH2023046), Clinical Research Project of the Jiangsu University Affiliated People's Hospital (Y2022019, JC-2023-004), Jiangsu University Medical Education and Research Collaborative Innovation Fund (JDYY2023016, JDYY2023017, JDYY2023018, JDYY2023023) and Jiangsu Research Hospital Association for Precision Medication Project number JY202227.

Project of Zhenjiang City Social Development, Jiangsu Province Maternal and Child Health Research Project, Jiangsu University Medical Education and Research Collaborative Innovation Fund, Jiangsu Research Hospital Association for Precision Medication Project number, Clinical Research Project of the Jiangsu University Affiliated People's Hospital, (grant number SH2023046, F202322, JDYY2023016, JDYY2023017, JDYY2023018, JDYY2023023, JY202227, Y2022019, JC-2023-004).

ORCID iD

Liang Yin

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